|
Iinhibitory activity against Escherichia coli DNA gyrase
|
Escherichia coli
|
0.25
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives.
Year : 2004
Volume : 47
Issue : 14
First Page : 3693
Last Page : 3696
Authors : Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Iwai N, Hiyama Y, Suzuki K, Ito H, Terauchi H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.
|
Inhibitory activity against Escherichia coli DNA gyrase
|
Escherichia coli
|
0.25
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and structure-activity relationship studies of novel indazole analogues as DNA gyrase inhibitors with Gram-positive antibacterial activity.
Year : 2004
Volume : 14
Issue : 11
First Page : 2857
Last Page : 2862
Authors : Tanitame A, Oyamada Y, Ofuji K, Kyoya Y, Suzuki K, Ito H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : In this study, we report the design, synthesis and structure-activity relationships of novel indazole derivatives as DNA gyrase inhibitors with Gram-positive antibacterial activity. Our results show that selected compounds from this series exhibit potent antibacterial activity against Gram-positive bacteria including multi-drug resistant strains that is methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE).
|
Iinhibitory activity against Staphylococcus aureus DNA gyrase
|
Staphylococcus aureus
|
0.25
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives.
Year : 2004
Volume : 47
Issue : 14
First Page : 3693
Last Page : 3696
Authors : Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Iwai N, Hiyama Y, Suzuki K, Ito H, Terauchi H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.
|
Iinhibitory activity against Escherichia coli DNA topoisomerase IV
|
Escherichia coli
|
3.5
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives.
Year : 2004
Volume : 47
Issue : 14
First Page : 3693
Last Page : 3696
Authors : Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Iwai N, Hiyama Y, Suzuki K, Ito H, Terauchi H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.
|
Iinhibitory activity against Staphylococcus aureus DNA topoisomerase IV
|
Staphylococcus aureus
|
28.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives.
Year : 2004
Volume : 47
Issue : 14
First Page : 3693
Last Page : 3696
Authors : Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Iwai N, Hiyama Y, Suzuki K, Ito H, Terauchi H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.
|
Iinhibitory activity against human DNA topoisomerase II
|
Homo sapiens
|
400.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of a novel series of potent DNA gyrase inhibitors. Pyrazole derivatives.
Year : 2004
Volume : 47
Issue : 14
First Page : 3693
Last Page : 3696
Authors : Tanitame A, Oyamada Y, Ofuji K, Fujimoto M, Iwai N, Hiyama Y, Suzuki K, Ito H, Terauchi H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.
|
Inhibitory activity against human DNA topoisomerase II
|
None
|
400.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and structure-activity relationship studies of novel indazole analogues as DNA gyrase inhibitors with Gram-positive antibacterial activity.
Year : 2004
Volume : 14
Issue : 11
First Page : 2857
Last Page : 2862
Authors : Tanitame A, Oyamada Y, Ofuji K, Kyoya Y, Suzuki K, Ito H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : In this study, we report the design, synthesis and structure-activity relationships of novel indazole derivatives as DNA gyrase inhibitors with Gram-positive antibacterial activity. Our results show that selected compounds from this series exhibit potent antibacterial activity against Gram-positive bacteria including multi-drug resistant strains that is methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE).
|
Inhibitory activity against Escherichia coli DNA topoisomerase IV
|
Escherichia coli
|
25.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and structure-activity relationship studies of novel indazole analogues as DNA gyrase inhibitors with Gram-positive antibacterial activity.
Year : 2004
Volume : 14
Issue : 11
First Page : 2857
Last Page : 2862
Authors : Tanitame A, Oyamada Y, Ofuji K, Kyoya Y, Suzuki K, Ito H, Kawasaki M, Nagai K, Wachi M, Yamagishi J.
Abstract : In this study, we report the design, synthesis and structure-activity relationships of novel indazole derivatives as DNA gyrase inhibitors with Gram-positive antibacterial activity. Our results show that selected compounds from this series exhibit potent antibacterial activity against Gram-positive bacteria including multi-drug resistant strains that is methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE).
|
Inhibitory activity against Escherichia coli DNA gyrase
|
Escherichia coli
|
0.25
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Fine Tuning of physico-chemical parameters to optimise a new series of novobiocin analogues.
Year : 2001
Volume : 11
Issue : 11
First Page : 1461
Last Page : 1464
Authors : Schio L, Chatreaux F, Loyau V, Murer M, Ferreira A, Mauvais P, Bonnefoy A, Klich M.
Abstract : A novel series of novobiocin analogues has been synthesised by removing the lipophilic aryl chain in novobiocin and introducing an amino substituent. The structural modifications have been dictated by the control of lipophilicity and the dissociation constant of the resulting compounds. Antibacterial activity of the new coumarin derivatives could be correlated with the amount of uncharged form in physiological conditions.
|
Percent inhibition of filarial parasite Setaria cervi by compound at 10 ug/mL concentration
|
Setaria cervi
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses of 2,4,6-trisubstituted pyrimidine derivatives as a new class of antifilarial topoisomerase II inhibitors.
Year : 2005
Volume : 15
Issue : 1
First Page : 47
Last Page : 50
Authors : Katiyar SB, Bansal I, Saxena JK, Chauhan PM.
Abstract : A series of 21 compounds of trisubstituted pyrimidine derivatives have been synthesized and evaluated for their in vitro topoisomerase II inhibitory activity against filarial parasite Setaria cervi. Out of these, seven compounds (8, 11-14, 25 and 28) have shown 60-80% inhibition at 40 and 20 microg/mL concentration. Five compounds (12, 13, 14, 25 and 28) exhibited 70-80% inhibition at 10 microg/mL concentration and three compounds (13, 14 and 28) have shown 40-60% inhibition at 5 microg/mL concentration. All the above mentioned compounds have shown better topo II inhibitory activity than standard antifilarial drug (DEC) and enzyme topo II inhibitors (Novobiocin, Nalidixic acid).
|
Percent inhibition of filarial parasite Setaria cervi by compound at 20 ug/mL concentration
|
Setaria cervi
|
20.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses of 2,4,6-trisubstituted pyrimidine derivatives as a new class of antifilarial topoisomerase II inhibitors.
Year : 2005
Volume : 15
Issue : 1
First Page : 47
Last Page : 50
Authors : Katiyar SB, Bansal I, Saxena JK, Chauhan PM.
Abstract : A series of 21 compounds of trisubstituted pyrimidine derivatives have been synthesized and evaluated for their in vitro topoisomerase II inhibitory activity against filarial parasite Setaria cervi. Out of these, seven compounds (8, 11-14, 25 and 28) have shown 60-80% inhibition at 40 and 20 microg/mL concentration. Five compounds (12, 13, 14, 25 and 28) exhibited 70-80% inhibition at 10 microg/mL concentration and three compounds (13, 14 and 28) have shown 40-60% inhibition at 5 microg/mL concentration. All the above mentioned compounds have shown better topo II inhibitory activity than standard antifilarial drug (DEC) and enzyme topo II inhibitors (Novobiocin, Nalidixic acid).
|
Percent inhibition of filarial parasite Setaria cervi by compound at 40 ug/mL concentration
|
Setaria cervi
|
80.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses of 2,4,6-trisubstituted pyrimidine derivatives as a new class of antifilarial topoisomerase II inhibitors.
Year : 2005
Volume : 15
Issue : 1
First Page : 47
Last Page : 50
Authors : Katiyar SB, Bansal I, Saxena JK, Chauhan PM.
Abstract : A series of 21 compounds of trisubstituted pyrimidine derivatives have been synthesized and evaluated for their in vitro topoisomerase II inhibitory activity against filarial parasite Setaria cervi. Out of these, seven compounds (8, 11-14, 25 and 28) have shown 60-80% inhibition at 40 and 20 microg/mL concentration. Five compounds (12, 13, 14, 25 and 28) exhibited 70-80% inhibition at 10 microg/mL concentration and three compounds (13, 14 and 28) have shown 40-60% inhibition at 5 microg/mL concentration. All the above mentioned compounds have shown better topo II inhibitory activity than standard antifilarial drug (DEC) and enzyme topo II inhibitors (Novobiocin, Nalidixic acid).
|
Inhibition of Staphylococcus aureus DNA gyrase
|
Staphylococcus aureus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships.
Year : 2008
Volume : 51
Issue : 17
First Page : 5243
Last Page : 5263
Authors : Charifson PS, Grillot AL, Grossman TH, Parsons JD, Badia M, Bellon S, Deininger DD, Drumm JE, Gross CH, LeTiran A, Liao Y, Mani N, Nicolau DP, Perola E, Ronkin S, Shannon D, Swenson LL, Tang Q, Tessier PR, Tian SK, Trudeau M, Wang T, Wei Y, Zhang H, Stamos D.
Abstract : The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.
|
Inhibition of Escherichia coli DNA gyrase
|
Escherichia coli
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships.
Year : 2008
Volume : 51
Issue : 17
First Page : 5243
Last Page : 5263
Authors : Charifson PS, Grillot AL, Grossman TH, Parsons JD, Badia M, Bellon S, Deininger DD, Drumm JE, Gross CH, LeTiran A, Liao Y, Mani N, Nicolau DP, Perola E, Ronkin S, Shannon D, Swenson LL, Tang Q, Tessier PR, Tian SK, Trudeau M, Wang T, Wei Y, Zhang H, Stamos D.
Abstract : The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.
|
Inhibition of Escherichia coli topoisomerase 4
|
Escherichia coli
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships.
Year : 2008
Volume : 51
Issue : 17
First Page : 5243
Last Page : 5263
Authors : Charifson PS, Grillot AL, Grossman TH, Parsons JD, Badia M, Bellon S, Deininger DD, Drumm JE, Gross CH, LeTiran A, Liao Y, Mani N, Nicolau DP, Perola E, Ronkin S, Shannon D, Swenson LL, Tang Q, Tessier PR, Tian SK, Trudeau M, Wang T, Wei Y, Zhang H, Stamos D.
Abstract : The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.
|
Inhibition of Escherichia coli GyrB ATPase activity assessed as inorganic phosphate release by malachite green complex formation assay
|
Escherichia coli
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: synthesis and antibacterial activity.
Year : 2009
Volume : 19
Issue : 3
First Page : 894
Last Page : 899
Authors : East SP, White CB, Barker O, Barker S, Bennett J, Brown D, Boyd EA, Brennan C, Chowdhury C, Collins I, Convers-Reignier E, Dymock BW, Fletcher R, Haydon DJ, Gardiner M, Hatcher S, Ingram P, Lancett P, Mortenson P, Papadopoulos K, Smee C, Thomaides-Brears HB, Tye H, Workman J, Czaplewski LG.
Abstract : The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency.
|
Inhibition of Staphylococcus aureus DNA gyrase
|
Staphylococcus aureus
|
0.25
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structure and antibacterial activity of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives.
Year : 2009
Volume : 17
Issue : 3
First Page : 1207
Last Page : 1213
Authors : Liu XH, Zhu J, Zhou AN, Song BA, Zhu HL, Bai LS, Bhadury PS, Pan CX.
Abstract : A series of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized. The results showed that compounds 9q and 10q can strongly inhibit Staphylococcus aureus DNA gyrase and Bacillus subtilis DNA gyrase (with IC(50s) of 0.125 and 0.25 microg/mL against S. aureus DNA gyrase, 0.25 and 0.125 microg/mL against B. subtilis DNA gyrase). On the basis of the biological results, structure-activity relationships were also discussed.
|
Inhibition of Bacillus subtilis DNA gyrase
|
Bacillus subtilis
|
0.5
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structure and antibacterial activity of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives.
Year : 2009
Volume : 17
Issue : 3
First Page : 1207
Last Page : 1213
Authors : Liu XH, Zhu J, Zhou AN, Song BA, Zhu HL, Bai LS, Bhadury PS, Pan CX.
Abstract : A series of new 2-(1-(2-(substituted-phenyl)-5-methyloxazol-4-yl)-3-(2-substitued-phenyl)-4,5-dihydro-1H-pyrazol-5-yl)-7-substitued-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized. The results showed that compounds 9q and 10q can strongly inhibit Staphylococcus aureus DNA gyrase and Bacillus subtilis DNA gyrase (with IC(50s) of 0.125 and 0.25 microg/mL against S. aureus DNA gyrase, 0.25 and 0.125 microg/mL against B. subtilis DNA gyrase). On the basis of the biological results, structure-activity relationships were also discussed.
|
Inhibition of Staphylococcus aureus DNA gyrase supercoiling activity
|
Staphylococcus aureus
|
0.28
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structure and antibacterial activity of novel 1-(5-substituted-3-substituted-4,5-dihydropyrazol-1-yl)ethanone oxime ester derivatives.
Year : 2008
Volume : 16
Issue : 7
First Page : 4075
Last Page : 4082
Authors : Liu XH, Cui P, Song BA, Bhadury PS, Zhu HL, Wang SF.
Abstract : A series of novel 1-(5-substituted-3-substituted-4,5-dihydropyrazol-1-yl)ethanone oxime ester derivatives are synthesized. The results show that compounds 14 and 26c can strongly inhibit Staphylococcus aureus DNA gyrase and Escherichia coli DNA gyrase (with IC(50) of 0.25 and 0.125 microg/mL against S. aureus DNA gyrase, 0.125 and 0.25 microg/mL against E. coli DNA gyrase). On the basis of the biological results, structure-activity relationships are also discussed.
|
Inhibition of Escherichia coli DNA gyrase supercoiling activity
|
Escherichia coli
|
0.31
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, structure and antibacterial activity of novel 1-(5-substituted-3-substituted-4,5-dihydropyrazol-1-yl)ethanone oxime ester derivatives.
Year : 2008
Volume : 16
Issue : 7
First Page : 4075
Last Page : 4082
Authors : Liu XH, Cui P, Song BA, Bhadury PS, Zhu HL, Wang SF.
Abstract : A series of novel 1-(5-substituted-3-substituted-4,5-dihydropyrazol-1-yl)ethanone oxime ester derivatives are synthesized. The results show that compounds 14 and 26c can strongly inhibit Staphylococcus aureus DNA gyrase and Escherichia coli DNA gyrase (with IC(50) of 0.25 and 0.125 microg/mL against S. aureus DNA gyrase, 0.125 and 0.25 microg/mL against E. coli DNA gyrase). On the basis of the biological results, structure-activity relationships are also discussed.
|
Neuroprotection against beta-amyloid peptide 1-42-induced toxicity in human SH-SY5Y cells assessed as lactate dehydrogenase release
|
Homo sapiens
|
48.39
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line.
Year : 2009
Volume : 17
Issue : 4
First Page : 1709
Last Page : 1715
Authors : Lu Y, Ansar S, Michaelis ML, Blagg BS.
Abstract : Alzheimer's disease (AD) neuropathology is characterized by loss of synapses and neurons, neuritic plaques consisting of beta-amyloid (Abeta) peptides, and neurofibrillary tangles consisting of intracellular aggregates of hyperphosphorylated tau protein in susceptible brain regions. Abeta oligomers trigger a cascade of pathogenic events including tau hyperphosphorylation and aggregation, inflammatory reactions, and excitotoxicity that contribute to the progression of AD. The molecular chaperone Hsp90 facilitates the folding of newly synthesized and denatured proteins and is believed to play a role in neurodegenerative disorders in which the defining pathology results in misfolded proteins and the accumulation of protein aggregates. Some agents that inhibit Hsp90 protect neurons against Abeta toxicity and tau aggregation, and assays for rapidly screening potential Hsp90 inhibitors are of interest. We used the release of the soluble cytosolic enzyme lactate dehydrogenase (LDH) as an indicator of the loss of cell membrane integrity and cytotoxicity resulting from exposure to Abeta peptides to evaluate the neuroprotective properties of novel novobiocin analogues and established Hsp90 inhibitors. Compounds were assessed for potency in protecting proliferating and differentiated SH-SY5Y neuronal cells against Abeta-induced cell death; the potential toxicity of each agent alone was also determined. The data indicated that several of the compounds decreased Abeta toxicity even at low nanomolar concentrations and, unexpectedly, were more potent in protecting the undifferentiated cells against Abeta. The novobiocin analogues alone were not toxic even up to 10 microM concentrations whereas GDA and the parent compound, novobiocin, were toxic at 1 and 10 microM, respectively. The results suggest that novobiocin analogues may provide novel leads for the development of neuroprotective drugs.
|
Inhibition of Mycobacterium leprae wild type DNA gyrase A2B2 assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
0.25
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Mycobacterium leprae DNA gyrase subunit A G89C mutant assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
0.3
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Mycobacterium leprae DNA gyrase subunit A A91V mutant assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
0.2
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Mycobacterium leprae wild type DNA gyrase subunit B D205N mutant assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
0.3
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Streptococcus pneumoniae SP-3 gyrB by enzyme coupled phosphate assay
|
Streptococcus pneumoniae
|
37.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-(2-Pyrimidinyl)-imidazo[1,2-a]pyridines are antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV.
