|
Evaluated for inhibition of enoyl acyl carrier protein reductase (FabI) in Escherichia coli.
|
Escherichia coli
|
430.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 1,4-Disubstituted imidazoles are potential antibacterial agents functioning as inhibitors of enoyl acyl carrier protein reductase (FabI).
Year : 2001
Volume : 11
Issue : 16
First Page : 2061
Last Page : 2065
Authors : Heerding DA, Chan G, DeWolf WE, Fosberry AP, Janson CA, Jaworski DD, McManus E, Miller WH, Moore TD, Payne DJ, Qiu X, Rittenhouse SF, Slater-Radosti C, Smith W, Takata DT, Vaidya KS, Yuan CC, Huffman WF.
Abstract : 1,4-Disubstituted imidazole inhibitors of Staphylococcus aureus and Escherichia coli enoyl acyl carrier protein reductase (FabI) have been identified. Crystal structure data shows the inhibitor 1 bound in the enzyme active site of E. coli FabI.
|
Antibacterial activity against Escherichia coli FabI
|
Escherichia coli
|
430.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of bacterial enoyl acyl carrier protein reductase (FabI): 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as potential antibacterial agents.
Year : 2001
Volume : 11
Issue : 17
First Page : 2241
Last Page : 2244
Authors : Seefeld MA, Miller WH, Newlander KA, Burgess WJ, Payne DJ, Rittenhouse SF, Moore TD, DeWolf WE, Keller PM, Qiu X, Janson CA, Vaidya K, Fosberry AP, Smyth MG, Jaworski DD, Slater-Radosti C, Huffman WF.
Abstract : An SAR study of a screening lead has led to the identification of 2,9-disubstituted 1,2,3,4-tetrahydropyrido[3,4-b]indoles as inhibitors of Staphylococcus aureus enoyl acyl carrier protein reductase (FabI).
|
Inhibitory activity against Enoyl-ACP reductase FabI in Escherichia coli
|
Escherichia coli
|
430.0
nM
|
|
Journal : J. Med. Chem.
Title : Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.
Year : 2003
Volume : 46
Issue : 9
First Page : 1627
Last Page : 1635
Authors : Seefeld MA, Miller WH, Newlander KA, Burgess WJ, DeWolf WE, Elkins PA, Head MS, Jakas DR, Janson CA, Keller PM, Manley PJ, Moore TD, Payne DJ, Pearson S, Polizzi BJ, Qiu X, Rittenhouse SF, Uzinskas IN, Wallis NG, Huffman WF.
Abstract : Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
|
Inhibitory activity against Enoyl-ACP reductase FabI in Staphylococcus aureus
|
Staphylococcus aureus
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK.
Year : 2003
Volume : 46
Issue : 9
First Page : 1627
Last Page : 1635
Authors : Seefeld MA, Miller WH, Newlander KA, Burgess WJ, DeWolf WE, Elkins PA, Head MS, Jakas DR, Janson CA, Keller PM, Manley PJ, Moore TD, Payne DJ, Pearson S, Polizzi BJ, Qiu X, Rittenhouse SF, Uzinskas IN, Wallis NG, Huffman WF.
Abstract : Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via intraperitoneal (ip) administration. Through iterative medicinal chemistry aided by X-ray crystal structure analysis, a new series of inhibitors has been developed with greatly increased potency against FabI-containing organisms. Several of these new inhibitors have potent antibacterial activity against multidrug resistant strains of S. aureus, and compound 30 demonstrates exceptional oral (po) in vivo efficacy in a S. aureus infection model in rats. While optimizing FabI inhibitory activity, compounds 29 and 30 were identified as having low micromolar FabK inhibitory activity, thereby increasing the antimicrobial spectrum of these compounds to include the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis. The results described herein support the hypothesis that bacterial enoyl-ACP reductases are valid targets for antibacterial agents.
|
Concentration required for the 50% inhibition of enoyl-ACP reductase from Staphylococcus aureus was determined.
|
None
|
70.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of aminopyridine-based inhibitors of bacterial enoyl-ACP reductase (FabI).
Year : 2002
Volume : 45
Issue : 15
First Page : 3246
Last Page : 3256
Authors : Miller WH, Seefeld MA, Newlander KA, Uzinskas IN, Burgess WJ, Heerding DA, Yuan CC, Head MS, Payne DJ, Rittenhouse SF, Moore TD, Pearson SC, Berry V, DeWolf WE, Keller PM, Polizzi BJ, Qiu X, Janson CA, Huffman WF.
Abstract : Bacterial enoyl-ACP reductase (FabI) catalyzes the final step in each cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. Our efforts to identify potent, selective FabI inhibitors began with screening of the GlaxoSmithKline proprietary compound collection, which identified several small-molecule inhibitors of Staphylococcus aureus FabI. Through a combination of iterative medicinal chemistry and X-ray crystal structure based design, one of these leads was developed into the novel aminopyridine derivative 9, a low micromolar inhibitor of FabI from S. aureus (IC(50) = 2.4 microM) and Haemophilus influenzae (IC(50) = 4.2 microM). Compound 9 has good in vitro antibacterial activity against several organisms, including S. aureus (MIC = 0.5 microg/mL), and is effective in vivo in a S. aureus groin abscess infection model in rats. Through FabI overexpressor and macromolecular synthesis studies, the mode of action of 9 has been confirmed to be inhibition of fatty acid biosynthesis via inhibition of FabI. Taken together, these results support FabI as a valid antibacterial target and demonstrate the potential of small-molecule FabI inhibitors for the treatment of bacterial infections.
|
Inhibition of PfENR enzymatic activity
|
Plasmodium falciparum
|
73.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis, biological activity, and X-ray crystal structural analysis of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 1: 4'-substituted triclosan derivatives.
Year : 2005
Volume : 15
Issue : 23
First Page : 5247
Last Page : 5252
Authors : Freundlich JS, Anderson JW, Sarantakis D, Shieh HM, Yu M, Valderramos JC, Lucumi E, Kuo M, Jacobs WR, Fidock DA, Schiehser GA, Jacobus DP, Sacchettini JC.
Abstract : A structure-based approach has been taken to develop 4'-substituted analogs of triclosan that target the key malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of these compounds exhibit nanomolar potency against purified PfENR enzyme and modest (2-10microM) potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite. X-ray crystal structures of nitro 29, aniline 30, methylamide 37, and urea 46 demonstrate the presence of hydrogen-bonding interactions with residues in the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular parasites.
|
Inhibition of Plasmodium falciparum ENR enzymatic activity
|
Plasmodium falciparum
|
73.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological activity of diaryl ether inhibitors of malarial enoyl acyl carrier protein reductase. Part 2: 2'-substituted triclosan derivatives.
Year : 2006
Volume : 16
Issue : 8
First Page : 2163
Last Page : 2169
Authors : Freundlich JS, Yu M, Lucumi E, Kuo M, Tsai HC, Valderramos JC, Karagyozov L, Jacobs WR, Schiehser GA, Fidock DA, Jacobus DP, Sacchettini JC.