Year : 2009
Volume : 19
Issue : 18
First Page : 5302
Last Page : 5306
Authors : Starr JT, Sciotti RJ, Hanna DL, Huband MD, Mullins LM, Cai H, Gage JW, Lockard M, Rauckhorst MR, Owen RM, Lall MS, Tomilo M, Chen H, McCurdy SP, Barbachyn MR.
Abstract : Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).
|
Antibacterial activity against Staphylococcus aureus UC76 by NCCLS method
|
Staphylococcus aureus
|
125.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-(2-Pyrimidinyl)-imidazo[1,2-a]pyridines are antibacterial agents targeting the ATPase domains of DNA gyrase and topoisomerase IV.
Year : 2009
Volume : 19
Issue : 18
First Page : 5302
Last Page : 5306
Authors : Starr JT, Sciotti RJ, Hanna DL, Huband MD, Mullins LM, Cai H, Gage JW, Lockard M, Rauckhorst MR, Owen RM, Lall MS, Tomilo M, Chen H, McCurdy SP, Barbachyn MR.
Abstract : Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).
|
Inhibition of Escherichia coli DNA gyrase B ATPase activity
|
Escherichia coli
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : In silico discovery of 2-amino-4-(2,4-dihydroxyphenyl)thiazoles as novel inhibitors of DNA gyrase B.
Year : 2010
Volume : 20
Issue : 3
First Page : 958
Last Page : 962
Authors : Brvar M, Perdih A, Oblak M, Masic LP, Solmajer T.
Abstract : Cyclothialidines are a class of bacterial DNA gyrase B (GyrB) subunit inhibitors, targeting its ATP-binding site. Starting from the available structural information on cyclothialidine GR122222X (2), an in silico virtual screening campaign was designed combining molecular docking calculations with three-dimensional structure-based pharmacophore information. A novel class of 2-amino-4-(2,4-dihydroxyphenyl)thiazole based inhibitors (5-9) with low micromolar antigyrase activity was discovered.
|
Inhibition of Escherichia coli DNA gyraseB assessed as inhibition of pBR322 supercoiling by densitometry
|
Escherichia coli
|
50.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and biological evaluation of a novel series of quercetin diacylglucosides as potent anti-MRSA and anti-VRE agents.
Year : 2010
Volume : 20
Issue : 17
First Page : 5349
Last Page : 5352
Authors : Hossion AM, Otsuka N, Kandahary RK, Tsuchiya T, Ogawa W, Iwado A, Zamami Y, Sasaki K.
Abstract : A series of novel quercetin diacylglucosides were designed and first synthesized by Steglich esterification on the basis of MRSA strains inhibiting natural compound A. The in vitro inhibition of different multi-drug resistant bacterial strains and Escherichia coli DNA gyrase B was investigated. In the series, compound 10h was up to 128-fold more potent against vancomycin-resistant enterococci and more effective than A, which represents a promising new candidate as a potent anti-MRSA and anti-VRE agent.
|
Inhibition of reconstituted Xanthomonas albilineans DNA gyrase subunit AB assessed as reduction of DNA supercoiling activity using pBR322 DNA substrate
|
Xanthomonas albilineans
|
800.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : DNA gyrase from the albicidin producer Xanthomonas albilineans has multiple-antibiotic-resistance and unusual enzymatic properties.
Year : 2008
Volume : 52
Issue : 4
First Page : 1382
Last Page : 1390
Authors : Hashimi SM, Huang G, Maxwell A, Birch RG.
Abstract : The sugarcane pathogen Xanthomonas albilineans produces a family of antibiotics and phytotoxins termed albicidins, which inhibit plant and bacterial DNA gyrase supercoiling activity, with a 50% inhibitory concentration (50 nM) comparable to those of coumarins and quinolones. Here we show that X. albilineans has an unusual, antibiotic-resistant DNA gyrase. The X. albilineans gyrA and gyrB genes are not clustered with previously described albicidin biosynthesis and self-protection genes. The GyrA and GyrB products differ from Escherichia coli homologues through several insertions and through changes in several amino acid residues implicated in quinolone and coumarin resistance. Reconstituted X. albilineans DNA gyrase showed 20- to 25-fold-higher resistance than E. coli DNA gyrase to albicidin and ciprofloxacin and 8-fold-higher resistance to novobiocin in the supercoiling assay. The X. albilineans DNA gyrase is unusual in showing a high degree of distributive supercoiling and little DNA relaxation activity. X. albilineans GyrA (XaA) forms a functional gyrase heterotetramer with E. coli GyrB (EcB) and can account for albicidin and quinolone resistance and low levels of relaxation activity. XaB probably contributes to both coumarin resistance and the distributive supercoiling pattern. Although XaB shows fewer apparent changes relative to EcB, the EcA.XaB hybrid relaxed DNA in the presence or absence of ATP and was unable to supercoil. A fuller understanding of structural differences between albicidin-sensitive and -resistant gyrases may provide new clues into features of the enzyme amenable to interference by novel antibiotics.
|
Inhibition of reconstituted Escherichia coli DNA gyrase subunit AB assessed as reduction of DNA supercoiling activity using pBR322 DNA substrate
|
Escherichia coli
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : DNA gyrase from the albicidin producer Xanthomonas albilineans has multiple-antibiotic-resistance and unusual enzymatic properties.
Year : 2008
Volume : 52
Issue : 4
First Page : 1382
Last Page : 1390
Authors : Hashimi SM, Huang G, Maxwell A, Birch RG.
Abstract : The sugarcane pathogen Xanthomonas albilineans produces a family of antibiotics and phytotoxins termed albicidins, which inhibit plant and bacterial DNA gyrase supercoiling activity, with a 50% inhibitory concentration (50 nM) comparable to those of coumarins and quinolones. Here we show that X. albilineans has an unusual, antibiotic-resistant DNA gyrase. The X. albilineans gyrA and gyrB genes are not clustered with previously described albicidin biosynthesis and self-protection genes. The GyrA and GyrB products differ from Escherichia coli homologues through several insertions and through changes in several amino acid residues implicated in quinolone and coumarin resistance. Reconstituted X. albilineans DNA gyrase showed 20- to 25-fold-higher resistance than E. coli DNA gyrase to albicidin and ciprofloxacin and 8-fold-higher resistance to novobiocin in the supercoiling assay. The X. albilineans DNA gyrase is unusual in showing a high degree of distributive supercoiling and little DNA relaxation activity. X. albilineans GyrA (XaA) forms a functional gyrase heterotetramer with E. coli GyrB (EcB) and can account for albicidin and quinolone resistance and low levels of relaxation activity. XaB probably contributes to both coumarin resistance and the distributive supercoiling pattern. Although XaB shows fewer apparent changes relative to EcB, the EcA.XaB hybrid relaxed DNA in the presence or absence of ATP and was unable to supercoil. A fuller understanding of structural differences between albicidin-sensitive and -resistant gyrases may provide new clues into features of the enzyme amenable to interference by novel antibiotics.
|
Inhibition of reconstituted Xanthomonas albilineans DNA gyrase A and Escherichia coli DNA gyrase subunit B hybrid assessed as reduction of DNA supercoiling activity using pBR322 DNA substrate
|
None
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : DNA gyrase from the albicidin producer Xanthomonas albilineans has multiple-antibiotic-resistance and unusual enzymatic properties.
Year : 2008
Volume : 52
Issue : 4
First Page : 1382
Last Page : 1390
Authors : Hashimi SM, Huang G, Maxwell A, Birch RG.
Abstract : The sugarcane pathogen Xanthomonas albilineans produces a family of antibiotics and phytotoxins termed albicidins, which inhibit plant and bacterial DNA gyrase supercoiling activity, with a 50% inhibitory concentration (50 nM) comparable to those of coumarins and quinolones. Here we show that X. albilineans has an unusual, antibiotic-resistant DNA gyrase. The X. albilineans gyrA and gyrB genes are not clustered with previously described albicidin biosynthesis and self-protection genes. The GyrA and GyrB products differ from Escherichia coli homologues through several insertions and through changes in several amino acid residues implicated in quinolone and coumarin resistance. Reconstituted X. albilineans DNA gyrase showed 20- to 25-fold-higher resistance than E. coli DNA gyrase to albicidin and ciprofloxacin and 8-fold-higher resistance to novobiocin in the supercoiling assay. The X. albilineans DNA gyrase is unusual in showing a high degree of distributive supercoiling and little DNA relaxation activity. X. albilineans GyrA (XaA) forms a functional gyrase heterotetramer with E. coli GyrB (EcB) and can account for albicidin and quinolone resistance and low levels of relaxation activity. XaB probably contributes to both coumarin resistance and the distributive supercoiling pattern. Although XaB shows fewer apparent changes relative to EcB, the EcA.XaB hybrid relaxed DNA in the presence or absence of ATP and was unable to supercoil. A fuller understanding of structural differences between albicidin-sensitive and -resistant gyrases may provide new clues into features of the enzyme amenable to interference by novel antibiotics.
|
Inhibition of Escherichia coli JM109 DNA gyrase subunit B assessed as ATP hydrolysis by ATPase assay
|
Escherichia coli
|
154.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Biological activities of novel gyrase inhibitors of the aminocoumarin class.
Year : 2008
Volume : 52
Issue : 6
First Page : 1982
Last Page : 1990
Authors : Anderle C, Stieger M, Burrell M, Reinelt S, Maxwell A, Page M, Heide L.
Abstract : Thirty-one aminocoumarin antibiotics derived from mutasynthesis experiments were investigated for their biological activities. Their inhibitory activities toward Escherichia coli DNA gyrase were determined in two different in vitro assays: an ATPase assay and a DNA supercoiling assay. The assays gave a similar rank order of the activities of the compounds tested, although the absolute 50% inhibitory concentrations (IC(50)s) obtained in each assay were different. To confirm that the compounds also acted as gyrase inhibitors in vivo, reporter gene assays were carried out with E. coli by using gyrA and sulA promoter fusions with the luxCDABE operon. A strong induction of both promoters was observed for those compounds that showed gyrase inhibitory activity in the biochemical assays. Compounds carrying analogs of the prenylated benzoyl moiety (ring A) of clorobiocin that were structurally very different showed high levels of activity both in the biochemical assay and in the reporter gene assay, indicating that the structure of this moiety can be varied considerably without a loss of affinity for bacterial gyrase. The experimentally determined IC(50)s were compared to the binding energies calculated in silico, which indicated that a shift of the pyrrole carboxylic acid moiety from the O-3'' to the O-2'' position of the deoxysugar moiety has a significant impact on the binding mode of the compounds. The aminocoumarin compounds were also investigated for their MICs against different bacterial pathogens. Several compounds showed high levels of activity against staphylococci, including a methicillin-resistant Staphylococcus aureus strain. However, they showed only poor activities against gram-negative strains.
|
Inhibition of Escherichia coli JM109 DNA gyrase subunit B assessed as DNA triple helix formation by supercoiling assay
|
Escherichia coli
|
200.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Biological activities of novel gyrase inhibitors of the aminocoumarin class.
Year : 2008
Volume : 52
Issue : 6
First Page : 1982
Last Page : 1990
Authors : Anderle C, Stieger M, Burrell M, Reinelt S, Maxwell A, Page M, Heide L.
Abstract : Thirty-one aminocoumarin antibiotics derived from mutasynthesis experiments were investigated for their biological activities. Their inhibitory activities toward Escherichia coli DNA gyrase were determined in two different in vitro assays: an ATPase assay and a DNA supercoiling assay. The assays gave a similar rank order of the activities of the compounds tested, although the absolute 50% inhibitory concentrations (IC(50)s) obtained in each assay were different. To confirm that the compounds also acted as gyrase inhibitors in vivo, reporter gene assays were carried out with E. coli by using gyrA and sulA promoter fusions with the luxCDABE operon. A strong induction of both promoters was observed for those compounds that showed gyrase inhibitory activity in the biochemical assays. Compounds carrying analogs of the prenylated benzoyl moiety (ring A) of clorobiocin that were structurally very different showed high levels of activity both in the biochemical assay and in the reporter gene assay, indicating that the structure of this moiety can be varied considerably without a loss of affinity for bacterial gyrase. The experimentally determined IC(50)s were compared to the binding energies calculated in silico, which indicated that a shift of the pyrrole carboxylic acid moiety from the O-3'' to the O-2'' position of the deoxysugar moiety has a significant impact on the binding mode of the compounds. The aminocoumarin compounds were also investigated for their MICs against different bacterial pathogens. Several compounds showed high levels of activity against staphylococci, including a methicillin-resistant Staphylococcus aureus strain. However, they showed only poor activities against gram-negative strains.
|
Inhibition of Escherichia coli DNA gyrase by gel electrophoresis
|
Escherichia coli
|
100.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Discovery and characterization of QPT-1, the progenitor of a new class of bacterial topoisomerase inhibitors.
Year : 2008
Volume : 52
Issue : 8
First Page : 2806
Last Page : 2812
Authors : Miller AA, Bundy GL, Mott JE, Skepner JE, Boyle TP, Harris DW, Hromockyj AE, Marotti KR, Zurenko GE, Munzner JB, Sweeney MT, Bammert GF, Hamel JC, Ford CW, Zhong WZ, Graber DR, Martin GE, Han F, Dolak LA, Seest EP, Ruble JC, Kamilar GM, Palmer JR, Banitt LS, Hurd AR, Barbachyn MR.
Abstract : QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (-)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the beta subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.
|
Inhibition of human topoisomerase 2alpha-mediated ATP hydrolysis at 400 uM after 30 mins by malachite green ATPase assay
|
Homo sapiens
|
60.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, biological evaluation, and molecular docking study of 3-(3'-heteroatom substituted-2'-hydroxy-1'-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor.
Year : 2011
Volume : 46
Issue : 6
First Page : 1964
Last Page : 1971
Authors : Jun KY, Lee EY, Jung MJ, Lee OH, Lee ES, Park Choo HY, Na Y, Kwon Y.
Abstract : Epoxide ring-opened xanthone derivatives were synthesized and tested for their topoisomerase inhibitory activity and cytotoxicity. Most of the compounds showed topo IIα specific inhibitory activity. To clarify the mechanism of action of these compounds, the most potent compound (compound 14) of the synthesized analogues was further studied by testing its ATPase inhibitory activity and through molecular docking experiments. The results showed that the topo IIα inhibitory activity of compound 14 was inversely proportional to ATP concentration. In the ATPase inhibitory test, ATP hydrolysis was reduced less efficiently by compound 14 (28.5±4.6%) than novobiocin (60.4±8.1%). Molecular docking study revealed compound 14 to have a stable binding pattern to the ATP-binding domain of human topo II.
|
Inhibition of Escherichia coli DNA gyrase assessed as inhibition of pBR322 supercoiling by densitometry
|
Escherichia coli
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents.
Year : 2011
Volume : 54
Issue : 11
First Page : 3686
Last Page : 3703
Authors : Hossion AM, Zamami Y, Kandahary RK, Tsuchiya T, Ogawa W, Iwado A, Sasaki K.
Abstract : A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6''-acylgalactoside, and quercetin 2'',6''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 μg/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure-activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent.
|
Inhibition of Escherichia coli DNA topoisomerase 4 subunit ParC/DNA topoisomerase 4 subunit ParE-mediated decatenation of kDNA by densitometry
|
Escherichia coli
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents.
Year : 2011
Volume : 54
Issue : 11
First Page : 3686
Last Page : 3703
Authors : Hossion AM, Zamami Y, Kandahary RK, Tsuchiya T, Ogawa W, Iwado A, Sasaki K.
Abstract : A structure-guided molecular design approach was used to optimize quercetin diacylglycoside analogues that inhibit bacterial DNA gyrase and topoisomerase IV and show potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. In this paper, such novel 3,7-diacylquercetin, quercetin 6''-acylgalactoside, and quercetin 2'',6''-diacylgalactoside analogues of lead compound 1 were prepared to assess their target specificities and preferences in bacteria. The significant enzymatic inhibition of both Escherichia coli DNA gyrase and Staphylococcus aureus topoIV suggest that these compounds are dual inhibitors. Most of the investigated compounds exhibited pronounced inhibition with MIC values ranging from 0.13 to 128 μg/mL toward the growth of multidrug-resistant Gram-positive methicillin-resistant S. aureus, methicillin sensitive S. aureus, vancomycin-resistant enterococci (VRE), vancomycin intermediate S. aureus, and Streptococcus pneumoniae bacterial strains. Structure-activity relationship studies revealed that the acyl moiety was absolutely essential for activity against Gram-positive organisms. The most active compound 5i was 512-fold more potent than vancomycin and 16-32-fold more potent than 1 against VRE strains. It also has realistic in situ intestinal absorption in rats and showed very low acute toxicity in mice. So far, this compound can be regarded as a leading antibacterial agent.
|
Displacement of novobiocin-TRX from Francisella tularensis Schu S4 gyraseB by fluorescence polarization assay
|
Francisella tularensis
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Mannich reaction derivatives of novobiocin with modulated physiochemical properties and their antibacterial activities.
Year : 2011
Volume : 21
Issue : 19
First Page : 5697
Last Page : 5700
Authors : Tambo-ong A, Chopra S, Glaser BT, Matsuyama K, Tran T, Madrid PB.
Abstract : Synthetic derivatives of the natural product antibiotic novobiocin were synthesized in order to improve their physiochemical properties. A Mannich reaction was used to introduce new side chains at a solvent-exposed position of the molecule, and a diverse panel of functional groups was evaluated at this position. Novobiocin and the new derivatives were tested for their binding to gyrase B and their antibacterial activities against Staphylococcus aureus, Mycobacterium tuberculosis, Francisella tularensis and Escherichia coli. While the new derivatives still bound the gyrase B protein potently (0.07-1.8 μM, IC(50)), they had significantly less antibacterial activity. Two compounds were identified with increased antibacterial activity against M. tuberculosis, with a minimum inhibitory concentration of 2.5 μg/ml.
|
Inhibition of DNA gyrase B
|
None
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In silico discovery and biophysical evaluation of novel 5-(2-hydroxybenzylidene) rhodanine inhibitors of DNA gyrase B.
Year : 2012
Volume : 20
Issue : 8
First Page : 2572
Last Page : 2580
Authors : Brvar M, Perdih A, Hodnik V, Renko M, Anderluh G, Jerala R, Solmajer T.
Abstract : Bacterial DNA gyrase is an established and validated target for the development of novel antibacterials. In our previous work, we identified a novel series of bacterial gyrase inhibitors from the class of 4-(2,4-dihydroxyphenyl) thiazoles. Our ongoing effort was designated to search for synthetically more available compounds with possibility of hit to lead development. By using the virtual screening approach, new potential inhibitors were carefully selected from the focused chemical library and tested for biological activity. Herein we report on a novel class of 5-(2-hydroxybenzylidene) rhodanines as gyrase B inhibitors with activity in low micromolar range and moderate antibacterial activity. The binding of the two most active compounds to the enzyme target was further characterised using surface plasmon resonance (SPR) and differential scanning fluorimetry methods (DSF).
|
Inhibition of Escherichia coli DNA gyrase B using relaxed pNO1 as substrate after 30 mins by fluorimetry
|
Escherichia coli
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : In silico discovery and biophysical evaluation of novel 5-(2-hydroxybenzylidene) rhodanine inhibitors of DNA gyrase B.
Year : 2012
Volume : 20
Issue : 8
First Page : 2572
Last Page : 2580
Authors : Brvar M, Perdih A, Hodnik V, Renko M, Anderluh G, Jerala R, Solmajer T.
Abstract : Bacterial DNA gyrase is an established and validated target for the development of novel antibacterials. In our previous work, we identified a novel series of bacterial gyrase inhibitors from the class of 4-(2,4-dihydroxyphenyl) thiazoles. Our ongoing effort was designated to search for synthetically more available compounds with possibility of hit to lead development. By using the virtual screening approach, new potential inhibitors were carefully selected from the focused chemical library and tested for biological activity. Herein we report on a novel class of 5-(2-hydroxybenzylidene) rhodanines as gyrase B inhibitors with activity in low micromolar range and moderate antibacterial activity. The binding of the two most active compounds to the enzyme target was further characterised using surface plasmon resonance (SPR) and differential scanning fluorimetry methods (DSF).
|
Binding affinity to Escherichia coli DNA gyrase subunit B N-terminal fragment G24 measured over 120 secs by surface plasmon resonance method
|
Escherichia coli
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-based discovery of substituted 4,5'-bithiazoles as novel DNA gyrase inhibitors.
Year : 2012
Volume : 55
Issue : 14
First Page : 6413
Last Page : 6426
Authors : Brvar M, Perdih A, Renko M, Anderluh G, Turk D, Solmajer T.
Abstract : Bacterial DNA gyrase is a well-established and validated target for the development of novel antibacterials. Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of 4'-methyl-N(2)-phenyl-[4,5'-bithiazole]-2,2'-diamine inhibitors of gyrase B with a low micromolar inhibitory activity by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques (differential scanning fluorimetry, surface plasmon resonance, and microscale thermophoresis). The binding mode of the potent inhibitor 18 was revealed by X-ray crystallography, confirming our initial in silico binding model. Furthermore, the high resolution of the complex structure allowed for the placement of the Gly97-Ser108 flexible loop, thus revealing its role in binding of this class of compounds. The crystal structure of the complex protein G24 and inhibitor 18 provides valuable information for further optimization of this novel class of DNA gyrase B inhibitors.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
58.1
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
84.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
85.6
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Binding affinity to Escherichia coli GyrB
|
Escherichia coli
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : ATP-binding site of bacterial enzymes as a target for antibacterial drug design.
Year : 2011
Volume : 54
Issue : 4
First Page : 915
Last Page : 929
Authors : Škedelj V, Tomašić T, Mašič LP, Zega A.
|
Inhibition of Escherichia coli His6-tagged ParC/ParE expressed in baculovirus-infected Sf9 cells by gel electrophoresis
|
Escherichia coli
|
210.0
nM
|
|
Journal : J. Med. Chem.
Title : ATP-binding site of bacterial enzymes as a target for antibacterial drug design.
Year : 2011
Volume : 54
Issue : 4
First Page : 915
Last Page : 929
Authors : Škedelj V, Tomašić T, Mašič LP, Zega A.
|
Inhibition of Escherichia coli ATPase activity of topoisomerase-4
|
Escherichia coli
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities.
Year : 2012
Volume : 22
Issue : 23
First Page : 7127
Last Page : 7130
Authors : Singh SB, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, de la Cruz M, Martín J, Vicente F, Genilloud O, Donald RG, Phillips JW.
Abstract : Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family.
|
Inhibition of Escherichia coli ATPase activity of DNA gyrase
|
Escherichia coli
|
23.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities.
Year : 2012
Volume : 22
Issue : 23
First Page : 7127
Last Page : 7130
Authors : Singh SB, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, de la Cruz M, Martín J, Vicente F, Genilloud O, Donald RG, Phillips JW.
Abstract : Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family.
|
Inhibition of Staphylococcus aureus DNA gyrase
|
Staphylococcus aureus
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities.
Year : 2012
Volume : 22
Issue : 23
First Page : 7127
Last Page : 7130
Authors : Singh SB, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, de la Cruz M, Martín J, Vicente F, Genilloud O, Donald RG, Phillips JW.
Abstract : Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family.
|
Inhibition of Escherichia coli DNA gyrase
|
Escherichia coli
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities.
Year : 2012
Volume : 22
Issue : 23
First Page : 7127
Last Page : 7130
Authors : Singh SB, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, Salowe S, Wiltsie J, Allocco J, Sigmund J, Dorso K, de la Cruz M, Martín J, Vicente F, Genilloud O, Donald RG, Phillips JW.
Abstract : Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family.
|
Inhibition of human DNA topoisomerase-2alpha ATPase activity using supercoiled pUC18 DNA as substrate assessed as inorganic phosphate release at 400 uM incubated for 30 mins prior to ATP addition measured after 30 mins by malachite green phosphate assay relative to control
|
Homo sapiens
|
76.8
%
|
|
Journal : Eur. J. Med. Chem.
Title : 3-(3-Butylamino-2-hydroxy-propoxy)-1-hydroxy-xanthen-9-one acts as a topoisomerase IIα catalytic inhibitor with low DNA damage.
Year : 2013
Volume : 69
First Page : 139
Last Page : 145
Authors : Park SE, Chang IH, Jun KY, Lee E, Lee ES, Na Y, Kwon Y.
Abstract : As a continuous study we prepared several alkylamine (n = 3-6) and evaluated for the pharmacological activity and mode of action. In the topoisomerase IIα (topo IIα) inhibition test, compound 4 showed strongest inhibitory activity among the compounds at 10 μM. Inhibitory activities of the compounds are in the order of 4 (n = 4) > 1 (n = 3) >> 5 (n = 5) ≈ 6 (n = 6); 8 (n = 4) >> 7 (n = 3) ≈ 9 (n = 5) ≈ 10 (n = 6) where n is the number of carbon in the aliphatic side chain in ring C and compounds 7-10 have additional methoxy group in ring A compared to compounds 1, 4-6. Compound 4 showed efficient cytotoxicities against T47D (IC₅₀: 0.93 ± 0.04 μM) and HCT15 (IC50: 0.78 ± 0.01 μM) cells, which are higher than etoposide. Compound 4 was also an ATP-competitive human topo IIα catalytic inhibitor with partially blocking human topo IIα-catalyzed ATP hydrolysis and intercalating into DNA. Compound 4 induced much less DNA damage than etoposide in HCT15 human colorectal carcinoma cells. Overall, compound 4 can be a potential anticancer agent acting as topo IIα catalytic inhibitor with low DNA damage.
|
Inhibition of human DNA topoisomerase-2alpha ATPase activity using supercoiled pUC18 DNA as substrate assessed as inorganic phosphate release at 300 uM incubated for 30 mins prior to ATP addition measured after 30 mins by malachite green phosphate assay relative to control
|
Homo sapiens
|
63.6
%
|
|
Journal : Eur. J. Med. Chem.
Title : 3-(3-Butylamino-2-hydroxy-propoxy)-1-hydroxy-xanthen-9-one acts as a topoisomerase IIα catalytic inhibitor with low DNA damage.
Year : 2013
Volume : 69
First Page : 139
Last Page : 145
Authors : Park SE, Chang IH, Jun KY, Lee E, Lee ES, Na Y, Kwon Y.
Abstract : As a continuous study we prepared several alkylamine (n = 3-6) and evaluated for the pharmacological activity and mode of action. In the topoisomerase IIα (topo IIα) inhibition test, compound 4 showed strongest inhibitory activity among the compounds at 10 μM. Inhibitory activities of the compounds are in the order of 4 (n = 4) > 1 (n = 3) >> 5 (n = 5) ≈ 6 (n = 6); 8 (n = 4) >> 7 (n = 3) ≈ 9 (n = 5) ≈ 10 (n = 6) where n is the number of carbon in the aliphatic side chain in ring C and compounds 7-10 have additional methoxy group in ring A compared to compounds 1, 4-6. Compound 4 showed efficient cytotoxicities against T47D (IC₅₀: 0.93 ± 0.04 μM) and HCT15 (IC50: 0.78 ± 0.01 μM) cells, which are higher than etoposide. Compound 4 was also an ATP-competitive human topo IIα catalytic inhibitor with partially blocking human topo IIα-catalyzed ATP hydrolysis and intercalating into DNA. Compound 4 induced much less DNA damage than etoposide in HCT15 human colorectal carcinoma cells. Overall, compound 4 can be a potential anticancer agent acting as topo IIα catalytic inhibitor with low DNA damage.
|
Inhibition of human DNA topoisomerase-2alpha ATPase activity using supercoiled pUC18 DNA as substrate assessed as inorganic phosphate release at 200 uM incubated for 30 mins prior to ATP addition measured after 30 mins by malachite green phosphate assay relative to control
|
Homo sapiens
|
14.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : 3-(3-Butylamino-2-hydroxy-propoxy)-1-hydroxy-xanthen-9-one acts as a topoisomerase IIα catalytic inhibitor with low DNA damage.
Year : 2013
Volume : 69
First Page : 139
Last Page : 145
Authors : Park SE, Chang IH, Jun KY, Lee E, Lee ES, Na Y, Kwon Y.
Abstract : As a continuous study we prepared several alkylamine (n = 3-6) and evaluated for the pharmacological activity and mode of action. In the topoisomerase IIα (topo IIα) inhibition test, compound 4 showed strongest inhibitory activity among the compounds at 10 μM. Inhibitory activities of the compounds are in the order of 4 (n = 4) > 1 (n = 3) >> 5 (n = 5) ≈ 6 (n = 6); 8 (n = 4) >> 7 (n = 3) ≈ 9 (n = 5) ≈ 10 (n = 6) where n is the number of carbon in the aliphatic side chain in ring C and compounds 7-10 have additional methoxy group in ring A compared to compounds 1, 4-6. Compound 4 showed efficient cytotoxicities against T47D (IC₅₀: 0.93 ± 0.04 μM) and HCT15 (IC50: 0.78 ± 0.01 μM) cells, which are higher than etoposide. Compound 4 was also an ATP-competitive human topo IIα catalytic inhibitor with partially blocking human topo IIα-catalyzed ATP hydrolysis and intercalating into DNA. Compound 4 induced much less DNA damage than etoposide in HCT15 human colorectal carcinoma cells. Overall, compound 4 can be a potential anticancer agent acting as topo IIα catalytic inhibitor with low DNA damage.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase super coiling activity of relaxed pBR322 using ethidium bromide staining by agarose gel electrophoresis
|
Mycobacterium tuberculosis
|
50.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors.
Year : 2013
Volume : 70
First Page : 143
Last Page : 153
Authors : Jeankumar VU, Renuka J, Santosh P, Soni V, Sridevi JP, Suryadevara P, Yogeeswari P, Sriram D.
Abstract : A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2-(phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase super coiling activity of relaxed pBR322 at 25 uM using ethidium bromide staining by agarose gel electrophoresis
|
Mycobacterium tuberculosis
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors.
Year : 2013
Volume : 70
First Page : 143
Last Page : 153
Authors : Jeankumar VU, Renuka J, Santosh P, Soni V, Sridevi JP, Suryadevara P, Yogeeswari P, Sriram D.
Abstract : A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2-(phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase super coiling activity of relaxed pBR322 at 50 uM using ethidium bromide staining by agarose gel electrophoresis
|
Mycobacterium tuberculosis
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors.
Year : 2013
Volume : 70
First Page : 143
Last Page : 153
Authors : Jeankumar VU, Renuka J, Santosh P, Soni V, Sridevi JP, Suryadevara P, Yogeeswari P, Sriram D.
Abstract : A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2-(phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM.
|
Inhibition of Mycobacterium smegmatis GyrB ATPase activity expressed in Escherichia coli BL21 (DE3) after 2 hrs
|
Mycobacterium smegmatis
|
200.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors.
Year : 2013
Volume : 70
First Page : 143
Last Page : 153
Authors : Jeankumar VU, Renuka J, Santosh P, Soni V, Sridevi JP, Suryadevara P, Yogeeswari P, Sriram D.
Abstract : A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2-(phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM.
|
Inhibition of Mycobacterium smegmatis GyrB ATPase activity expressed in Escherichia coli BL21 (DE3) at 25 uM after 2 hrs
|
Mycobacterium smegmatis
|
96.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors.
Year : 2013
Volume : 70
First Page : 143
Last Page : 153
Authors : Jeankumar VU, Renuka J, Santosh P, Soni V, Sridevi JP, Suryadevara P, Yogeeswari P, Sriram D.
Abstract : A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2-(phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM.
|
Inhibition of Mycobacterium smegmatis GyrB ATPase activity expressed in Escherichia coli BL21 (DE3) at 50 uM after 2 hrs
|
Mycobacterium smegmatis
|
98.2
%
|
|
Journal : Eur. J. Med. Chem.
Title : Thiazole-aminopiperidine hybrid analogues: design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors.
Year : 2013
Volume : 70
First Page : 143
Last Page : 153
Authors : Jeankumar VU, Renuka J, Santosh P, Soni V, Sridevi JP, Suryadevara P, Yogeeswari P, Sriram D.
Abstract : A series of ethyl-4-(4-((substituted benzyl)amino)piperidin-1-yl)-2-(phenyl/pyridyl)thiazole-5-carboxylates was designed by molecular hybridization and synthesized from aryl thioamides in five steps. The compounds were evaluated for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antituberculosis activity and cytotoxicity. Among the twenty four compounds studied, ethyl-4-(4-((4-fluorobenzyl)amino)piperidin-1-yl)-2-phenylthiazole-5-carboxylate (14) was found to be the promising compound which showed activity against all test with MS GyrB IC50 of 24.0 ± 2.1 μM, 79% inhibition of MTB DNA gyrase at 50 μM, MTB MIC of 28.44 μM, and not cytotoxic at 50 μM.
|
Inhibition of ACE (unknown origin) assessed as 3-Hydroxybutyril-glycil-glycil-glycine conversion to 3-hydroxybutyric acid at 500 uM after 60 mins by WST assay relative to control
|
Homo sapiens
|
75.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental confirmation of new drug-target interactions predicted by Drug Profile Matching.