Abstract : 2'-Substituted analogs of triclosan have been synthesized to target inhibition of the key malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of these compounds exhibit good potency (EC50<500 nM) against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and modest (IC50=1-20 microM) potency against purified PfENR enzyme. Compared to triclosan, this survey of 2'-substituted derivatives has afforded gains in excess of 20- and 30-fold versus the 3D7 and Dd2 strains of parasite, respectively.
|
Inhibition of Plasmodium falciparum ENR by fluorescence quenching in presence of EGCG
|
Plasmodium falciparum
|
7.29
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR by fluorescence quenching in presence of ECG
|
Plasmodium falciparum
|
28.31
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR by fluorescence quenching in presence of EGC
|
Plasmodium falciparum
|
52.71
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR by fluorescence quenching in presence of quercetin
|
Plasmodium falciparum
|
30.54
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR by fluorescence quenching in presence of butein
|
Plasmodium falciparum
|
71.02
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of EGCG by dilution assay
|
Plasmodium falciparum
|
0.0019
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of EGC by dilution assay
|
Plasmodium falciparum
|
0.109
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of ECG by dilution assay
|
Plasmodium falciparum
|
0.05206
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of quercetin by dilution assay
|
Plasmodium falciparum
|
0.2806
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of butein by dilution assay
|
Plasmodium falciparum
|
0.7983
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of EGCG
|
Plasmodium falciparum
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of EGC
|
Plasmodium falciparum
|
8.25
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of ECG
|
Plasmodium falciparum
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of quercetin
|
Plasmodium falciparum
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Plasmodium falciparum ENR in presence of butein
|
Plasmodium falciparum
|
13.72
nM
|
|
Journal : J. Med. Chem.
Title : Green tea catechins potentiate triclosan binding to enoyl-ACP reductase from Plasmodium falciparum (PfENR).
Year : 2007
Volume : 50
Issue : 4
First Page : 765
Last Page : 775
Authors : Sharma SK, Parasuraman P, Kumar G, Surolia N, Surolia A.
Abstract : We have investigated the mechanism of inhibition of enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) by triclosan in the presence of a few important catechins and related plant polyphenols. The examined flavonoids inhibited PfENR reversibly with Ki values in the nanomolar range, EGCG being the best with 79 +/- 2.67 nM. The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. Additionally, all of them potentiated the binding of triclosan with PfENR by a two-step mechanism resulting in an overall inhibition constant of triclosan in the low picomolar concentration range. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The enhancement in the potency of triclosan induced by these compounds holds great promise for the development of effective antimalarial therapy.
|
Inhibition of Escherichia coli DH5-alpha His tagged Fab1
|
Escherichia coli
|
510.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 4-Pyridone derivatives as new inhibitors of bacterial enoyl-ACP reductase FabI.
Year : 2007
Volume : 15
Issue : 2
First Page : 1106
Last Page : 1116
Authors : Kitagawa H, Kumura K, Takahata S, Iida M, Atsumi K.
Abstract : Bacterial FAS provides essential fatty acids for use in the assembly of key cellular components. Among them, FabI is an enoyl-ACP reductase which catalyzes the final and rate-limiting step of bacterial FAS. It is a potential target for selective antibacterial action, because it shows low overall sequence homology with mammalian enzymes. Until today, various compounds have been reported as inhibitors of bacterial FabI-inhibitory compounds. To discover novel small-molecular FabI inhibitors, we initially screened our compound library for inhibitory activity toward FabI of Escherichia coli. And discovered 4-pyridone derivatives as a lead compound. Structure optimization studies yielded 4-pyridone derivatives 7n having strong FabI-inhibitory and antibacterial activities against Staphylococcus aureus. There have been no reports concerning 4-pyridone derivatives as FabI inhibitor.
|
Effect on Streptococcus mutans LMG 14558 assessed as inhibition of biofilm formation in modified Robbin's device at 5 ug/ml relative to BHIS control
|
Streptococcus mutans
|
78.13
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro inhibition of Streptococcus mutans biofilm formation on hydroxyapatite by subinhibitory concentrations of anthraquinones.
Year : 2007
Volume : 51
Issue : 4
First Page : 1541
Last Page : 1544
Authors : Coenye T, Honraet K, Rigole P, Nadal Jimenez P, Nelis HJ.
Abstract : We report that certain anthraquinones (AQs) reduce Streptococcus mutans biofilm formation on hydroxyapatite at concentrations below the MIC. Although AQs are known to generate reactive oxygen species, the latter do not underlie the observed effect. Our results suggest that AQs inhibit S. mutans biofilm formation by causing membrane perturbation.
|
Effect on Streptococcus mutans LMG 14558 assessed as inhibition of biofilm formation in modified Robbin's device at 1333 ug/ml relative to BHIS control
|
Streptococcus mutans
|
10.9
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : In vitro inhibition of Streptococcus mutans biofilm formation on hydroxyapatite by subinhibitory concentrations of anthraquinones.
Year : 2007
Volume : 51
Issue : 4
First Page : 1541
Last Page : 1544
Authors : Coenye T, Honraet K, Rigole P, Nadal Jimenez P, Nelis HJ.
Abstract : We report that certain anthraquinones (AQs) reduce Streptococcus mutans biofilm formation on hydroxyapatite at concentrations below the MIC. Although AQs are known to generate reactive oxygen species, the latter do not underlie the observed effect. Our results suggest that AQs inhibit S. mutans biofilm formation by causing membrane perturbation.
|
Inhibition of Plasmodium falciparum recombinant enoyl ACP reductase expressed in BL21 (DE3) cells
|
Plasmodium falciparum
|
66.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a rhodanine class of compounds as inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase.
Year : 2007
Volume : 50
Issue : 11
First Page : 2665
Last Page : 2675
Authors : Kumar G, Parasuraman P, Sharma SK, Banerjee T, Karmodiya K, Surolia N, Surolia A.
Abstract : Enoyl acyl carrier protein (ACP) reductase, one of the enzymes of the type II fatty acid biosynthesis pathway, has been established as a promising target for the development of new drugs for malaria. Here we present the discovery of a rhodanine (2-thioxothiazolidin-4-one) class of compounds as inhibitors of this enzyme using a combined approach of rational selection of compounds for screening, analogue search, docking studies, and lead optimization. The most potent inhibitor exhibits an IC(50) of 35.6 nM against Plasmodium falciparum enoyl ACP reductase (PfENR) and inhibits growth of the parasite in red blood cell cultures at an IC(50) value of 750 nM. Many more compounds of this class were found to inhibit PfENR at low nanomolar to low micromolar concentrations, expanding the scope for developing new antimalarial drugs. The structure-activity relationship of these rhodanine compounds is discussed.
|
Inhibition of Plasmodium falciparum recombinant enoyl ACP reductase expressed in BL21 (DE3) cells with respect to crotonyl CoA
|
Plasmodium falciparum
|
660.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a rhodanine class of compounds as inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase.