Year : 2013
Volume : 56
Issue : 21
First Page : 8377
Last Page : 8388
Authors : Végner L, Peragovics Á, Tombor L, Jelinek B, Czobor P, Bender A, Simon Z, Málnási-Csizmadia A.
Abstract : We recently introduced Drug Profile Matching (DPM), a novel affinity fingerprinting-based in silico drug repositioning approach. DPM is able to quantitatively predict the complete effect profiles of compounds via probability scores. In the present work, in order to investigate the predictive power of DPM, three effect categories, namely, angiotensin-converting enzyme inhibitor, cyclooxygenase inhibitor, and dopamine agent, were selected and predictions were verified by literature analysis as well as experimentally. A total of 72% of the newly predicted and tested dopaminergic compounds were confirmed by tests on D1 and D2 expressing cell cultures. 33% and 23% of the ACE and COX inhibitory predictions were confirmed by in vitro tests, respectively. Dose-dependent inhibition curves were measured for seven drugs, and their inhibitory constants (Ki) were determined. Our study overall demonstrates that DPM is an effective approach to reveal novel drug-target pairs that may result in repositioning these drugs.
|
Inhibition of purified Mycobacterium smegmatis GyrB at 50 to 100 uM after 100 mins by ATPase assay
|
Mycobacterium smegmatis
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition.
Year : 2014
Volume : 22
Issue : 23
First Page : 6552
Last Page : 6563
Authors : Reddy KI, Srihari K, Renuka J, Sree KS, Chuppala A, Jeankumar VU, Sridevi JP, Babu KS, Yogeeswari P, Sriram D.
Abstract : A series of twenty eight molecules of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by molecular hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorimetry. Also the orientation and the ligand-protein interactions of the top hit molecules with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compounds studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 ± 0.23 μM, 0.42 ± 0.23 against MTB DNA gyrase, MTB MIC of 3.64 μM, and was not cytotoxic in eukaryotic cells at 100 μM. Moreover the interaction of protein-ligand complex was stable and showed a positive shift of 3.5 °C in differential scanning fluorimetric evaluations
|
Inhibition of Mycobacterium tuberculosis DNA gyrase using relaxed pBR322 as substrate after 30 mins by supercoiling assay
|
Mycobacterium tuberculosis
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : An efficient synthesis and biological screening of benzofuran and benzo[d]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition.
Year : 2014
Volume : 22
Issue : 23
First Page : 6552
Last Page : 6563
Authors : Reddy KI, Srihari K, Renuka J, Sree KS, Chuppala A, Jeankumar VU, Sridevi JP, Babu KS, Yogeeswari P, Sriram D.
Abstract : A series of twenty eight molecules of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by molecular hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorimetry. Also the orientation and the ligand-protein interactions of the top hit molecules with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compounds studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 ± 0.23 μM, 0.42 ± 0.23 against MTB DNA gyrase, MTB MIC of 3.64 μM, and was not cytotoxic in eukaryotic cells at 100 μM. Moreover the interaction of protein-ligand complex was stable and showed a positive shift of 3.5 °C in differential scanning fluorimetric evaluations
|
Inhibition of Staphylococcus aureus DNA gyrase B ATPase activity
|
Staphylococcus aureus
|
125.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided design and development of novel benzimidazole class of compounds targeting DNA gyraseB enzyme of Staphylococcus aureus.
Year : 2014
Volume : 22
Issue : 21
First Page : 5970
Last Page : 5987
Authors : Janupally R, Jeankumar VU, Bobesh KA, Soni V, Devi PB, Pulla VK, Suryadevara P, Chennubhotla KS, Kulkarni P, Yogeeswari P, Sriram D.
Abstract : The gyraseB subunit of Staphylococcus aureus DNA gyrase is a well-established and validated target though less explored for the development of novel antimicrobial agents. Starting from the available structural information in PDB (3TTZ), we identified a novel series of benzimidazole used as inhibitors of DNA gyraseB with low micromolar inhibitory activity by employing structure-based drug design strategy. Subsequently, this chemical class of DNA gyrase inhibitors was extensively investigated biologically through in vitro assays, biofilm inhibition assays, cytotoxicity, and in vivo studies. The binding affinity of the most potent inhibitor 10 was further ascertained biophysically through differential scanning fluorimetry. Further, the most potent analogues did not show any signs of cardiotoxicity in Zebra fish ether-a-go-go-related gene (zERG), a major breakthrough among the previously reported cardiotoxic gyraseB inhibitors.
|
Inhibition of Staphylococcus aureus DNA gyrase-mediated supercoiling of relaxed DNA using pBR 322 as substrate by agarose gel electrophoresis analysis
|
Staphylococcus aureus
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided design and development of novel benzimidazole class of compounds targeting DNA gyraseB enzyme of Staphylococcus aureus.
Year : 2014
Volume : 22
Issue : 21
First Page : 5970
Last Page : 5987
Authors : Janupally R, Jeankumar VU, Bobesh KA, Soni V, Devi PB, Pulla VK, Suryadevara P, Chennubhotla KS, Kulkarni P, Yogeeswari P, Sriram D.
Abstract : The gyraseB subunit of Staphylococcus aureus DNA gyrase is a well-established and validated target though less explored for the development of novel antimicrobial agents. Starting from the available structural information in PDB (3TTZ), we identified a novel series of benzimidazole used as inhibitors of DNA gyraseB with low micromolar inhibitory activity by employing structure-based drug design strategy. Subsequently, this chemical class of DNA gyrase inhibitors was extensively investigated biologically through in vitro assays, biofilm inhibition assays, cytotoxicity, and in vivo studies. The binding affinity of the most potent inhibitor 10 was further ascertained biophysically through differential scanning fluorimetry. Further, the most potent analogues did not show any signs of cardiotoxicity in Zebra fish ether-a-go-go-related gene (zERG), a major breakthrough among the previously reported cardiotoxic gyraseB inhibitors.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase-mediated relaxed pBR322 DNA supercoiling by gel electrophoresis
|
Mycobacterium tuberculosis
|
15.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : 2-Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against Mycobacterium tuberculosis.
Year : 2014
Volume : 5
Issue : 9
First Page : 1005
Last Page : 1009
Authors : Naik M, Ghorpade S, Jena LK, Gorai G, Narayan A, Guptha S, Sharma S, Dinesh N, Kaur P, Nandishaiah R, Bhat J, Balakrishnan G, Humnabadkar V, Ramachandran V, Naviri LK, Khadtare P, Panda M, Iyer PS, Chatterji M.
Abstract : A cellular activity-based screen on Mycobacterium tuberculosis (Mtb) H37Rv using a focused library from the AstraZeneca corporate collection led to the identification of 2-phenylindoles and arylsulphonamides, novel antimycobacterial scaffolds. Both the series were bactericidal in vitro and in an intracellular macrophage infection model, active against drug sensitive and drug resistant Mtb clinical isolates, and specific to mycobacteria. The scaffolds showed promising structure-activity relationships; compounds with submicromolar cellular potency were identified during the hit to lead exploration. Furthermore, compounds from both scaffolds were tested for inhibition of known target enzymes or pathways of antimycobacterial drugs including InhA, RNA polymerase, DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation. Compounds did not inhibit any of the targets suggesting the potential of a possible novel mode of action(s). Hence, both scaffolds provide the opportunity to be developed further as leads and tool compounds to uncover novel mechanisms for tuberculosis drug discovery.
|
Cytotoxicity against mouse RAW264.7 cells at 100 uM after 48 hrs by MTT assay
|
Mus musculus
|
29.44
%
|
|
Journal : Eur. J. Med. Chem.
Title : Extending the N-linked aminopiperidine class to the mycobacterial gyrase domain: pharmacophore mapping from known antibacterial leads.
Year : 2014
Volume : 85
First Page : 593
Last Page : 604
Authors : Bobesh KA, Renuka J, Jeankumar VU, Shruti SK, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 μM, and not cytotoxic at 50 μM in eukaryotic cell line.
|
Inhibition of Mycobacterium tuberculosis GyrA/GyrB using relaxed pBR322 as substrate at 0.97 uM after 30 mins by DNA supercoiling assay
|
Mycobacterium tuberculosis
|
61.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Extending the N-linked aminopiperidine class to the mycobacterial gyrase domain: pharmacophore mapping from known antibacterial leads.
Year : 2014
Volume : 85
First Page : 593
Last Page : 604
Authors : Bobesh KA, Renuka J, Jeankumar VU, Shruti SK, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 μM, and not cytotoxic at 50 μM in eukaryotic cell line.
|
Inhibition of 6-His-tagged Mycobacterium smegmatis GyrB expressed in Escherichia coli BL21 (DE3) pLysS cells incubated for 100 mins in presence of ATP by malachite green dye based ATP assay
|
Mycobacterium smegmatis
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis.
Year : 2014
Volume : 22
Issue : 17
First Page : 4924
Last Page : 4934
Authors : Renuka J, Reddy KI, Srihari K, Jeankumar VU, Shravan M, Sridevi JP, Yogeeswari P, Babu KS, Sriram D.
Abstract : DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase and is a well-established and validated target for the development of novel therapeutics. By adapting the medium throughput screening approach, we present the discovery and optimization of ethyl 5-(piperazin-1-yl) benzofuran-2-carboxylate series of mycobacterial DNA gyraseB inhibitors, selected from Birla Institute of Technology and Science (BITS) database chemical library of about 3000 molecules. These compounds were tested for their biological activity; the compound 22 emerged as the most active potent lead with an IC50 of 3.2±0.15μM against Mycobacterium smegmatis DNA gyraseB enzyme and 0.81±0.24μM in MTB supercoiling activity. Subsequently, the binding of the most active compound to the DNA gyraseB enzyme and its thermal stability was further characterized using differential scanning fluorimetry method.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase supercoiling activity using relaxed pBR322 substrate incubated for 30 mins by ethidium bromide staining method
|
Mycobacterium tuberculosis
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis.
Year : 2014
Volume : 22
Issue : 17
First Page : 4924
Last Page : 4934
Authors : Renuka J, Reddy KI, Srihari K, Jeankumar VU, Shravan M, Sridevi JP, Yogeeswari P, Babu KS, Sriram D.
Abstract : DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase and is a well-established and validated target for the development of novel therapeutics. By adapting the medium throughput screening approach, we present the discovery and optimization of ethyl 5-(piperazin-1-yl) benzofuran-2-carboxylate series of mycobacterial DNA gyraseB inhibitors, selected from Birla Institute of Technology and Science (BITS) database chemical library of about 3000 molecules. These compounds were tested for their biological activity; the compound 22 emerged as the most active potent lead with an IC50 of 3.2±0.15μM against Mycobacterium smegmatis DNA gyraseB enzyme and 0.81±0.24μM in MTB supercoiling activity. Subsequently, the binding of the most active compound to the DNA gyraseB enzyme and its thermal stability was further characterized using differential scanning fluorimetry method.
|
Cytotoxicity against mouse RAW264.7 cells assessed as inhibition of cell viability at 100 uM after 48 hrs by MTT assay
|
Mus musculus
|
19.36
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis.
Year : 2014
Volume : 22
Issue : 17
First Page : 4924
Last Page : 4934
Authors : Renuka J, Reddy KI, Srihari K, Jeankumar VU, Shravan M, Sridevi JP, Yogeeswari P, Babu KS, Sriram D.
Abstract : DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase and is a well-established and validated target for the development of novel therapeutics. By adapting the medium throughput screening approach, we present the discovery and optimization of ethyl 5-(piperazin-1-yl) benzofuran-2-carboxylate series of mycobacterial DNA gyraseB inhibitors, selected from Birla Institute of Technology and Science (BITS) database chemical library of about 3000 molecules. These compounds were tested for their biological activity; the compound 22 emerged as the most active potent lead with an IC50 of 3.2±0.15μM against Mycobacterium smegmatis DNA gyraseB enzyme and 0.81±0.24μM in MTB supercoiling activity. Subsequently, the binding of the most active compound to the DNA gyraseB enzyme and its thermal stability was further characterized using differential scanning fluorimetry method.
|
Inhibition of Mycobacterium tuberculosis DNA GyrA/B heterotetramer assessed as inhibition of pBR322 supercoiling after 30 mins by gel electrophoresis
|
Mycobacterium tuberculosis
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Development of 2-amino-5-phenylthiophene-3-carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain.
Year : 2015
Volume : 23
Issue : 7
First Page : 1402
Last Page : 1412
Authors : Saxena S, Samala G, Renuka J, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis (Mtb), unlike other bacteria and its absence in human being makes it a clinically validated target for developing anti-tubercular leads against Mtb. In the present study, our effort was to optimize and synthesize a series of compounds by a combination of molecular docking, and synthetic chemistry approach for better activity. A series of twenty eight substituted 2-amino-5-phenylthiophene-3-carboxamide derivatives were designed based on our earlier reported Mtb GyrB inhibitor lead. Hit expansion of the previously identified lead by chemical synthesis led to improved inhibitor with an IC50 value of 0.86±0.81μM against Mtb DNA gyrase supercoiling and Mycobacterium smegmatis GyrB IC50 of 1.35±0.58μM. Further a biophysical investigation using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain.
|
Inhibition of Mycobacterium smegmatis DNA GyrB domain assessed as inhibition of inorganic phosphate release after 100 mins at room temperature by ATPase assay
|
Mycobacterium smegmatis
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Development of 2-amino-5-phenylthiophene-3-carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain.
Year : 2015
Volume : 23
Issue : 7
First Page : 1402
Last Page : 1412
Authors : Saxena S, Samala G, Renuka J, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis (Mtb), unlike other bacteria and its absence in human being makes it a clinically validated target for developing anti-tubercular leads against Mtb. In the present study, our effort was to optimize and synthesize a series of compounds by a combination of molecular docking, and synthetic chemistry approach for better activity. A series of twenty eight substituted 2-amino-5-phenylthiophene-3-carboxamide derivatives were designed based on our earlier reported Mtb GyrB inhibitor lead. Hit expansion of the previously identified lead by chemical synthesis led to improved inhibitor with an IC50 value of 0.86±0.81μM against Mtb DNA gyrase supercoiling and Mycobacterium smegmatis GyrB IC50 of 1.35±0.58μM. Further a biophysical investigation using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain.
|
Cytotoxicity against mouse RAW264.7 cells at 100 uM after 48 hrs by MTT assay
|
Mus musculus
|
81.67
%
|
|
Journal : Bioorg. Med. Chem.
Title : Development of 2-amino-5-phenylthiophene-3-carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain.
Year : 2015
Volume : 23
Issue : 7
First Page : 1402
Last Page : 1412
Authors : Saxena S, Samala G, Renuka J, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : DNA gyrase is the only type II topoisomerase in Mycobacterium tuberculosis (Mtb), unlike other bacteria and its absence in human being makes it a clinically validated target for developing anti-tubercular leads against Mtb. In the present study, our effort was to optimize and synthesize a series of compounds by a combination of molecular docking, and synthetic chemistry approach for better activity. A series of twenty eight substituted 2-amino-5-phenylthiophene-3-carboxamide derivatives were designed based on our earlier reported Mtb GyrB inhibitor lead. Hit expansion of the previously identified lead by chemical synthesis led to improved inhibitor with an IC50 value of 0.86±0.81μM against Mtb DNA gyrase supercoiling and Mycobacterium smegmatis GyrB IC50 of 1.35±0.58μM. Further a biophysical investigation using differential scanning fluorimetry experiments re-ascertained the affinity of these molecules towards the GyrB domain.
|
Inhibition of Mycobacterium smegmatis GyrB ATPase activity expressed in Escherichia coli BL21 (DE3) pLysS cells after 100 mins by inorganic phosphate release detection based malachite green reagent assay
|
Mycobacterium smegmatis
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of novel quinoline-aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors.
Year : 2015
Volume : 23
Issue : 9
First Page : 2062
Last Page : 2078
Authors : Medapi B, Renuka J, Saxena S, Sridevi JP, Medishetti R, Kulkarni P, Yogeeswari P, Sriram D.
Abstract : Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today's battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well-established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline-aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2-methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC₅₀ of 0.95 ± 0.12 μM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC₅₀ of 0.62 ± 0.16 μM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a-go-go-related gene (zERG).
|
Inhibition of Mycobacterium tuberculosis GyrA/GyrB using relaxed pBR322 substrate incubated for 30 mins by ethidium bromide staining and electrophoresis based DNA supercoiling assay
|
Mycobacterium tuberculosis
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design and synthesis of novel quinoline-aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors.
Year : 2015
Volume : 23
Issue : 9
First Page : 2062
Last Page : 2078
Authors : Medapi B, Renuka J, Saxena S, Sridevi JP, Medishetti R, Kulkarni P, Yogeeswari P, Sriram D.
Abstract : Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today's battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well-established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline-aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2-methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC₅₀ of 0.95 ± 0.12 μM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC₅₀ of 0.62 ± 0.16 μM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a-go-go-related gene (zERG).
|
Inhibition of Escherichia coli DNA Gyrase ATPase activity assessed as reduction in conversion of NADH to NAD+ using linear pBR322 substrate
|
Escherichia coli
|
130.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.
Year : 2015
Volume : 58
Issue : 14
First Page : 5501
Last Page : 5521
Authors : Tomašič T, Katsamakas S, Hodnik Ž, Ilaš J, Brvar M, Solmajer T, Montalvão S, Tammela P, Banjanac M, Ergović G, Anderluh M, Peterlin Mašič L, Kikelj D.
Abstract : Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
|
Inhibition of Escherichia coli DNA gyrase using relaxed pNO1 plasmid and biotinylated oligonucelotide incubated for 30 mins by fluorescence based DNA super-coiling assay
|
Escherichia coli
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.
Year : 2015
Volume : 58
Issue : 14
First Page : 5501
Last Page : 5521
Authors : Tomašič T, Katsamakas S, Hodnik Ž, Ilaš J, Brvar M, Solmajer T, Montalvão S, Tammela P, Banjanac M, Ergović G, Anderluh M, Peterlin Mašič L, Kikelj D.
Abstract : Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
|
Inhibition of Staphylococcus aureus DNA gyrase using relaxed pNO1 plasmid and biotinylated oligonucelotide incubated for 30 mins by fluorescence based DNA super-coiling assay
|
Staphylococcus aureus
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.
Year : 2015
Volume : 58
Issue : 14
First Page : 5501
Last Page : 5521
Authors : Tomašič T, Katsamakas S, Hodnik Ž, Ilaš J, Brvar M, Solmajer T, Montalvão S, Tammela P, Banjanac M, Ergović G, Anderluh M, Peterlin Mašič L, Kikelj D.
Abstract : Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
|
Inhibition of Staphylococcus aureus DNA gyrase using relaxed pBR322 DNA as substrate after 3 hrs by DNA super-coiling assay
|
Staphylococcus aureus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.
Year : 2015
Volume : 58
Issue : 14
First Page : 5501
Last Page : 5521
Authors : Tomašič T, Katsamakas S, Hodnik Ž, Ilaš J, Brvar M, Solmajer T, Montalvão S, Tammela P, Banjanac M, Ergović G, Anderluh M, Peterlin Mašič L, Kikelj D.
Abstract : Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
|
Inhibition of Escherichia coli DNA gyrase using relaxed pBR322 DNA as substrate after 3 hrs by DNA super-coiling assay
|
Escherichia coli
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.
Year : 2015
Volume : 58
Issue : 14
First Page : 5501
Last Page : 5521
Authors : Tomašič T, Katsamakas S, Hodnik Ž, Ilaš J, Brvar M, Solmajer T, Montalvão S, Tammela P, Banjanac M, Ergović G, Anderluh M, Peterlin Mašič L, Kikelj D.
Abstract : Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
|
Inhibition of Mycobacterium smegmatis DNA gyrase B expressed in Escherichia coli BL21 (DE3) pLysS cells assessed as reduction in ATPase activity incubated for 100 mins by inorganic phosphate detection assay
|
Mycobacterium smegmatis
|
180.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation.
Year : 2015
Volume : 103
First Page : 1
Last Page : 16
Authors : Medapi B, Suryadevara P, Renuka J, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of antitubercular drug discovery. In the present study, we employed structural optimization of the reported GyrB inhibitor resulting in synthesis of a series of 46 novel quinoline derivatives. The compounds were evaluated for their in vitro Mycobacterium smegmatis GyrB inhibitory ability and Mycobacterium tuberculosis DNA supercoiling inhibitory activity. The antitubercular activity of these compounds was tested over Mtb H37Rv strain and their safety profile was checked against mouse macrophage RAW 264.7 cell line. Among all, three compounds (23, 28, and 53) emerged to be active displaying IC₅₀ values below 1 μM against Msm GyrB and were found to be non-cytotoxic at 50 μM concentration. Compound 53 was identified to be potent GyrB inhibitor with 0.86 ± 0.16 μM and an MIC (minimum inhibitory concentration) of 3.3 μM. The binding affinity of this compound towards GyrB protein was analysed by differential scanning fluorimetry which resulted in a positive shift of 3.3 °C in melting temperature (Tm) when compared to the native protein thereby reacertaining the stabilization effect of the compound over protein.
|
Inhibition of DNA gyrase GyrA/GyrB in Mycobacterium tuberculosis incubated for 30 mins assessed as reduction in supercoiling of relaxed relaxed pBR322 DNA by ethidium bromide staining based agarose gel electrophoresis method
|
Mycobacterium tuberculosis
|
46.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : 4-Aminoquinoline derivatives as novel Mycobacterium tuberculosis GyrB inhibitors: Structural optimization, synthesis and biological evaluation.
Year : 2015
Volume : 103
First Page : 1
Last Page : 16
Authors : Medapi B, Suryadevara P, Renuka J, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of antitubercular drug discovery. In the present study, we employed structural optimization of the reported GyrB inhibitor resulting in synthesis of a series of 46 novel quinoline derivatives. The compounds were evaluated for their in vitro Mycobacterium smegmatis GyrB inhibitory ability and Mycobacterium tuberculosis DNA supercoiling inhibitory activity. The antitubercular activity of these compounds was tested over Mtb H37Rv strain and their safety profile was checked against mouse macrophage RAW 264.7 cell line. Among all, three compounds (23, 28, and 53) emerged to be active displaying IC₅₀ values below 1 μM against Msm GyrB and were found to be non-cytotoxic at 50 μM concentration. Compound 53 was identified to be potent GyrB inhibitor with 0.86 ± 0.16 μM and an MIC (minimum inhibitory concentration) of 3.3 μM. The binding affinity of this compound towards GyrB protein was analysed by differential scanning fluorimetry which resulted in a positive shift of 3.3 °C in melting temperature (Tm) when compared to the native protein thereby reacertaining the stabilization effect of the compound over protein.
|
Cytotoxicity against mouse RAW264.7 cells at 50 uM after 48 hrs by MTT assay
|
Mus musculus
|
19.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Replacement of cardiotoxic aminopiperidine linker with piperazine moiety reduces cardiotoxicity? Mycobacterium tuberculosis novel bacterial topoisomerase inhibitors.
Year : 2016
Volume : 24
Issue : 1
First Page : 42
Last Page : 52
Authors : Bobesh KA, Renuka J, Srilakshmi RR, Yellanki S, Kulkarni P, Yogeeswari P, Sriram D.
Abstract : Recently numerous non-fluoroquinolone-based bacterial type II topoisomerase inhibitors from both the GyrA and GyrB classes have been reported as antibacterial agents. Inhibitors of the GyrA class include aminopiperidine-based novel bacterial type II topoisomerase inhibitors (NBTIs). However, inhibition of the cardiac ion channel remains a serious liability for the aminopiperidine based NBTIs. In this paper we replaced central aminopiperidine linker with piperazine moiety and tested for its biological activity. We developed a series of twenty four compounds with a piperazine linker 1-(2-(piperazin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one, by following a multistep protocol. Among them compound 4-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)-N-(4-nitrophenyl)piperazine-1-carboxamide (11) was the most promising inhibitor with Mycobacterium tuberculosis (MTB) DNA gyrase enzyme supercoiling IC50 of 0.29±0.22μM, with a good MTB MIC of 3.45μM. These kind of compounds retains good potency and showed reduced cardiotoxicity compared to aminopiperidines.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase assessed as inhibition of DNA supercoiling after 30 mins by electrophoresis
|
Mycobacterium tuberculosis
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Development of acridine derivatives as selective Mycobacterium tuberculosis DNA gyrase inhibitors.
Year : 2016
Volume : 24
Issue : 4
First Page : 877
Last Page : 885
Authors : Medapi B, Meda N, Kulkarni P, Yogeeswari P, Sriram D.
Abstract : In this study we have designed p-phenylene diamine linked acridine derivative from our earlier reported quinoline-aminopiperidine hybrid MTB DNA gyrase inhibitors with aiming more potency and less cardiotoxicity. We synthesized thirty six compounds using four step synthesis from 2-chloro benzoic acid. Among them compound 4-chloro-N-(4-((2-methylacridin-9-yl)amino)phenyl)benzenesulphonamide (6) was found to be more potent with MTB DNA gyrase super coiling IC50 of 5.21±0.51μM; MTB MIC of 6.59μM and no zHERG cardiotoxicity at 30μM and 11.78% inhibition at 50μM against mouse macrophage cell line RAW 264.7.
|
Inhibition of Escherichia coli DNA gyrase assessed as supercoiling of relaxed pNO1 plasmid after 30 mins by SybrGOLD staining based fluorescence assay
|
Escherichia coli
|
168.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase.
Year : 2016
Volume : 117
First Page : 197
Last Page : 211
Authors : Zidar N, Tomašič T, Macut H, Sirc A, Brvar M, Montalvão S, Tammela P, Ilaš J, Kikelj D.
Abstract : Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
|
Inhibition of Staphylococcus aureus DNA gyrase assessed as supercoiling of relaxed pNO1 plasmid after 30 mins by SybrGOLD staining based fluorescence assay
|
Staphylococcus aureus
|
41.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase.
Year : 2016
Volume : 117
First Page : 197
Last Page : 211
Authors : Zidar N, Tomašič T, Macut H, Sirc A, Brvar M, Montalvão S, Tammela P, Ilaš J, Kikelj D.
Abstract : Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
|
Binding affinity to Escherichia coli DNA gyrase B by surface plasmon resonance assay
|
Escherichia coli
|
28.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase.
Year : 2016
Volume : 117
First Page : 197
Last Page : 211
Authors : Zidar N, Tomašič T, Macut H, Sirc A, Brvar M, Montalvão S, Tammela P, Ilaš J, Kikelj D.
Abstract : Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
|
Inhibition of Escherichia coli DNA gyrase assessed as supercoiling of relaxed pBR322 plasmid after 45 mins by ethidium bromide staining based agarose gel electrophoresis
|
Escherichia coli
|
80.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase.
Year : 2016
Volume : 117
First Page : 197
Last Page : 211
Authors : Zidar N, Tomašič T, Macut H, Sirc A, Brvar M, Montalvão S, Tammela P, Ilaš J, Kikelj D.
Abstract : Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
|
Inhibition of Staphylococcus aureus DNA gyrase assessed as supercoiling of relaxed pBR322 plasmid after 45 mins by ethidium bromide staining based agarose gel electrophoresis
|
Staphylococcus aureus
|
10.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase.
Year : 2016
Volume : 117
First Page : 197
Last Page : 211
Authors : Zidar N, Tomašič T, Macut H, Sirc A, Brvar M, Montalvão S, Tammela P, Ilaš J, Kikelj D.
Abstract : Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
|
Binding affinity to Escherichia coli DNA gyrase B
|
Escherichia coli
|
19.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New N-phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATPase inhibitors of DNA gyrase.
Year : 2016
Volume : 117
First Page : 197
Last Page : 211
Authors : Zidar N, Tomašič T, Macut H, Sirc A, Brvar M, Montalvão S, Tammela P, Ilaš J, Kikelj D.
Abstract : Following the withdrawal of novobiocin, the introduction of a new ATPase inhibitor of DNA gyrase to the clinic would add the first representative of this mechanistic class to the antibacterial pipeline. This would be of great importance because of the well-known problems associated with antibacterial resistance. Using structure-based design and starting from the recently determined crystal structure of the N-phenyl-4,5-dibromopyrrolamide inhibitor-DNA gyrase B complex, we have prepared 28 new N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides and evaluated them against DNA gyrase from Escherichia coli. The most potent compound was 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a), with an IC50 of 0.18 μM against E. coli gyrase. A selected set of compounds was evaluated against DNA gyrase from Staphylococcus aureus and against topoisomerase IV from E. coli and S. aureus, but the activities were weaker. The binding affinity of 2-((4-(4,5-dibromo-1H-pyrrole-2-carboxamido)phenyl)amino)-2-oxoacetic acid (9a) to E. coli gyrase was studied using surface plasmon resonance. In the design of the present series, the focus was on the optimisation of biological activities of compounds - especially by varying their size, the position and orientation of key functional groups, and their acid-base properties. The structure-activity relationship (SAR) was examined and the results were rationalised with molecular docking.
|
Inhibition of Escherichia coli DNA gyrase B ATP binding site assessed as reduction in supercoiling of relaxed pNO1 DNA after 30 mins in presence of biotinylated oligonucleotide by sybrGOLD staining based fluorescence assay
|
Escherichia coli
|
170.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors.
Year : 2016
Volume : 59
Issue : 19
First Page : 8941
Last Page : 8954
Authors : Gjorgjieva M, Tomašič T, Barančokova M, Katsamakas S, Ilaš J, Tammela P, Peterlin Mašič L, Kikelj D.
Abstract : Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV from both E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATP-binding pocket. Only some compounds possessed weak antibacterial activity against Gram-positive bacteria. These results provide a basis for structure-based optimization toward dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
|
Inhibition of Staphylococcus aureus DNA gyrase B ATP binding site assessed as reduction in supercoiling of relaxed pNO1 DNA after 30 mins in presence of biotinylated oligonucleotide by sybrGOLD staining based fluorescence assay
|
Staphylococcus aureus
|
40.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Benzothiazole Scaffold-Based DNA Gyrase B Inhibitors.
Year : 2016
Volume : 59
Issue : 19
First Page : 8941
Last Page : 8954
Authors : Gjorgjieva M, Tomašič T, Barančokova M, Katsamakas S, Ilaš J, Tammela P, Peterlin Mašič L, Kikelj D.
Abstract : Bacterial DNA gyrase and topoisomerase IV control the topological state of DNA during replication and are validated targets for antibacterial drug discovery. Starting from our recently reported 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-based DNA gyrase B inhibitors, we replaced their central core with benzothiazole-2,6-diamine scaffold and interchanged substituents in positions 2 and 6. This resulted in equipotent nanomolar inhibitors of DNA gyrase from Escherichia coli displaying improved inhibition of Staphylococcus aureus DNA gyrase and topoisomerase IV from both bacteria. Compound 27 was the most balanced inhibitor of DNA gyrase and topoisomerase IV from both E. coli and S. aureus. The crystal structure of the 2-((2-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzothiazol-6-yl)amino)-2-oxoacetic acid (24) in complex with E. coli DNA gyrase B revealed the binding mode of the inhibitor in the ATP-binding pocket. Only some compounds possessed weak antibacterial activity against Gram-positive bacteria. These results provide a basis for structure-based optimization toward dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.
|
Inhibition of Mycobacterium smegmatis 155 6His-tagged DNA gyrase B catalytic domain ATPase activity expressed in Escherichia coli BL21 (DE3) pLysS cells assessed as inorganic phosphate release after 120 mins in presence of ATP by malachite green dye based assay
|
Mycobacterium smegmatis str. MC2 155
|
46.0
nM
|
|
Journal : Eur J Med Chem
Title : Engineering another class of anti-tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors.
Year : 2016
Volume : 122
First Page : 216
Last Page : 231
Authors : Jeankumar VU, Reshma RS, Vats R, Janupally R, Saxena S, Yogeeswari P, Sriram D.
Abstract : A structure based medium throughput virtual screening campaign of BITS-Pilani in house chemical library to identify novel binders of Mycobacterium tuberculosis gyrase ATPase domain led to the discovery of a quinoline scaffold. Further medicinal chemistry explorations on the right hand core of the early hit, engendered a potent lead demonstrating superior efficacy both in the enzyme and whole cell screening assay. The binding affinity shown at the enzyme level was further corroborated by biophysical characterization techniques. Early pharmacokinetic evaluation of the optimized analogue was encouraging and provides interesting potential for further optimization.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase subunit A2B2 supercoiling activity using relaxed pBR322 as substrate after 30 mins in presence of ATP by agarose gel electrophoresis
|
Mycobacterium tuberculosis
|
180.0
nM
|
|
Journal : Eur J Med Chem
Title : Engineering another class of anti-tubercular lead: Hit to lead optimization of an intriguing class of gyrase ATPase inhibitors.