Year : 2007
Volume : 50
Issue : 11
First Page : 2665
Last Page : 2675
Authors : Kumar G, Parasuraman P, Sharma SK, Banerjee T, Karmodiya K, Surolia N, Surolia A.
Abstract : Enoyl acyl carrier protein (ACP) reductase, one of the enzymes of the type II fatty acid biosynthesis pathway, has been established as a promising target for the development of new drugs for malaria. Here we present the discovery of a rhodanine (2-thioxothiazolidin-4-one) class of compounds as inhibitors of this enzyme using a combined approach of rational selection of compounds for screening, analogue search, docking studies, and lead optimization. The most potent inhibitor exhibits an IC(50) of 35.6 nM against Plasmodium falciparum enoyl ACP reductase (PfENR) and inhibits growth of the parasite in red blood cell cultures at an IC(50) value of 750 nM. Many more compounds of this class were found to inhibit PfENR at low nanomolar to low micromolar concentrations, expanding the scope for developing new antimalarial drugs. The structure-activity relationship of these rhodanine compounds is discussed.
|
Inhibition of Escherichia coli FabI
|
Escherichia coli
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Phenylimidazole derivatives of 4-pyridone as dual inhibitors of bacterial enoyl-acyl carrier protein reductases FabI and FabK.
Year : 2007
Volume : 50
Issue : 19
First Page : 4710
Last Page : 4720
Authors : Kitagawa H, Ozawa T, Takahata S, Iida M, Saito J, Yamada M.
Abstract : FabI and FabK are bacterial enoyl-acyl carrier protein (ACP) reductases that catalyze the final and rate-limiting step of bacterial fatty acid biosynthesis (FAS) and are potential targets of novel antibacterial agents. We have reported 4-pyridone derivative 3 as a FabI inhibitor and phenylimidazole derivative 5 as a FabK inhibitor. Here, we will report phenylimidazole derivatives of 4-pyridone as FabI and FabK dual inhibitors based on an iterative medicinal chemistry and crystallographic study of FabK from Streptococcus pneumoniae/compound 26. A representative compound 6 showed strong FabI inhibitory (IC50 = 0.38 microM) and FabK inhibitory (IC50 = 0.0045 microM) activities with potent antibacterial activity against S. pneumoniae (MIC = 0.5 microg/mL). Since elevated MIC value was observed against S. pneumoniae mutant possessing one amino acid substitution in FabK, the antibacterial activity of the compound was considered to be due to the inhibition of FabK. Moreover, this compound showed no significant cytotoxicity (IC50 > 69 microM). These results support compound 6 as a novel agent for the treatment of bacterial infections.
|
Inhibition of Escherichia coli enoyl-ACP reductase FabI
|
Escherichia coli
|
900.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Phenylimidazole derivatives as specific inhibitors of bacterial enoyl-acyl carrier protein reductase FabK.
Year : 2007
Volume : 15
Issue : 23
First Page : 7325
Last Page : 7336
Authors : Ozawa T, Kitagawa H, Yamamoto Y, Takahata S, Iida M, Osaki Y, Yamada K.
Abstract : Bacterial enoyl-acyl carrier protein (ACP) reductases (FabI and FabK) catalyze the final step in each cycle of bacterial fatty acid biosynthesis and are attractive targets for the development of new antibacterial agents. Here, we report the development of novel FabK inhibitors with antibacterial activity against Streptococcus pneumoniae. Based on structure-activity relationship (SAR) studies of our screening hits, we have developed novel phenylimidazole derivatives as potent FabK inhibitors.
|
Inhibition of transthyretin fibril formation assessed as turbidity at 21.6 uM at pH 4.4 after 3 hrs
|
None
|
62.0
%
|
|
Journal : J. Med. Chem.
Title : Design of mechanism-based inhibitors of transthyretin amyloidosis: studies with biphenyl ethers and new structural templates.
Year : 2007
Volume : 50
Issue : 23
First Page : 5589
Last Page : 5599
Authors : Gupta S, Chhibber M, Sinha S, Surolia A.
Abstract : Transthyretin (TTR), a tetrameric thyroxine (T4) carrier protein, is associated with a variety of amyloid diseases. In this study, we explore the potential of biphenyl ethers (BPE), which are shown to interact with a high affinity to its T4 binding site thereby preventing its aggregation and fibrillogenesis. They prevent fibrillogenesis by stabilizing the tetrameric ground state of transthyretin. Additionally, we identify two new structural templates (2-(5-mercapto-[1,3,4]oxadiazol-2-yl)-phenol and 2,3,6-trichloro-N-(4H-[1,2,4]triazol-3-yl) represented as compounds 11 and 12, respectively, throughout the manuscript) exhibiting the ability to arrest TTR amyloidosis. The dissociation constants for the binding of BPEs and compound 11 and 12 to TTR correlate with their efficacies of inhibiting amyloidosis. They also have the ability to inhibit the elongation of intermediate fibrils as well as show nearly complete (>90%) disruption of the preformed fibrils. The present study thus establishes biphenyl ethers and compounds 11 and 12 as very potent inhibitors of TTR fibrillization and inducible cytotoxicity.
|
Inhibition of Plasmodium falciparum FabI
|
Plasmodium falciparum
|
0.014
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli.
Year : 2007
Volume : 15
Issue : 21
First Page : 6834
Last Page : 6845
Authors : Tasdemir D, Topaloglu B, Perozzo R, Brun R, O'Neill R, Carballeira NM, Zhang X, Tonge PJ, Linden A, Rüedi P.
Abstract : The type II fatty acid pathway (FAS-II) is a validated target for antimicrobial drug discovery. An activity-guided isolation procedure based on Plasmodium falciparum enoyl-ACP reductase (PfFabI) enzyme inhibition assay on the n-hexane-, the CHCl(3-) and the aq MeOH extracts of the Turkish marine sponge Agelas oroides yielded six pure metabolites [24-ethyl-cholest-5alpha-7-en-3-beta-ol (1), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (2), 4,5-dibromopyrrole-2-carboxylic acid (3), (E)-oroidin (4), 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (5), taurine (6)] and some minor, complex fatty acid mixtures (FAMA-FAMG). FAMA, consisting of a 1:2 mixture of (5Z,9Z)-5,9-tricosadienoic (7) and (5Z,9Z)-5,9-tetracosadienoic (8) acids, and FAMB composed of 8, (5Z,9Z)-5,9-pentacosadienoic (9) and (5Z,9Z)-5,9-hexacosadienoic (10) acids in approximately 3:3:2 ratio were the most active PfFabI inhibitory principles of the hexane extract (IC(50) values 0.35 microg/ml). (E)-Oroidin isolated as free base (4a) was identified as the active component of the CHCl(3) extract. Compound 4a was a more potent PfFabI inhibitor (IC(50) 0.30 microg/ml=0.77 microM) than the (E)-oroidin TFA salt (4b), the active and major component of the aq MeOH extract (IC(50) 5.0 microg/ml). Enzyme kinetic studies showed 4a to be an uncompetitive PfFabI inhibitor (K(i): 0.4+/-0.2 and 0.8+/-0.2 microM with respect to substrate and cofactor). In addition, FAMA and FAMD (mainly consisting of methyl-branched fatty acids) inhibited FabI of Mycobacterium tuberculosis (MtFabI, IC(50)s 9.4 and 8.2 microg/ml, respectively) and Escherichia coli (EcFabI, IC(50)s 0.5 and 0.07 microg/ml, respectively). The majority of the compounds exhibited in vitro antiplasmodial, as well as trypanocidal and leishmanicidal activities without cytotoxicity towards mammalian cells. This study represents the first marine metabolites that inhibit FabI, a clinically relevant enzyme target from the FAS-II pathway of several pathogenic microorganisms.