Year : 2016
Volume : 122
First Page : 216
Last Page : 231
Authors : Jeankumar VU, Reshma RS, Vats R, Janupally R, Saxena S, Yogeeswari P, Sriram D.
Abstract : A structure based medium throughput virtual screening campaign of BITS-Pilani in house chemical library to identify novel binders of Mycobacterium tuberculosis gyrase ATPase domain led to the discovery of a quinoline scaffold. Further medicinal chemistry explorations on the right hand core of the early hit, engendered a potent lead demonstrating superior efficacy both in the enzyme and whole cell screening assay. The binding affinity shown at the enzyme level was further corroborated by biophysical characterization techniques. Early pharmacokinetic evaluation of the optimized analogue was encouraging and provides interesting potential for further optimization.
|
Inhibition of Escherichia coli DNA gyrase supercoiling activity using relaxed pNO1 as substrate after 30 mins in presence of biotin-labeled oligonucleotide and ATP by SybrGOLD staining based fluorescence assay
|
Escherichia coli
|
170.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 4,5-dibromo-N-(thiazol-2-yl)-1H-pyrrole-2-carboxamide derivatives as novel DNA gyrase inhibitors.
Year : 2017
Volume : 25
Issue : 1
First Page : 338
Last Page : 349
Authors : Tomašič T, Mirt M, Barančoková M, Ilaš J, Zidar N, Tammela P, Kikelj D.
Abstract : Development of novel DNA gyrase B inhibitors is an important field of antibacterial drug discovery whose aim is to introduce a more effective representative of this mechanistic class into the clinic. In the present study, two new series of Escherichia coli DNA gyrase inhibitors bearing the 4,5-dibromopyrrolamide moiety have been designed and synthesized. 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole-2,6-diamine derivatives inhibited E. coli DNA gyrase in the submicromolar to low micromolar range (IC50 values between 0.891 and 10.4μM). Their "ring-opened" analogues, based on the 2-(2-aminothiazol-4-yl)acetic acid scaffold, displayed weaker DNA gyrase inhibition with IC50 values between 15.9 and 169μM. Molecular docking experiments were conducted to study the binding modes of inhibitors.
|
Binding affinity to Escherichia coli H560 DNA gyrase B
|
Escherichia coli
|
7.0
nM
|
|
Journal : Eur J Med Chem
Title : Mycobacterium Tuberculosis (MTB) GyrB inhibitors: An attractive approach for developing novel drugs against TB.
Year : 2016
Volume : 124
First Page : 160
Last Page : 185
Authors : Chaudhari K, Surana S, Jain P, Patel HM.
Abstract : New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance (MDR and XDR) to existing agents and shorten the duration of therapy. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. In the present review, we discussed the synthesis, structural optimization and docking study of effective potent DNA gyrase inhibitor against M. tuberculosis, with improved properties such as enhanced activity against MDR strains, reduced toxicity. Based on this progress, if we can successfully leverage the opportunities in this target, there is hope that we will be able to raise novel gyrase inhibitor in earnest in the long.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase assessed as inhibition of DNA supercoiling activity using relaxed pBR322 as substrate incubated for 30 mins by ethidium bromide staining based agarose gel electrophoresis
|
Mycobacterium tuberculosis
|
46.0
nM
|
|
Journal : Eur J Med Chem
Title : Mycobacterium Tuberculosis (MTB) GyrB inhibitors: An attractive approach for developing novel drugs against TB.
Year : 2016
Volume : 124
First Page : 160
Last Page : 185
Authors : Chaudhari K, Surana S, Jain P, Patel HM.
Abstract : New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance (MDR and XDR) to existing agents and shorten the duration of therapy. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. In the present review, we discussed the synthesis, structural optimization and docking study of effective potent DNA gyrase inhibitor against M. tuberculosis, with improved properties such as enhanced activity against MDR strains, reduced toxicity. Based on this progress, if we can successfully leverage the opportunities in this target, there is hope that we will be able to raise novel gyrase inhibitor in earnest in the long.
|
Inhibition of Escherichia coli H560 DNA gyrase B ATPase activity after 30 mins by ammonium molybdate/malachite green-based phosphate detection assay
|
Escherichia coli
|
7.0
nM
|
|
Journal : Eur J Med Chem
Title : Mycobacterium Tuberculosis (MTB) GyrB inhibitors: An attractive approach for developing novel drugs against TB.
Year : 2016
Volume : 124
First Page : 160
Last Page : 185
Authors : Chaudhari K, Surana S, Jain P, Patel HM.
Abstract : New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance (MDR and XDR) to existing agents and shorten the duration of therapy. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. In the present review, we discussed the synthesis, structural optimization and docking study of effective potent DNA gyrase inhibitor against M. tuberculosis, with improved properties such as enhanced activity against MDR strains, reduced toxicity. Based on this progress, if we can successfully leverage the opportunities in this target, there is hope that we will be able to raise novel gyrase inhibitor in earnest in the long.
|
Cytotoxicity against mouse RAW264.7 cells assessed as inhibition of cell viability at 100 uM measured after 48 hrs by MTT assay relative to control
|
Mus musculus
|
7.56
%
|
|
Journal : Eur J Med Chem
Title : Mycobacterium Tuberculosis (MTB) GyrB inhibitors: An attractive approach for developing novel drugs against TB.
Year : 2016
Volume : 124
First Page : 160
Last Page : 185
Authors : Chaudhari K, Surana S, Jain P, Patel HM.
Abstract : New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance (MDR and XDR) to existing agents and shorten the duration of therapy. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. In the present review, we discussed the synthesis, structural optimization and docking study of effective potent DNA gyrase inhibitor against M. tuberculosis, with improved properties such as enhanced activity against MDR strains, reduced toxicity. Based on this progress, if we can successfully leverage the opportunities in this target, there is hope that we will be able to raise novel gyrase inhibitor in earnest in the long.
|
Inhibition of human DNA topoisomerase-2alpha ATPase activity at 400 uM using supercoiled pBR322 DNA as substrate after 1 hr by malachite green dye based assay relative to control
|
Homo sapiens
|
55.9
%
|
|
Journal : Eur J Med Chem
Title : Novel 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridines as potent DNA non-intercalative topoisomerase catalytic inhibitors.
Year : 2017
Volume : 125
First Page : 14
Last Page : 28
Authors : Park S, Kadayat TM, Jun KY, Thapa Magar TB, Bist G, Shrestha A, Lee ES, Kwon Y.
Abstract : On the basis of previous reports on the importance of thienyl, furyl or phenol group substitution on 5H-indeno[1,2-b]pyridine skeleton, a new series of rigid 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridine derivatives were systematically designed and synthesized. Topoisomerase inhibitory activity and antiproliferative activity of all the synthesized compounds were determined using human colorectal (HCT15), breast (T47D), prostate (DU145) and cervix (HeLa) cancer cells. Compounds 9, 10, 12, 13, 15, 16, 18 and 19 with thienyl or furyl moiety at the 2-position and hydroxyl group at the meta or para positions of 4-phenyl ring displayed strong to moderate topoisomerase IIα (topo IIα) inhibitory activity and significant antiproliferative activity. The evaluation of compound 16 to determine its mechanism of action was performed with topo IIα-DNA cleavable complex, topo IIα-mediated ATPase assay, DNA unwinding and in vitro and ex vivo topo IIα relaxation assay. Compound 16 functioned as a DNA non-intercalative topo IIα catalytic inhibitor with better potency than etoposide in T47D breast cancer cells. Molecular docking study revealed that compound 16 cannot intercalate into regularly stacked base-pairs of DNA duplex but can interact or intercalate to topo IIα-bound DNA.
|
Inhibition of human DNA topoisomerase-2alpha ATPase activity at 300 uM using supercoiled pBR322 DNA as substrate after 1 hr by malachite green dye based assay relative to control
|
Homo sapiens
|
33.3
%
|
|
Journal : Eur J Med Chem
Title : Novel 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridines as potent DNA non-intercalative topoisomerase catalytic inhibitors.
Year : 2017
Volume : 125
First Page : 14
Last Page : 28
Authors : Park S, Kadayat TM, Jun KY, Thapa Magar TB, Bist G, Shrestha A, Lee ES, Kwon Y.
Abstract : On the basis of previous reports on the importance of thienyl, furyl or phenol group substitution on 5H-indeno[1,2-b]pyridine skeleton, a new series of rigid 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridine derivatives were systematically designed and synthesized. Topoisomerase inhibitory activity and antiproliferative activity of all the synthesized compounds were determined using human colorectal (HCT15), breast (T47D), prostate (DU145) and cervix (HeLa) cancer cells. Compounds 9, 10, 12, 13, 15, 16, 18 and 19 with thienyl or furyl moiety at the 2-position and hydroxyl group at the meta or para positions of 4-phenyl ring displayed strong to moderate topoisomerase IIα (topo IIα) inhibitory activity and significant antiproliferative activity. The evaluation of compound 16 to determine its mechanism of action was performed with topo IIα-DNA cleavable complex, topo IIα-mediated ATPase assay, DNA unwinding and in vitro and ex vivo topo IIα relaxation assay. Compound 16 functioned as a DNA non-intercalative topo IIα catalytic inhibitor with better potency than etoposide in T47D breast cancer cells. Molecular docking study revealed that compound 16 cannot intercalate into regularly stacked base-pairs of DNA duplex but can interact or intercalate to topo IIα-bound DNA.
|
Inhibition of human DNA topoisomerase-2alpha ATPase activity at 200 uM using supercoiled pBR322 DNA as substrate after 1 hr by malachite green dye based assay relative to control
|
Homo sapiens
|
22.7
%
|
|
Journal : Eur J Med Chem
Title : Novel 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridines as potent DNA non-intercalative topoisomerase catalytic inhibitors.
Year : 2017
Volume : 125
First Page : 14
Last Page : 28
Authors : Park S, Kadayat TM, Jun KY, Thapa Magar TB, Bist G, Shrestha A, Lee ES, Kwon Y.
Abstract : On the basis of previous reports on the importance of thienyl, furyl or phenol group substitution on 5H-indeno[1,2-b]pyridine skeleton, a new series of rigid 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridine derivatives were systematically designed and synthesized. Topoisomerase inhibitory activity and antiproliferative activity of all the synthesized compounds were determined using human colorectal (HCT15), breast (T47D), prostate (DU145) and cervix (HeLa) cancer cells. Compounds 9, 10, 12, 13, 15, 16, 18 and 19 with thienyl or furyl moiety at the 2-position and hydroxyl group at the meta or para positions of 4-phenyl ring displayed strong to moderate topoisomerase IIα (topo IIα) inhibitory activity and significant antiproliferative activity. The evaluation of compound 16 to determine its mechanism of action was performed with topo IIα-DNA cleavable complex, topo IIα-mediated ATPase assay, DNA unwinding and in vitro and ex vivo topo IIα relaxation assay. Compound 16 functioned as a DNA non-intercalative topo IIα catalytic inhibitor with better potency than etoposide in T47D breast cancer cells. Molecular docking study revealed that compound 16 cannot intercalate into regularly stacked base-pairs of DNA duplex but can interact or intercalate to topo IIα-bound DNA.
|
Inhibition of Escherichia coli DNA gyrase A/DNA gyrase B supercoiling activity using relaxed pNO1 DNA as substrate after 30 mins in presence of biotin-labeled oligonucleotide by SybrGOLD staining based fluorescence assay
|
Escherichia coli
|
170.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors.
Year : 2017
Volume : 130
First Page : 171
Last Page : 184
Authors : Jakopin Ž, Ilaš J, Barančoková M, Brvar M, Tammela P, Sollner Dolenc M, Tomašič T, Kikelj D.
Abstract : DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 μM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Gram-positive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 μM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV.
|
Inhibition of Staphylococcus aureus DNA gyrase A/DNA gyrase B supercoiling activity using relaxed pNO1 DNA as substrate after 30 mins in presence of biotin-labeled oligonucleotide by SybrGOLD staining based fluorescence assay
|
Staphylococcus aureus
|
41.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors.
Year : 2017
Volume : 130
First Page : 171
Last Page : 184
Authors : Jakopin Ž, Ilaš J, Barančoková M, Brvar M, Tammela P, Sollner Dolenc M, Tomašič T, Kikelj D.
Abstract : DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 μM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Gram-positive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 μM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV.
|
Inhibition of Escherichia coli DNA gyrase supercoiling activity using relaxed pBR322 DNA as substrate after 45 mins by ethidium-bromide staining based agarose gel electrophoresis
|
Escherichia coli
|
80.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors.
Year : 2017
Volume : 130
First Page : 171
Last Page : 184
Authors : Jakopin Ž, Ilaš J, Barančoková M, Brvar M, Tammela P, Sollner Dolenc M, Tomašič T, Kikelj D.
Abstract : DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 μM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Gram-positive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 μM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV.
|
Inhibition of Staphylococcus aureus DNA gyrase supercoiling activity using relaxed pBR322 DNA as substrate after 45 mins by ethidium-bromide staining based agarose gel electrophoresis
|
Staphylococcus aureus
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors.
Year : 2017
Volume : 130
First Page : 171
Last Page : 184
Authors : Jakopin Ž, Ilaš J, Barančoková M, Brvar M, Tammela P, Sollner Dolenc M, Tomašič T, Kikelj D.
Abstract : DNA gyrase and topoisomerase IV are type IIa topoisomerases that are essential bacterial enzymes required to oversee the topological state of DNA during transcription and replication processes. Their ATPase domains, GyrB and ParE, respectively, are recognized as viable targets for small molecule inhibitors, however, no synthetic or natural product GyrB/ParE inhibitors have so far reached the clinic for use as novel antibacterial agents, except for novobiocin which was withdrawn from the market. In the present study, a series of substituted oxadiazoles have been designed and synthesized as potential DNA gyrase inhibitors. Structure-based optimization resulted in the identification of compound 35, displaying an IC50 of 1.2 μM for Escherichia coli DNA gyrase, while also exhibiting a balanced low micromolar inhibition of E. coli topoisomerase IV and of the respective Staphylococcus aureus homologues. The most promising inhibitors identified from each series were ultimately evaluated against selected Gram-positive and Gram-negative bacterial strains, of which compound 35 inhibited Enterococcus faecalis with a MIC90 of 75 μM. Our study thus provides further insight into the structural requirements of substituted oxadiazoles for dual inhibition of DNA gyrase and topoisomerase IV.
|
Inhibition of bacterial DNA gyrase subunit B
|
Bacteria
|
80.0
nM
|
|
Journal : J Med Chem
Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.
Year : 2018
Volume : 61
Issue : 6
First Page : 2166
Last Page : 2210
Authors : Talele TT.
Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.
|
Inhibition of Escherichia coli ATCC 25922 DNA gyrase B using relaxed pNO1 DNA as substrate incubated for 30 mins and measured by sybrGOLD staining based fluorescence assay
|
Escherichia coli ATCC 25922
|
170.0
nM
|
|
Journal : Eur J Med Chem
Title : Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B.
Year : 2017
Volume : 125
First Page : 500
Last Page : 514
Authors : Jukič M, Ilaš J, Brvar M, Kikelj D, Cesar J, Anderluh M.
Abstract : Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp3-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC50 value of 16 and 0.5 μM respectively.
|
Inhibition of Staphylococcus aureus DNA gyrase B using relaxed pNO1 DNA as substrate incubated for 30 mins and measured by sybrGOLD staining based fluorescence assay
|
Staphylococcus aureus
|
41.0
nM
|
|
Journal : Eur J Med Chem
Title : Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B.
Year : 2017
Volume : 125
First Page : 500
Last Page : 514
Authors : Jukič M, Ilaš J, Brvar M, Kikelj D, Cesar J, Anderluh M.
Abstract : Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp3-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC50 value of 16 and 0.5 μM respectively.
|
Inhibition of Escherichia coli DNA gyrase using relaxed pBR322 DNA as substrate after 3 hrs by agarose electrophoresis
|
Escherichia coli
|
80.0
nM
|
|
Journal : Eur J Med Chem
Title : Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B.
Year : 2017
Volume : 125
First Page : 500
Last Page : 514
Authors : Jukič M, Ilaš J, Brvar M, Kikelj D, Cesar J, Anderluh M.
Abstract : Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp3-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC50 value of 16 and 0.5 μM respectively.
|
Inhibition of Staphylococcus aureus DNA gyrase using relaxed pBR322 DNA as substrate after 3 hrs by agarose electrophoresis
|
Staphylococcus aureus
|
10.0
nM
|
|
Journal : Eur J Med Chem
Title : Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B.