|
Inhibition of Mycobacterium tuberculosis H37RV InhA
|
Mycobacterium tuberculosis
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and in vitro antimycobacterial activity of B-ring modified diaryl ether InhA inhibitors.
Year : 2008
Volume : 18
Issue : 10
First Page : 3029
Last Page : 3033
Authors : am Ende CW, Knudson SE, Liu N, Childs J, Sullivan TJ, Boyne M, Xu H, Gegina Y, Knudson DL, Johnson F, Peloquin CA, Slayden RA, Tonge PJ.
Abstract : Previous structure-based design studies resulted in the discovery of alkyl substituted diphenyl ether inhibitors of InhA, the enoyl reductase from Mycobacterium tuberculosis. Compounds such as 5-hexyl-2-phenoxyphenol 19 are nM inhibitors of InhA and inhibit the growth of both sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis with MIC(90) values of 1-2 microg/mL. However, despite their promising in vitro activity, these compounds have ClogP values of over 5. In efforts to reduce the lipophilicity of the compounds, and potentially enhance compound bioavailability, a series of B ring analogues of 19 were synthesized that contained either heterocylic nitrogen rings or phenyl rings having amino, nitro, amide, or piperazine functionalities. Compounds 3c, 3e, and 14a show comparable MIC(90) values to that of 19, but have improved ClogP values.
|
Inhibition of Plasmodium falciparum ENR
|
Plasmodium falciparum
|
73.0
nM
|
|
Journal : J. Biol. Chem.
Title : X-ray structural analysis of Plasmodium falciparum enoyl acyl carrier protein reductase as a pathway toward the optimization of triclosan antimalarial efficacy.
Year : 2007
Volume : 282
Issue : 35
First Page : 25436
Last Page : 25444
Authors : Freundlich JS, Wang F, Tsai HC, Kuo M, Shieh HM, Anderson JW, Nkrumah LJ, Valderramos JC, Yu M, Kumar TR, Valderramos SG, Jacobs WR, Schiehser GA, Jacobus DP, Fidock DA, Sacchettini JC.
Abstract : The x-ray crystal structures of five triclosan analogs, in addition to that of the isoniazid-NAD adduct, are described in relation to their integral role in the design of potent inhibitors of the malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of the novel 5-substituted analogs exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and inhibit purified PfENR enzyme with IC50 values of <200 nM. This study has significantly expanded the knowledge base with regard to the structure-activity relationship of triclosan while affording gains against cultured parasites and purified PfENR enzyme. In contrast to a recent report in the literature, these results demonstrate the ability to improve the in vitro potency of triclosan significantly by replacing the suboptimal 5-chloro group with larger hydrophobic moieties. The biological and x-ray crystallographic data thus demonstrate the flexibility of the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular Plasmodium parasites.
|
Inhibition of Bacillus anthracis Enoyl ACP reductase
|
Bacillus anthracis
|
500.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design and synthesis of 2-pyridones as novel inhibitors of the Bacillus anthracis enoyl-ACP reductase.
Year : 2008
Volume : 18
Issue : 12
First Page : 3565
Last Page : 3569
Authors : Tipparaju SK, Joyasawal S, Forrester S, Mulhearn DC, Pegan S, Johnson ME, Mesecar AD, Kozikowski AP.
Abstract : Enoyl-ACP reductase (ENR), the product of the FabI gene, from Bacillus anthracis (BaENR) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis. A number of novel 2-pyridone derivatives were synthesized and shown to be potent inhibitors of BaENR.
|
Binding affinity to human recombinant carbonyl reductase 1 expressed in Escherichia coli assessed as NADPH oxidation using isatin as substrate
|
Homo sapiens
|
400.0
nM
|
|
Binding affinity to human recombinant carbonyl reductase 1 expressed in Escherichia coli assessed as NADPH oxidation using isatin as substrate
|
Homo sapiens
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of a potent and selective inhibitor for human carbonyl reductase 1 from propionate scanning applied to the macrolide zearalenone.
Year : 2009
Volume : 17
Issue : 2
First Page : 530
Last Page : 536
Authors : Zimmermann TJ, Niesen FH, Pilka ES, Knapp S, Oppermann U, Maier ME.
Abstract : In order to extend the chemical diversity available for organic polyketide synthesis, the concept of propionate scanning was developed. We observed that naturally occurring polyketides frequently comprise not only acetate, but also some propionate as building blocks. Therefore our approach consists of a systematic replacement of some of the acetate building blocks during synthesis by propionate moieties, resulting in additional methyl groups that may give rise to different properties of the polyketides. Here we present the results of a first 'proof of concept' study where a novel zearalenone analogue 5 was prepared that comprises an additional methyl group at C5'. Key steps in the synthesis of 5 include a Marshall-Tamaru reaction, a Suzuki cross-coupling reaction, and a Mitsunobu lactonization. Compared to the parent zearalenone (1), analogue 5 showed reduced binding to a panel of human protein kinases and no binding to human Hsp90. On the other hand, however, 5 turned out to be a potent (IC(50)=210 nM) inhibitor of human carbonyl reductase 1 (CBR1).
|
Antimalarial activity after 48 hrs against Plasmodium falciparum 7G8 by [3H]hypoxanthine uptake
|
Plasmodium falciparum
|
773.9
nM
|
|
Journal : J. Biol. Chem.
Title : In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin.
Year : 2007
Volume : 282
Issue : 4
First Page : 2494
Last Page : 2504
Authors : Sidhu AB, Sun Q, Nkrumah LJ, Dunne MW, Sacchettini JC, Fidock DA.
Abstract : Azithromycin (AZ), a broad-spectrum antibacterial macrolide that inhibits protein synthesis, also manifests reasonable efficacy as an antimalarial. Its mode of action against malarial parasites, however, has remained undefined. Our in vitro investigations with the human malarial parasite Plasmodium falciparum document a remarkable increase in AZ potency when exposure is prolonged from one to two generations of intraerythrocytic growth, with AZ producing 50% inhibition of parasite growth at concentrations in the mid to low nanomolar range. In our culture-adapted lines, AZ displayed no synergy with chloroquine (CQ), amodiaquine, or artesunate. AZ activity was also unaffected by mutations in the pfcrt (P. falciparum chloroquine resistance transporter) or pfmdr1 (P. falciparum multidrug resistance-1) drug resistance loci, as determined using transgenic lines. We have selected mutant, AZ-resistant 7G8 and Dd2 parasite lines. In the AZ-resistant 7G8 line, the bacterial-like apicoplast large subunit ribosomal RNA harbored a U438C mutation in domain I. Both AZ-resistant lines revealed a G76V mutation in a conserved region of the apicoplast-encoded P. falciparum ribosomal protein L4 (PfRpl4). This protein is predicted to associate with the nuclear genome-encoded P. falciparum ribosomal protein L22 (PfRpl22) and the large subunit rRNA to form the 50 S ribosome polypeptide exit tunnel that can be occupied by AZ. The PfRpl22 sequence remained unchanged. Molecular modeling of mutant PfRpl4 with AZ suggests an altered orientation of the L75 side chain that could preclude AZ binding. These data imply that AZ acts on the apicoplast bacterial-like translation machinery and identify Pfrpl4 as a potential marker of resistance.
|
Antimalarial activity after 96hrs against Plasmodium falciparum 7G8 by [3H]hypoxanthine uptake
|
Plasmodium falciparum
|
424.4
nM
|
|
Journal : J. Biol. Chem.
Title : In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin.
Year : 2007
Volume : 282
Issue : 4
First Page : 2494
Last Page : 2504
Authors : Sidhu AB, Sun Q, Nkrumah LJ, Dunne MW, Sacchettini JC, Fidock DA.
Abstract : Azithromycin (AZ), a broad-spectrum antibacterial macrolide that inhibits protein synthesis, also manifests reasonable efficacy as an antimalarial. Its mode of action against malarial parasites, however, has remained undefined. Our in vitro investigations with the human malarial parasite Plasmodium falciparum document a remarkable increase in AZ potency when exposure is prolonged from one to two generations of intraerythrocytic growth, with AZ producing 50% inhibition of parasite growth at concentrations in the mid to low nanomolar range. In our culture-adapted lines, AZ displayed no synergy with chloroquine (CQ), amodiaquine, or artesunate. AZ activity was also unaffected by mutations in the pfcrt (P. falciparum chloroquine resistance transporter) or pfmdr1 (P. falciparum multidrug resistance-1) drug resistance loci, as determined using transgenic lines. We have selected mutant, AZ-resistant 7G8 and Dd2 parasite lines. In the AZ-resistant 7G8 line, the bacterial-like apicoplast large subunit ribosomal RNA harbored a U438C mutation in domain I. Both AZ-resistant lines revealed a G76V mutation in a conserved region of the apicoplast-encoded P. falciparum ribosomal protein L4 (PfRpl4). This protein is predicted to associate with the nuclear genome-encoded P. falciparum ribosomal protein L22 (PfRpl22) and the large subunit rRNA to form the 50 S ribosome polypeptide exit tunnel that can be occupied by AZ. The PfRpl22 sequence remained unchanged. Molecular modeling of mutant PfRpl4 with AZ suggests an altered orientation of the L75 side chain that could preclude AZ binding. These data imply that AZ acts on the apicoplast bacterial-like translation machinery and identify Pfrpl4 as a potential marker of resistance.
|
Inhibition of Plasmodium falciparum recombinant FabI
|
Plasmodium falciparum
|
70.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mass spectrometry-based systems approach for identification of inhibitors of Plasmodium falciparum fatty acid synthase.
Year : 2007
Volume : 51
Issue : 7
First Page : 2552
Last Page : 2558
Authors : Sharma S, Sharma SK, Modak R, Karmodiya K, Surolia N, Surolia A.
Abstract : The emergence of strains of Plasmodium falciparum resistant to the commonly used antimalarials warrants the development of new antimalarial agents. The discovery of type II fatty acid synthase (FAS) in Plasmodium distinct from the FAS in its human host (type I FAS) opened up new avenues for the development of novel antimalarials. The process of fatty acid synthesis takes place by iterative elongation of butyryl-acyl carrier protein (butyryl-ACP) by two carbon units, with the successive action of four enzymes constituting the elongation module of FAS until the desired acyl length is obtained. The study of the fatty acid synthesis machinery of the parasite inside the red blood cell culture has always been a challenging task. Here, we report the in vitro reconstitution of the elongation module of the FAS of malaria parasite involving all four enzymes, FabB/F (beta-ketoacyl-ACP synthase), FabG (beta-ketoacyl-ACP reductase), FabZ (beta-ketoacyl-ACP dehydratase), and FabI (enoyl-ACP reductase), and its analysis by matrix-assisted laser desorption-time of flight mass spectrometry (MALDI-TOF MS). That this in vitro systems approach completely mimics the in vivo machinery is confirmed by the distribution of acyl products. Using known inhibitors of the enzymes of the elongation module, cerulenin, triclosan, NAS-21/91, and (-)-catechin gallate, we demonstrate that accumulation of intermediates resulting from the inhibition of any of the enzymes can be unambiguously followed by MALDI-TOF MS. Thus, this work not only offers a powerful tool for easier and faster throughput screening of inhibitors but also allows for the study of the biochemical properties of the FAS pathway of the malaria parasite.
|
Antiparasitic activity against Plasmodium falciparum in RBCs
|
Plasmodium falciparum
|
700.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mass spectrometry-based systems approach for identification of inhibitors of Plasmodium falciparum fatty acid synthase.
Year : 2007
Volume : 51
Issue : 7
First Page : 2552
Last Page : 2558
Authors : Sharma S, Sharma SK, Modak R, Karmodiya K, Surolia N, Surolia A.
Abstract : The emergence of strains of Plasmodium falciparum resistant to the commonly used antimalarials warrants the development of new antimalarial agents. The discovery of type II fatty acid synthase (FAS) in Plasmodium distinct from the FAS in its human host (type I FAS) opened up new avenues for the development of novel antimalarials. The process of fatty acid synthesis takes place by iterative elongation of butyryl-acyl carrier protein (butyryl-ACP) by two carbon units, with the successive action of four enzymes constituting the elongation module of FAS until the desired acyl length is obtained. The study of the fatty acid synthesis machinery of the parasite inside the red blood cell culture has always been a challenging task. Here, we report the in vitro reconstitution of the elongation module of the FAS of malaria parasite involving all four enzymes, FabB/F (beta-ketoacyl-ACP synthase), FabG (beta-ketoacyl-ACP reductase), FabZ (beta-ketoacyl-ACP dehydratase), and FabI (enoyl-ACP reductase), and its analysis by matrix-assisted laser desorption-time of flight mass spectrometry (MALDI-TOF MS). That this in vitro systems approach completely mimics the in vivo machinery is confirmed by the distribution of acyl products. Using known inhibitors of the enzymes of the elongation module, cerulenin, triclosan, NAS-21/91, and (-)-catechin gallate, we demonstrate that accumulation of intermediates resulting from the inhibition of any of the enzymes can be unambiguously followed by MALDI-TOF MS. Thus, this work not only offers a powerful tool for easier and faster throughput screening of inhibitors but also allows for the study of the biochemical properties of the FAS pathway of the malaria parasite.
|
Inhibition of Plasmodium falciparum recombinant FabI A217V mutant
|
Plasmodium falciparum
|
232.0
nM
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mass spectrometry-based systems approach for identification of inhibitors of Plasmodium falciparum fatty acid synthase.