Year : 2017
Volume : 125
First Page : 500
Last Page : 514
Authors : Jukič M, Ilaš J, Brvar M, Kikelj D, Cesar J, Anderluh M.
Abstract : Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp3-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC50 value of 16 and 0.5 μM respectively.
|
Inhibition of human DNA topoisomerase 2 ATPase activity at 200 mM by Topo-2 ATPase assay
|
Homo sapiens
|
38.54
%
|
|
Journal : Bioorg Med Chem
Title : Recent synthetic and medicinal perspectives of tryptanthrin.
Year : 2017
Volume : 25
Issue : 17
First Page : 4533
Last Page : 4552
Authors : Kaur R, Manjal SK, Rawal RK, Kumar K.
Abstract : Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities.
|
Inhibition of human DNA topoisomerase 2 ATPase activity at 400 mM by Topo-2 ATPase assay
|
Homo sapiens
|
60.23
%
|
|
Journal : Bioorg Med Chem
Title : Recent synthetic and medicinal perspectives of tryptanthrin.
Year : 2017
Volume : 25
Issue : 17
First Page : 4533
Last Page : 4552
Authors : Kaur R, Manjal SK, Rawal RK, Kumar K.
Abstract : Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities.
|
Inhibition of human DNA topoisomerase 2 ATPase activity at 300 mM by Topo-2 ATPase assay
|
Homo sapiens
|
45.86
%
|
|
Journal : Bioorg Med Chem
Title : Recent synthetic and medicinal perspectives of tryptanthrin.
Year : 2017
Volume : 25
Issue : 17
First Page : 4533
Last Page : 4552
Authors : Kaur R, Manjal SK, Rawal RK, Kumar K.
Abstract : Tryptanthrin is a natural alkaloidal compound having basic indoloquinazoline moiety. It is obtained from various natural plant sources as well as different cell cultures including yeast etc. Trptanthrin is considered as biogenetic precursor for phaitanthrin A-C, pyrroloindoloquinazoline, (±)-cruciferane. Different synthetic approaches for the synthesis of tryptanthrin have been very well reported. It has broad spectrum of biological activities including anticancer activity, anti-inflammatory, antiprotozoal, antiallergic, antioxidant, and antimicrobial. In this review, our focus will be, on the various approaches for the synthesis of tryptanthrins and its derivatives along with the biological activities.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase supercoiling activity using relaxed pBR322 as substrate at 10 uM after 30 mins in presence of ATP by ethidium bromide staining based agarose gel electrophoresis relative to control
|
Mycobacterium tuberculosis
|
100.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Three-component, one-pot synthesis of anthranilamide Schiff bases bearing 4-aminoquinoline moiety as Mycobacterium tuberculosis gyrase inhibitors.
Year : 2017
Volume : 27
Issue : 8
First Page : 1859
Last Page : 1866
Authors : Salve PS, Alegaon SG, Sriram D.
Abstract : An efficient three-component, one-pot protocol is described for the synthesis of biologically interesting 2-(benzylideneamino)-N-(7-chloroquinolin-4-yl)benzohydrazide derivatives from isatoic anhydride, 7-chloro-4-hydrazinylquinoline and aromatic and/or hetero aromatic aldehydes under catalyst free condensation by using water as reaction media. All synthesized compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (MTB) and cytotoxicity activity against normal VERO cell lines. The synthesized compounds exhibited minimum inhibitory concentration (MIC) ranging from 0.78 to 25μM. Among the tested compounds 4c, 4o, 4r, and 4u exhibited promising inhibitory activity (MIC=3.12μM). Compounds 4h and 4i stand out, showing MIC values of 0.78 and 1.56μM respectively. Both compounds were further screened for their Mycobacterium tuberculosis DNA gyrase inhibitory assay which suggested that these compounds have a great potential for further optimization and development as antitubercular agents.
|
Inhibition of Staphylococcus aureus N-terminal His6-tagged DNA gyrase subunit GyrA/GyrB supercoiling activity expressed in Escherichia coli BL21 (DE3) using relaxed pBR322 DNA as substrate after 1 hr by agarose gel electrophoresis
|
Staphylococcus aureus
|
125.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.
Year : 2017
Volume : 60
Issue : 9
First Page : 3755
Last Page : 3775
Authors : Panchaud P, Bruyère T, Blumstein AC, Bur D, Chambovey A, Ertel EA, Gude M, Hubschwerlen C, Jacob L, Kimmerlin T, Pfeifer T, Prade L, Seiler P, Ritz D, Rueedi G.
Abstract : Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.
|
Inhibition of fluoroquinolone-resistant Staphylococcus aureus clinical isolate DNA gyrase subunit GyrB/GyrA S84L mutant supercoiling activity using relaxed pBR322 DNA as substrate after 1 hr by agarose gel electrophoresis
|
Staphylococcus aureus
|
30.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.
Year : 2017
Volume : 60
Issue : 9
First Page : 3755
Last Page : 3775
Authors : Panchaud P, Bruyère T, Blumstein AC, Bur D, Chambovey A, Ertel EA, Gude M, Hubschwerlen C, Jacob L, Kimmerlin T, Pfeifer T, Prade L, Seiler P, Ritz D, Rueedi G.
Abstract : Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.
|
Inhibition of fluoroquinolone-resistant Streptococcus pneumoniae A-70 clinical isolate DNA gyrase subunit GyrB/GyrA S81F mutant supercoiling activity using relaxed pBR322 DNA as substrate after 1 hr mins by agarose gel electrophoresis
|
Streptococcus pneumoniae
|
500.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.
Year : 2017
Volume : 60
Issue : 9
First Page : 3755
Last Page : 3775
Authors : Panchaud P, Bruyère T, Blumstein AC, Bur D, Chambovey A, Ertel EA, Gude M, Hubschwerlen C, Jacob L, Kimmerlin T, Pfeifer T, Prade L, Seiler P, Ritz D, Rueedi G.
Abstract : Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.
|
Inhibition of Haemophilus influenzae DNA gyrase subunit GyrA/GyrB supercoiling activity expressed in Escherichia coli BL21 (DE3) using relaxed pBR322 DNA as substrate after 1 hr mins by agarose gel electrophoresis
|
Haemophilus influenzae
|
500.0
nM
|
|
Journal : J Med Chem
Title : Discovery and Optimization of Isoquinoline Ethyl Ureas as Antibacterial Agents.
Year : 2017
Volume : 60
Issue : 9
First Page : 3755
Last Page : 3775
Authors : Panchaud P, Bruyère T, Blumstein AC, Bur D, Chambovey A, Ertel EA, Gude M, Hubschwerlen C, Jacob L, Kimmerlin T, Pfeifer T, Prade L, Seiler P, Ritz D, Rueedi G.
Abstract : Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.
|
Inhibition of Escherichia coli C-terminal His6-tagged DNA gyrase B expressed in Escherichia coli BL21(DE3) preincubated for 10 mins followed by ATP addition measured after 30 mins by purine nucleoside phosphorylase enzyme coupled spectrophotometric method
|
Escherichia coli
|
170.0
nM
|
|
Journal : Eur J Med Chem
Title : New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity.
Year : 2018
Volume : 154
First Page : 117
Last Page : 132
Authors : Durcik M, Lovison D, Skok Ž, Durante Cruz C, Tammela P, Tomašič T, Benedetto Tiz D, Draskovits G, Nyerges Á, Pál C, Ilaš J, Peterlin Mašič L, Kikelj D, Zidar N.
Abstract : The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 μM against Enterococcus faecalis, and 3.13 μM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 μM.
|
Inhibition of Staphylococcus aureus DNA gyrase B preincubated for 10 mins followed by ATP addition measured after 30 mins by purine nucleoside phosphorylase enzyme coupled spectrophotometric method
|
Staphylococcus aureus
|
41.0
nM
|
|
Journal : Eur J Med Chem
Title : New N-phenylpyrrolamide DNA gyrase B inhibitors: Optimization of efficacy and antibacterial activity.
Year : 2018
Volume : 154
First Page : 117
Last Page : 132
Authors : Durcik M, Lovison D, Skok Ž, Durante Cruz C, Tammela P, Tomašič T, Benedetto Tiz D, Draskovits G, Nyerges Á, Pál C, Ilaš J, Peterlin Mašič L, Kikelj D, Zidar N.
Abstract : The ATP binding site located on the subunit B of DNA gyrase is an attractive target for the development of new antibacterial agents. In recent decades, several small-molecule inhibitor classes have been discovered but none has so far reached the market. We present here the discovery of a promising new series of N-phenylpyrrolamides with low nanomolar IC50 values against DNA gyrase, and submicromolar IC50 values against topoisomerase IV from Escherichia coli and Staphylococcus aureus. The most potent compound in the series has an IC50 value of 13 nM against E. coli gyrase. Minimum inhibitory concentrations (MICs) against Gram-positive bacteria are in the low micromolar range. The oxadiazolone derivative 11a, with an IC50 value of 85 nM against E. coli DNA gyrase displays the most potent antibacterial activity, with MIC values of 1.56 μM against Enterococcus faecalis, and 3.13 μM against wild type S. aureus, methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). The activity against wild type E. coli in the presence of efflux pump inhibitor phenylalanine-arginine β-naphthylamide (PAβN) is 4.6 μM.
|
Cytotoxicity against human HepG2 cells after 24 hrs by CellTiter-Glo assay
|
Homo sapiens
|
32.0
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase.
Year : 2018
Volume : 28
Issue : 17
First Page : 2998
Last Page : 3003
Authors : McGarry DH, Cooper IR, Walker R, Warrilow CE, Pichowicz M, Ratcliffe AJ, Salisbury AM, Savage VJ, Moyo E, Maclean J, Smith A, Charrier C, Stokes NR, Lindsay DM, Kerr WJ.
Abstract : According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase activity
|
Mycobacterium tuberculosis
|
85.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase.
Year : 2018
Volume : 28
Issue : 17
First Page : 2998
Last Page : 3003
Authors : McGarry DH, Cooper IR, Walker R, Warrilow CE, Pichowicz M, Ratcliffe AJ, Salisbury AM, Savage VJ, Moyo E, Maclean J, Smith A, Charrier C, Stokes NR, Lindsay DM, Kerr WJ.
Abstract : According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase ATPase activity
|
Mycobacterium tuberculosis
|
20.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and antibacterial properties of pyrimido[4,5-b]indol-8-amine inhibitors of DNA gyrase.
Year : 2018
Volume : 28
Issue : 17
First Page : 2998
Last Page : 3003
Authors : McGarry DH, Cooper IR, Walker R, Warrilow CE, Pichowicz M, Ratcliffe AJ, Salisbury AM, Savage VJ, Moyo E, Maclean J, Smith A, Charrier C, Stokes NR, Lindsay DM, Kerr WJ.
Abstract : According to the World Health Organization (WHO), approximately 1.7 million deaths per year are caused by tuberculosis infections. Furthermore, it has been predicted that, by 2050, antibacterial resistance will be the cause of approximately 10 million deaths annually if the issue is not tackled. As a result, novel approaches to treating broad-spectrum bacterial infections are of vital importance. During the course of our wider efforts to discover unique methods of targeting multidrug-resistant (MDR) pathogens, we identified a novel series of amide-linked pyrimido[4,5-b]indol-8-amine inhibitors of bacterial type II topoisomerases. Compounds from the series were highly potent against gram-positive bacteria and mycobacteria, with excellent potency being retained against a panel of relevant Mycobacterium tuberculosis drug-resistant clinical isolates.
|
Inhibition of Escherichia coli DNA gyrase assessed as inhibition of pUC19 supercoiling after 30 mins by agarose gel electrophoresis
|
Escherichia coli
|
144.0
nM
|
|
Journal : MedChemComm
Title : Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase.
Year : 2017
Volume : 8
Issue : 5
First Page : 942
Last Page : 951
Authors : Hurley KA, Santos TMA, Fensterwald MR, Rajendran M, Moore JT, Balmond EI, Blahnik BJ, Faulkner KC, Foss MH, Heinrich VA, Lammers MG, Moore LC, Reynolds GD, Shearn-Nance GP, Stearns BA, Yao ZW, Shaw JT, Weibel DB.
Abstract : Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs-from a library of 183 derivatives-that are potent inhibitors of DNA gyrase and are active against clinical strains of gram-negative bacteria (<i>Escherichia coli</i>, <i>Shigella flexneri</i>, and <i>Salmonella enterica;</i> 3 of 10 wild-type strains tested) and gram-positive bacteria (<i>Bacillus spp.</i>, <i>Enterococcus spp.</i>, <i>Staphylococcus spp.</i>, and <i>Streptococcus spp.</i>; all 9 of the wild-type strains tested). <i>E. coli</i> strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC<sub>50</sub>s of 47-170 nM) but do not alter the enzyme's ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (<i>gyrA</i> and <i>gyrB</i> genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.
|
Inhibition of Escherichia coli DNA gyrase ATPase activity using DNA as substrate after 60 mins
|
Escherichia coli
|
245.0
nM
|
|
Journal : MedChemComm
Title : Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase.
Year : 2017
Volume : 8
Issue : 5
First Page : 942
Last Page : 951
Authors : Hurley KA, Santos TMA, Fensterwald MR, Rajendran M, Moore JT, Balmond EI, Blahnik BJ, Faulkner KC, Foss MH, Heinrich VA, Lammers MG, Moore LC, Reynolds GD, Shearn-Nance GP, Stearns BA, Yao ZW, Shaw JT, Weibel DB.
Abstract : Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs-from a library of 183 derivatives-that are potent inhibitors of DNA gyrase and are active against clinical strains of gram-negative bacteria (<i>Escherichia coli</i>, <i>Shigella flexneri</i>, and <i>Salmonella enterica;</i> 3 of 10 wild-type strains tested) and gram-positive bacteria (<i>Bacillus spp.</i>, <i>Enterococcus spp.</i>, <i>Staphylococcus spp.</i>, and <i>Streptococcus spp.</i>; all 9 of the wild-type strains tested). <i>E. coli</i> strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC<sub>50</sub>s of 47-170 nM) but do not alter the enzyme's ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (<i>gyrA</i> and <i>gyrB</i> genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.
|
Inhibition of Escherichia coli DNA topoisomerase-2 mediated DNA relaxation using supercoiled pBR322 plasmid DNA as substrate after 60 mins by ethidium bromide staining based agarose gel electrophoresis
|
Escherichia coli
|
0.5
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Novel coumarin-pyrazole carboxamide derivatives as potential topoisomerase II inhibitors: Design, synthesis and antibacterial activity.
Year : 2018
Volume : 157
First Page : 81
Last Page : 87
Authors : Liu H, Ren ZL, Wang W, Gong JX, Chu MJ, Ma QW, Wang JC, Lv XH.
Abstract : The identification of novel Topoisomerase II (Topo II) inhibitors is one of the most attractive directions in the field of bactericide research and development. In our ongoing efforts to pursue the class of inhibitors, six series of 70 novel coumarin-pyrazole carboxamide derivatives were designed and synthesized. As a result of the evaluation against four destructive bacteria, including Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8III-k (MIC = 0.25 mg/L) showed considerable inhibitory activity than ciprofloxacin (MIC = 0.5 mg/L) against Escherichia coli and 8V-c (MIC = 0.05 mg/L) exhibited excellent antibacterial activity than ciprofloxacin (MIC = 0.25 mg/L) against Salmonella. The selected compounds (8III-k, 8V-c and 8V-k) exhibit potent inhibition against Topo II and Topo IV with IC50 values (9.4-25 mg/L). Molecular docking model showed that the compounds 8V-c and 8V-k can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial Topo II inhibiting bactericides.
|
Inhibition of Escherichia coli DNA topoisomerase-4 mediated decatenation using kinetoplast DNA as substrate after 30 mins agarose gel electrophoresis method
|
Escherichia coli
|
4.0
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Novel coumarin-pyrazole carboxamide derivatives as potential topoisomerase II inhibitors: Design, synthesis and antibacterial activity.
Year : 2018
Volume : 157
First Page : 81
Last Page : 87
Authors : Liu H, Ren ZL, Wang W, Gong JX, Chu MJ, Ma QW, Wang JC, Lv XH.