Year : 2007
Volume : 51
Issue : 7
First Page : 2552
Last Page : 2558
Authors : Sharma S, Sharma SK, Modak R, Karmodiya K, Surolia N, Surolia A.
Abstract : The emergence of strains of Plasmodium falciparum resistant to the commonly used antimalarials warrants the development of new antimalarial agents. The discovery of type II fatty acid synthase (FAS) in Plasmodium distinct from the FAS in its human host (type I FAS) opened up new avenues for the development of novel antimalarials. The process of fatty acid synthesis takes place by iterative elongation of butyryl-acyl carrier protein (butyryl-ACP) by two carbon units, with the successive action of four enzymes constituting the elongation module of FAS until the desired acyl length is obtained. The study of the fatty acid synthesis machinery of the parasite inside the red blood cell culture has always been a challenging task. Here, we report the in vitro reconstitution of the elongation module of the FAS of malaria parasite involving all four enzymes, FabB/F (beta-ketoacyl-ACP synthase), FabG (beta-ketoacyl-ACP reductase), FabZ (beta-ketoacyl-ACP dehydratase), and FabI (enoyl-ACP reductase), and its analysis by matrix-assisted laser desorption-time of flight mass spectrometry (MALDI-TOF MS). That this in vitro systems approach completely mimics the in vivo machinery is confirmed by the distribution of acyl products. Using known inhibitors of the enzymes of the elongation module, cerulenin, triclosan, NAS-21/91, and (-)-catechin gallate, we demonstrate that accumulation of intermediates resulting from the inhibition of any of the enzymes can be unambiguously followed by MALDI-TOF MS. Thus, this work not only offers a powerful tool for easier and faster throughput screening of inhibitors but also allows for the study of the biochemical properties of the FAS pathway of the malaria parasite.
|
Antibacterial activity against wild type Escherichia coli K12 after 12 hrs by microdilution method
|
Escherichia coli
|
750.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis, and application of novel triclosan prodrugs as potential antimalarial and antibacterial agents.
Year : 2008
Volume : 16
Issue : 10
First Page : 5536
Last Page : 5546
Authors : Mishra S, Karmodiya K, Parasuraman P, Surolia A, Surolia N.
Abstract : A number of new triclosan-conjugated analogs bearing biodegradable ester linkage have been synthesized, characterized and evaluated for their antimalarial and antibacterial activities. Many of these compounds exhibit good inhibition against Plasmodium falciparum and Escherichia coli. Among them tertiary amine containing triclosan-conjugated prodrug (5) inhibited both P. falciparum (IC(50); 0.62microM) and E. coli (IC(50); 0.26microM) at lower concentrations as compared to triclosan. Owing to the presence of a cleavable ester moiety, these new prodrugs are hydrolyzed under physiological conditions and parent molecule, triclosan, is released. Further, introduction of tertiary/quaternary functionality increases their cellular uptake. These properties impart them with higher potency to their antimalarial as well as antibacterial activities. The best compound among them 5 shows close to four-fold enhanced activities against P. falciparum and E. coli cultures as compared to triclosan.
|
Inhibition of Plasmodium falciparum enoyl-acyl carrier protein reductase
|
Plasmodium falciparum
|
73.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and in silico screening of combinatorial library of antimalarial analogs of triclosan inhibiting Plasmodium falciparum enoyl-acyl carrier protein reductase.
Year : 2009
Volume : 44
Issue : 7
First Page : 3009
Last Page : 3019
Authors : Frecer V, Megnassan E, Miertus S.
Abstract : Enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) is an important target for antimalarial agents that interfere with the FAS-II pathway of lipid synthesis, which is specific for the parasite. Recent studies showed that substituted analogs of triclosan (TCL) inhibit the purified PfENR enzyme with IC(50) values below 200 nM when the suboptimal 5-chloro group was replaced by larger hydrophobic moieties. We have used computer-assisted combinatorial techniques to design, focus and in silico screen a virtual library of TCL analogs substituted at positions 5, 4' and 2'. Our study can thus direct synthetic chemists working on the antimalarial FAS-II inhibitors towards the explored subset of the chemical space, which is predicted to contain compounds with PfENR inhibition potencies in the low nanomolar range and favorable ADME properties.
|
Inhibition of Plasmodium falciparum enoyl-acyl carrier protein reductase expressed in Escherichia coli BL21(DE3) by spectrophotometry
|
Plasmodium falciparum
|
50.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design and in silico screening of combinatorial library of antimalarial analogs of triclosan inhibiting Plasmodium falciparum enoyl-acyl carrier protein reductase.
Year : 2009
Volume : 44
Issue : 7
First Page : 3009
Last Page : 3019
Authors : Frecer V, Megnassan E, Miertus S.
Abstract : Enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) is an important target for antimalarial agents that interfere with the FAS-II pathway of lipid synthesis, which is specific for the parasite. Recent studies showed that substituted analogs of triclosan (TCL) inhibit the purified PfENR enzyme with IC(50) values below 200 nM when the suboptimal 5-chloro group was replaced by larger hydrophobic moieties. We have used computer-assisted combinatorial techniques to design, focus and in silico screen a virtual library of TCL analogs substituted at positions 5, 4' and 2'. Our study can thus direct synthetic chemists working on the antimalarial FAS-II inhibitors towards the explored subset of the chemical space, which is predicted to contain compounds with PfENR inhibition potencies in the low nanomolar range and favorable ADME properties.
|
Inhibition of Pseudomonas aeruginosa PA0170 fabV assessed as reduction of Enoyl-[acyl-carrier-protein] reductase activity at 15 ug/ml
|
Pseudomonas aeruginosa
|
15.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Triclosan resistance of Pseudomonas aeruginosa PAO1 is due to FabV, a triclosan-resistant enoyl-acyl carrier protein reductase.
Year : 2010
Volume : 54
Issue : 2
First Page : 689
Last Page : 698
Authors : Zhu L, Lin J, Ma J, Cronan JE, Wang H.
Abstract : Triclosan, a very widely used biocide, specifically inhibits fatty acid synthesis by inhibition of enoyl-acyl carrier protein (ACP) reductase. Escherichia coli FabI is the prototypical triclosan-sensitive enoyl-ACP reductase, and E. coli is extremely sensitive to the biocide. However, other bacteria are resistant to triclosan, because they encode triclosan-resistant enoyl-ACP reductase isozymes. In contrast, the triclosan resistance of Pseudomonas aeruginosa PAO1 has been attributed to active efflux of the compound (R. Chuanchuen, R. R. Karkhoff-Schweizer, and H. P. Schweizer, Am. J. Infect. Control 31:124-127, 2003). We report that P. aeruginosa contains two enoyl-ACP reductase isozymes, the previously characterized FabI homologue plus a homologue of FabV, a triclosan-resistant enoyl-ACP reductase recently demonstrated in Vibrio cholerae. By deletion of the genes encoding P. aeruginosa FabI and FabV, we demonstrated that FabV confers triclosan resistance on P. aeruginosa. Upon deletion of the fabV gene, the mutant strain became extremely sensitive to triclosan (>2,000-fold more sensitive than the wild-type strain), whereas the mutant strain lacking FabI remained completely resistant to the biocide.
|
Inhibition of wild type Pseudomonas aeruginosa ENR at 15 ug/ml
|
Pseudomonas aeruginosa
|
29.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Triclosan resistance of Pseudomonas aeruginosa PAO1 is due to FabV, a triclosan-resistant enoyl-acyl carrier protein reductase.
Year : 2010
Volume : 54
Issue : 2
First Page : 689
Last Page : 698
Authors : Zhu L, Lin J, Ma J, Cronan JE, Wang H.
Abstract : Triclosan, a very widely used biocide, specifically inhibits fatty acid synthesis by inhibition of enoyl-acyl carrier protein (ACP) reductase. Escherichia coli FabI is the prototypical triclosan-sensitive enoyl-ACP reductase, and E. coli is extremely sensitive to the biocide. However, other bacteria are resistant to triclosan, because they encode triclosan-resistant enoyl-ACP reductase isozymes. In contrast, the triclosan resistance of Pseudomonas aeruginosa PAO1 has been attributed to active efflux of the compound (R. Chuanchuen, R. R. Karkhoff-Schweizer, and H. P. Schweizer, Am. J. Infect. Control 31:124-127, 2003). We report that P. aeruginosa contains two enoyl-ACP reductase isozymes, the previously characterized FabI homologue plus a homologue of FabV, a triclosan-resistant enoyl-ACP reductase recently demonstrated in Vibrio cholerae. By deletion of the genes encoding P. aeruginosa FabI and FabV, we demonstrated that FabV confers triclosan resistance on P. aeruginosa. Upon deletion of the fabV gene, the mutant strain became extremely sensitive to triclosan (>2,000-fold more sensitive than the wild-type strain), whereas the mutant strain lacking FabI remained completely resistant to the biocide.
|
Inhibition of Toxoplasma gondii enoyl reductase
|
Toxoplasma gondii
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase.
Year : 2010
Volume : 53
Issue : 17
First Page : 6287
Last Page : 6300
Authors : Tipparaju SK, Muench SP, Mui EJ, Ruzheinikov SN, Lu JZ, Hutson SL, Kirisits MJ, Prigge ST, Roberts CW, Henriquez FL, Kozikowski AP, Rice DW, McLeod RL.
Abstract : Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s < or = 6 microM without toxicity to host cells, three compounds have IC(90)s < 45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.
|
Inhibition of Plasmodium falciparum FabI by spectrophotometric analysis
|
Plasmodium falciparum
|
0.014
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : 2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections.
Year : 2010
Volume : 18
Issue : 21
First Page : 7475
Last Page : 7485
Authors : Tasdemir D, Sanabria D, Lauinger IL, Tarun A, Herman R, Perozzo R, Zloh M, Kappe SH, Brun R, Carballeira NM.
Abstract : Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 μg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 μg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 μg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 μg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 μg/ml), Trypanosoma cruzi (only 2-HDA, IC(50) 20.2 μg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 μg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes.
|
PUBCHEM_BIOASSAY: A screen for inhibitors of the PhoP region in Salmonella Typhimurium using a modified counterscreen. (Class of assay: confirmatory) [Related pubchem assays: 2253, 1863, 1874 ]
|
None
|
680.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: A Counter Screen to identiry small molecule screen for inhibitors of the PhoP region in Salmonella Typhimurium. (Class of assay: confirmatory) [Related pubchem assays: 2253, 1863, 1981, 1874 ]
|
None
|
490.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: A small molecule screen for inhibitors of the PhoP region in Salmonella Typhimurium. (Class of assay: confirmatory) [Related pubchem assays: 2253, 1981, 1874 ]
|
None
|
820.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: A counter screen for small molecule screen for inhibitors of the PhoP region in Salmonella typhi. (Class of assay: confirmatory) [Related pubchem assays: 1850, 1864, 2252, 1985 ]
|
None
|
550.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: A small molecule screen for inhibitors of the PhoP region in Salmonella typhi. (Class of assay: confirmatory) [Related pubchem assays: 1864, 2252, 1985 ]
|
None
|
670.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: A screen for inhibitors of the PhoP region in Salmonella Typhi using a modified counterscreen. (Class of assay: confirmatory)
|
None
|
369.0
nM
|
|
Title : PubChem BioAssay data set
|
Antiproliferative activity against Theileria parva-induced proliferation of bovine BL3 cells assessed as inhibition of [3H]thymidine uptake after 32 hrs
|
Bos taurus
|
75.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Theileria apicoplast as a target for chemotherapy.
Year : 2009
Volume : 53
Issue : 3
First Page : 1213
Last Page : 1217
Authors : Lizundia R, Werling D, Langsley G, Ralph SA.
Abstract : Theileria parasites cause severe bovine disease and death in a large part of the world. These apicomplexan parasites possess a relic plastid (apicoplast), whose metabolic pathways include several promising drug targets. Putative inhibitors of these targets were screened, and we identified antiproliferative compounds that merit further characterization.
|
Induction of toxin TSST-1 production in Staphylococcus aureus FRI-1187 at 0.50 mM after 24 hrs relative to control
|
Staphylococcus aureus
|
3.7
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Surfactants, aromatic and isoprenoid compounds, and fatty acid biosynthesis inhibitors suppress Staphylococcus aureus production of toxic shock syndrome toxin 1.
Year : 2009
Volume : 53
Issue : 5
First Page : 1898
Last Page : 1906
Authors : McNamara PJ, Syverson RE, Milligan-Myhre K, Frolova O, Schroeder S, Kidder J, Hoang T, Proctor RA.