Abstract : The identification of novel Topoisomerase II (Topo II) inhibitors is one of the most attractive directions in the field of bactericide research and development. In our ongoing efforts to pursue the class of inhibitors, six series of 70 novel coumarin-pyrazole carboxamide derivatives were designed and synthesized. As a result of the evaluation against four destructive bacteria, including Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8III-k (MIC = 0.25 mg/L) showed considerable inhibitory activity than ciprofloxacin (MIC = 0.5 mg/L) against Escherichia coli and 8V-c (MIC = 0.05 mg/L) exhibited excellent antibacterial activity than ciprofloxacin (MIC = 0.25 mg/L) against Salmonella. The selected compounds (8III-k, 8V-c and 8V-k) exhibit potent inhibition against Topo II and Topo IV with IC50 values (9.4-25 mg/L). Molecular docking model showed that the compounds 8V-c and 8V-k can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial Topo II inhibiting bactericides.
|
Inhibition of Staphylococcus aureus DNA gyrase supercoiling activity using relaxed pHOT-1 DNA as substrate after 60 mins by ethidium bromide-based gel electrophoresis
|
Staphylococcus aureus
|
40.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Novel DNA Gyrase-Inhibiting Spiropyrimidinetriones as Potent Antibiotics for Treatment of Infections Caused by Multidrug-Resistant Gram-Positive Bacteria.
Year : 2019
Volume : 62
Issue : 6
First Page : 2950
Last Page : 2973
Authors : Shi C, Zhang Y, Wang T, Lu W, Zhang S, Guo B, Chen Q, Luo C, Zhou X, Yang Y.
Abstract : Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX0914, we carried out systematic structural modification of this compound, and a number of compounds with increased potency were obtained. The most promising compound 33e, with incorporation of a spirocyclopropane at the oxazolidinone 5 position reduced metabolism, exhibited excellent antibacterial activity against Gram-positive pathogens and a good pharmacokinetic profile combined with high aqueous solubility. In addition, compound 33e exhibited good selectivity for Staphylococcus aureus gyrase over human Topo IIα. In a murine model of systemic methicillin-resistant S. aureus infection, 33e exhibited superior in vivo efficacy (ED50 = 3.87 mg/kg) compared to ETX0914 (ED50 = 11.51 mg/kg).
|
Inhibition of NS2B-NS3 protease in Zika virus Puerto Rico/PRVABC5 infected in African green monkey Vero cells assessed as antiviral activity measured 48 hrs post infection by RT-PCR method
|
Zika virus
|
15.21
ug.mL-1
|
|
Journal : J Med Chem
Title : Drugs for the Treatment of Zika Virus Infection.
Year : 2020
Volume : 63
Issue : 2
First Page : 470
Last Page : 489
Authors : Bernatchez JA, Tran LT, Li J, Luan Y, Siqueira-Neto JL, Li R.
Abstract : Zika virus is an emerging flavivirus that causes the neurodevelopmental congenital Zika syndrome and that has been linked to the neuroinflammatory Guillain-Barré syndrome. The absence of a vaccine or a clinically approved drug to treat the disease combined with the likelihood that another outbreak will occur in the future defines an unmet medical need. Several promising drug candidate molecules have been reported via repurposing studies, high-throughput compound library screening, and de novo design in the short span of a few years. Intense research activity in this area has occurred in response to the World Health Organization declaration of a Public Health Emergency of International Concern on February 1, 2016. In this Perspective, the authors review the emergence of Zika virus, the biology of its replication, targets for therapeutic intervention, target product profile, and current drug development initiatives.
|
Inhibition of NS2B-NS3 protease in Zika virus Puerto Rico/PRVABC5 infected in human Huh7 cells assessed as antiviral activity measured 48 hrs post infection by RT-PCR method
|
Zika virus
|
15.21
ug.mL-1
|
|
Journal : J Med Chem
Title : Drugs for the Treatment of Zika Virus Infection.
Year : 2020
Volume : 63
Issue : 2
First Page : 470
Last Page : 489
Authors : Bernatchez JA, Tran LT, Li J, Luan Y, Siqueira-Neto JL, Li R.
Abstract : Zika virus is an emerging flavivirus that causes the neurodevelopmental congenital Zika syndrome and that has been linked to the neuroinflammatory Guillain-Barré syndrome. The absence of a vaccine or a clinically approved drug to treat the disease combined with the likelihood that another outbreak will occur in the future defines an unmet medical need. Several promising drug candidate molecules have been reported via repurposing studies, high-throughput compound library screening, and de novo design in the short span of a few years. Intense research activity in this area has occurred in response to the World Health Organization declaration of a Public Health Emergency of International Concern on February 1, 2016. In this Perspective, the authors review the emergence of Zika virus, the biology of its replication, targets for therapeutic intervention, target product profile, and current drug development initiatives.
|
Inhibition of NS2B-NS3 protease in Zika virus Puerto Rico/PRVABC5 assessed as antiviral activity measured 48 hrs post infection by plaque reduction assay
|
Zika virus
|
15.21
ug.mL-1
|
|
Journal : J Med Chem
Title : Drugs for the Treatment of Zika Virus Infection.
Year : 2020
Volume : 63
Issue : 2
First Page : 470
Last Page : 489
Authors : Bernatchez JA, Tran LT, Li J, Luan Y, Siqueira-Neto JL, Li R.
Abstract : Zika virus is an emerging flavivirus that causes the neurodevelopmental congenital Zika syndrome and that has been linked to the neuroinflammatory Guillain-Barré syndrome. The absence of a vaccine or a clinically approved drug to treat the disease combined with the likelihood that another outbreak will occur in the future defines an unmet medical need. Several promising drug candidate molecules have been reported via repurposing studies, high-throughput compound library screening, and de novo design in the short span of a few years. Intense research activity in this area has occurred in response to the World Health Organization declaration of a Public Health Emergency of International Concern on February 1, 2016. In this Perspective, the authors review the emergence of Zika virus, the biology of its replication, targets for therapeutic intervention, target product profile, and current drug development initiatives.
|
Inhibition of Escherichia coli DNA gyrase using relaxed pNO1 plasmid DNA as substrate incubated for 30 mins by fluorescence assay
|
Escherichia coli
|
170.0
nM
|
|
Journal : MedChemComm
Title : New <i>N</i>-phenyl-4,5-dibromopyrrolamides as DNA gyrase B inhibitors.
Year : 2019
Volume : 10
Issue : 6
First Page : 1007
Last Page : 1017
Authors : Zidar N, Macut H, Tomašič T, Peterlin Mašič L, Ilaš J, Zega A, Tammela P, Kikelj D.
Abstract : Due to the rapid development of antimicrobial resistance, the discovery of new antibacterials is essential in the fight against potentially lethal infections. The DNA gyrase B (GyrB) subunit of bacterial DNA gyrase is an excellent target for the design of antibacterials, as it has been clinically validated by novobiocin. However, there are currently no drugs in clinical use that target GyrB. We prepared a new series of <i>N</i>-phenyl-4,5-dibromopyrrolamides and evaluated them against DNA gyrase and against the structurally and functionally similar enzyme, topoisomerase IV. The most active compound, <b>28</b>, had an IC<sub>50</sub> of 20 nM against <i>Escherichia coli</i> DNA gyrase. The IC<sub>50</sub> values of <b>28</b> against <i>Staphylococcus aureus</i> DNA gyrase, and <i>E. coli</i> and <i>S. aureus</i> topoisomerase IV were in the low micromolar range. However, the compounds evaluated did not show significant antibacterial activities against selected Gram-positive and Gram-negative bacteria. Our results indicate that for potent inhibition of DNA gyrase, a combination of polar groups on the carboxylic end of the molecule and substituents that reach into the 'lipophilic floor' of the enzyme is required.
|
Inhibition of Staphylococcus aureus DNA gyrase using relaxed pNO1 plasmid DNA as substrate incubated for 30 mins by fluorescence assay
|
Staphylococcus aureus
|
41.0
nM
|
|
Journal : MedChemComm
Title : New <i>N</i>-phenyl-4,5-dibromopyrrolamides as DNA gyrase B inhibitors.
Year : 2019
Volume : 10
Issue : 6
First Page : 1007
Last Page : 1017
Authors : Zidar N, Macut H, Tomašič T, Peterlin Mašič L, Ilaš J, Zega A, Tammela P, Kikelj D.
Abstract : Due to the rapid development of antimicrobial resistance, the discovery of new antibacterials is essential in the fight against potentially lethal infections. The DNA gyrase B (GyrB) subunit of bacterial DNA gyrase is an excellent target for the design of antibacterials, as it has been clinically validated by novobiocin. However, there are currently no drugs in clinical use that target GyrB. We prepared a new series of <i>N</i>-phenyl-4,5-dibromopyrrolamides and evaluated them against DNA gyrase and against the structurally and functionally similar enzyme, topoisomerase IV. The most active compound, <b>28</b>, had an IC<sub>50</sub> of 20 nM against <i>Escherichia coli</i> DNA gyrase. The IC<sub>50</sub> values of <b>28</b> against <i>Staphylococcus aureus</i> DNA gyrase, and <i>E. coli</i> and <i>S. aureus</i> topoisomerase IV were in the low micromolar range. However, the compounds evaluated did not show significant antibacterial activities against selected Gram-positive and Gram-negative bacteria. Our results indicate that for potent inhibition of DNA gyrase, a combination of polar groups on the carboxylic end of the molecule and substituents that reach into the 'lipophilic floor' of the enzyme is required.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.53
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.03
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.03
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of Staphylococcus aureus DNA gyrase using biotinylated oligonucleotide as substrate incubated for 30 mins in presence of ATP by fluorescence-based microplate reader assay
|
Staphylococcus aureus
|
41.0
nM
|
|
Journal : Eur J Med Chem
Title : An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors.
Year : 2019
Volume : 167
First Page : 269
Last Page : 290
Authors : Tiz DB,Skok Ž,Durcik M,Tomašič T,Mašič LP,Ilaš J,Zega A,Draskovits G,Révész T,Nyerges Á,Pál C,Cruz CD,Tammela P,Žigon D,Kikelj D,Zidar N
Abstract : ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.
|
Inhibition of Escherichia coli DNA gyrase using biotinylated oligonucleotide as substrate incubated for 30 mins in presence of ATP by fluorescence-based microplate reader assay
|
Escherichia coli
|
170.0
nM
|
|
Journal : Eur J Med Chem
Title : An optimised series of substituted N-phenylpyrrolamides as DNA gyrase B inhibitors.
Year : 2019
Volume : 167
First Page : 269
Last Page : 290
Authors : Tiz DB,Skok Ž,Durcik M,Tomašič T,Mašič LP,Ilaš J,Zega A,Draskovits G,Révész T,Nyerges Á,Pál C,Cruz CD,Tammela P,Žigon D,Kikelj D,Zidar N
Abstract : ATP competitive inhibitors of DNA gyrase and topoisomerase IV have great therapeutic potential, but none of the described synthetic compounds has so far reached the market. To optimise the activities and physicochemical properties of our previously reported N-phenylpyrrolamide inhibitors, we have synthesized an improved, chemically variegated selection of compounds and evaluated them against DNA gyrase and topoisomerase IV enzymes, and against selected Gram-positive and Gram-negative bacteria. The most potent compound displayed IC values of 6.9 nM against Escherichia coli DNA gyrase and 960 nM against Staphylococcus aureus topoisomerase IV. Several compounds displayed minimum inhibitory concentrations (MICs) against Gram-positive strains in the 1-50 μM range, one of which inhibited the growth of Enterococcus faecalis, Enterococcus faecium, S. aureus and Streptococcus pyogenes with MIC values of 1.56 μM, 1.56 μM, 0.78 μM and 0.72 μM, respectively. This compound has been investigated further on methicillin-resistant S. aureus (MRSA) and on ciprofloxacin non-susceptible and extremely drug resistant strain of S. aureus (MRSA VISA). It exhibited the MIC value of 2.5 μM on both strains, and MIC value of 32 μM against MRSA in the presence of inactivated human blood serum. Further studies are needed to confirm its mode of action.
|
Inhibition of Escherichia coli DNA gyrase using relaxed pNO1 plasmid DNA as substrate incubated for 30 mins by fluorescence assay
|
Escherichia coli
|
168.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors.
Year : 2020
Volume : 11
Issue : 12.0
First Page : 2433
Last Page : 2440
Authors : Skok Ž,Barančoková M,Benek O,Cruz CD,Tammela P,Tomašič T,Zidar N,Mašič LP,Zega A,Stevenson CEM,Mundy JEA,Lawson DM,Maxwell A,Kikelj D,Ilaš J
Abstract : We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 μM), and efflux impaired E. coli strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.
|
Inhibition of Staphylococcus aureus DNA gyrase using relaxed pNO1 plasmid DNA as substrate incubated for 30 mins by fluorescence assay
|
Staphylococcus aureus
|
41.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Exploring the Chemical Space of Benzothiazole-Based DNA Gyrase B Inhibitors.
Year : 2020
Volume : 11
Issue : 12.0
First Page : 2433
Last Page : 2440
Authors : Skok Ž,Barančoková M,Benek O,Cruz CD,Tammela P,Tomašič T,Zidar N,Mašič LP,Zega A,Stevenson CEM,Mundy JEA,Lawson DM,Maxwell A,Kikelj D,Ilaš J
Abstract : We designed and synthesized a series of inhibitors of the bacterial enzymes DNA gyrase and DNA topoisomerase IV, based on our recently published benzothiazole-based inhibitor bearing an oxalyl moiety. To improve the antibacterial activity and retain potent enzymatic activity, we systematically explored the chemical space. Several strategies of modification were followed: varying substituents on the pyrrole carboxamide moiety, alteration of the central scaffold, including variation of substitution position and, most importantly, modification of the oxalyl moiety. Compounds with acidic, basic, and neutral properties were synthesized. To understand the mechanism of action and binding mode, we have obtained a crystal structure of compound 16a, bearing a primary amino group, in complex with the N-terminal domain of E. coli gyrase B (24 kDa) (PDB: 6YD9). Compound 15a, with a low molecular weight of 383 Da, potent inhibitory activity on E. coli gyrase (IC = 9.5 nM), potent antibacterial activity on E. faecalis (MIC = 3.13 μM), and efflux impaired E. coli strain (MIC = 0.78 μM), is an important contribution for the development of novel gyrase and topoisomerase IV inhibitors in Gram-negative bacteria.
|
Inhibition of Staphylococcus aureus Gyrase B using linear pBR322 DNA as substrate incubated for 30 mins in presence of ATP by ADP-Glo assay
|
Staphylococcus aureus
|
15.0
nM
|
|
Journal : Eur J Med Chem
Title : N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification.
Year : 2020
Volume : 188
First Page : 112022
Last Page : 112022
Authors : Xue W,Li X,Ma G,Zhang H,Chen Y,Kirchmair J,Xia J,Wu S
Abstract : Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 μg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25-1 μg/mL vs. 1-64 μg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6-155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.
|
Inhibition of Escherichia coli DNA gyrase by measuring supercoiling activity incubated for 60 mins by fluorescence based assay
|
Escherichia coli
|
23.88
nM
|
|
Journal : Bioorg Med Chem
Title : Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors.
Year : 2020
Volume : 28
Issue : 22
First Page : 115776
Last Page : 115776
Authors : Ushiyama F,Amada H,Mihara Y,Takeuchi T,Tanaka-Yamamoto N,Mima M,Kamitani M,Wada R,Tamura Y,Endo M,Masuko A,Takata I,Hitaka K,Sugiyama H,Ohtake N
Abstract : The global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 μg/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class.
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Inhibition of Escherichia coli topoisomerase IV by measuring relaxation activity incubated for 30 mins by fluorescence based assay
|
Escherichia coli
|
820.4
nM
|
|
Journal : Bioorg Med Chem
Title : Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors.
Year : 2020
Volume : 28
Issue : 22
First Page : 115776
Last Page : 115776
Authors : Ushiyama F,Amada H,Mihara Y,Takeuchi T,Tanaka-Yamamoto N,Mima M,Kamitani M,Wada R,Tamura Y,Endo M,Masuko A,Takata I,Hitaka K,Sugiyama H,Ohtake N
Abstract : The global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets. TP0480066 (compound 32) has been identified by using structure-based optimization originated from lead compound 1, which was obtained as a result of our previous lead identification studies. The MIC values of TP0480066 against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and genotype penicillin-resistant Streptococcus pneumoniae (gPRSP) were 0.25, 0.015, and 0.06 μg/mL, respectively. Hence, TP0480066 can be regarded as a promising antibacterial drug candidate of this chemical class.
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Inhibition of Escherichia coli DNA gyrase assessed as reduction in relaxation of supercoiled pNO1 DNA measured after 30 mins by fluorescence assay
|
Escherichia coli
|
170.0
nM
|
|
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Inhibition of Staphylococcus aureus DNA gyrase assessed reduction in relaxation of supercoiled pNO1 DNA measured after 30 mins by fluorescence assay
|
Staphylococcus aureus
|
34.0
nM
|
|