Abstract : Menstrual toxic shock syndrome is a rare but potentially life-threatening illness manifest through the actions of Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1). Previous studies have shown that tampon additives can influence staphylococcal TSST-1 production. We report here on the TSST-1-suppressing activity of 34 compounds that are commonly used additives in the pharmaceutical, food, and perfume industries. Many of the tested chemicals had a minimal impact on the growth of S. aureus and yet were potent inhibitors of TSST-1 production. The TSST-1-reducing compounds included surfactants with an ether, amide, or amine linkage to their fatty acid moiety (e.g., myreth-3-myristate, Laureth-3, disodium lauroamphodiacetate, disodium lauramido monoethanolamido, sodium lauriminodipropionic acid, and triethanolamine laureth sulfate); aromatic compounds (e.g. phenylethyl and benzyl alcohols); and several isoprenoids and related compounds (e.g., terpineol and menthol). The membrane-targeting and -altering effects of the TSST-1-suppressing compounds led us to assess the activity of molecules that are known to inhibit fatty acid biosynthesis (e.g., cerulenin, triclosan, and hexachlorophene). These compounds also reduced S. aureus TSST-1 production. This study suggests that more additives than previously recognized inhibit the production of TSST-1.
|
Induction of toxin TSST-1 production in Staphylococcus aureus FRI-1187 at 0.05 mM after 24 hrs relative to control
|
Staphylococcus aureus
|
9.9
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Surfactants, aromatic and isoprenoid compounds, and fatty acid biosynthesis inhibitors suppress Staphylococcus aureus production of toxic shock syndrome toxin 1.
Year : 2009
Volume : 53
Issue : 5
First Page : 1898
Last Page : 1906
Authors : McNamara PJ, Syverson RE, Milligan-Myhre K, Frolova O, Schroeder S, Kidder J, Hoang T, Proctor RA.
Abstract : Menstrual toxic shock syndrome is a rare but potentially life-threatening illness manifest through the actions of Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1). Previous studies have shown that tampon additives can influence staphylococcal TSST-1 production. We report here on the TSST-1-suppressing activity of 34 compounds that are commonly used additives in the pharmaceutical, food, and perfume industries. Many of the tested chemicals had a minimal impact on the growth of S. aureus and yet were potent inhibitors of TSST-1 production. The TSST-1-reducing compounds included surfactants with an ether, amide, or amine linkage to their fatty acid moiety (e.g., myreth-3-myristate, Laureth-3, disodium lauroamphodiacetate, disodium lauramido monoethanolamido, sodium lauriminodipropionic acid, and triethanolamine laureth sulfate); aromatic compounds (e.g. phenylethyl and benzyl alcohols); and several isoprenoids and related compounds (e.g., terpineol and menthol). The membrane-targeting and -altering effects of the TSST-1-suppressing compounds led us to assess the activity of molecules that are known to inhibit fatty acid biosynthesis (e.g., cerulenin, triclosan, and hexachlorophene). These compounds also reduced S. aureus TSST-1 production. This study suggests that more additives than previously recognized inhibit the production of TSST-1.
|
Inhibition of Plasmodium falciparum Enoyl-ACP reductase using crotonyl-CoA as substrate peincubated for 5 mins measured after 10 mins of substrate addition by UV-vis spectrophotometry
|
Plasmodium falciparum
|
200.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isoflavone dimers and other bioactive constituents from the figs of Ficus mucuso.
Year : 2011
Volume : 74
Issue : 6
First Page : 1370
Last Page : 1378
Authors : Bankeu JJ, Khayala R, Lenta BN, Noungoué DT, Ngouela SA, Mustafa SA, Asaad K, Choudhary MI, Prigge ST, Hasanov R, Nkengfack AE, Tsamo E, Ali MS.
Abstract : Phytochemical investigation of the figs of Ficus mucuso led to the isolation of three new isoflavone dimer derivatives, mucusisoflavones A-C (1-3), together with 16 known compounds. Some of the isolates were tested in vitro for their inhibitory properties toward β-glucuronidase and Plasmodium falciparum enoyl-ACP reductase (PfENR) enzymes. Compound 1 (IC₅₀) 0.68 μM) showed inhibitory activity on β-glucuronidase enzyme, while 3 (IC₅₀) 7.69 μM) exhibited a weak inhibitory activity against P. falciparum enoyl-ACP reductase (PfENR).
|
Inhibition of Plasmodium falciparum Enoyl-ACP reductase using crotonyl-CoA as substrate at 0.05 mM peincubated for 5 mins measured after 10 mins of substrate addition by UV-vis spectrophotometry
|
Plasmodium falciparum
|
99.5
%
|
|
Journal : J. Nat. Prod.
Title : Isoflavone dimers and other bioactive constituents from the figs of Ficus mucuso.
Year : 2011
Volume : 74
Issue : 6
First Page : 1370
Last Page : 1378
Authors : Bankeu JJ, Khayala R, Lenta BN, Noungoué DT, Ngouela SA, Mustafa SA, Asaad K, Choudhary MI, Prigge ST, Hasanov R, Nkengfack AE, Tsamo E, Ali MS.
Abstract : Phytochemical investigation of the figs of Ficus mucuso led to the isolation of three new isoflavone dimer derivatives, mucusisoflavones A-C (1-3), together with 16 known compounds. Some of the isolates were tested in vitro for their inhibitory properties toward β-glucuronidase and Plasmodium falciparum enoyl-ACP reductase (PfENR) enzymes. Compound 1 (IC₅₀) 0.68 μM) showed inhibitory activity on β-glucuronidase enzyme, while 3 (IC₅₀) 7.69 μM) exhibited a weak inhibitory activity against P. falciparum enoyl-ACP reductase (PfENR).
|
Inhibition of Mycobacterium tuberculosis InhA expressed in Escherichia coli BL21 using trans-2-dodecenoyl-Coenzyme A as substrate at 10 uM by spectrophotometry
|
Mycobacterium tuberculosis
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents.
Year : 2011
Volume : 46
Issue : 11
First Page : 5524
Last Page : 5531
Authors : Menendez C, Gau S, Lherbet C, Rodriguez F, Inard C, Pasca MR, Baltas M.
Abstract : InhA, the enoyl reductase from the mycobacterial type II fatty acid biosynthesis pathway, is a target for the development of novel drugs against tuberculosis. We exploited copper-catalyzed [3+2] cycloaddition between alkynes and different azides to afford 1,4-disubstituted triazole or α-ketotriazole derivatives. Several compounds bearing a lipophilic chain mimicking the substrate were able to inhibit InhA. Among them, 1-dodecyl-4-phenethyl-1H-1,2,3-triazole displayed a minimum inhibitory concentration inferior to 2 μg/mL against Mycobacterium tuberculosis H37Rv.
|
Inhibition of Mycobacterium tuberculosis InhA using 2-trans-decenoyl-CoA as substrate at 10 uM after 5 mins using by spectrophotometry
|
Mycobacterium tuberculosis
|
37.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Chemical synthesis, biological evaluation and structure-activity relationship analysis of azaisoindolinones, a novel class of direct enoyl-ACP reductase inhibitors as potential antimycobacterial agents.
Year : 2011
Volume : 19
Issue : 21
First Page : 6225
Last Page : 6232
Authors : Deraeve C, Dorobantu IM, Rebbah F, Le Quéméner F, Constant P, Quémard A, Bernardes-Génisson V, Bernadou J, Pratviel G.
Abstract : The synthesis and biological evaluation of azaisoindolinone compounds embedding a lipophilic chain on the framework were performed. These compounds were designed as InhA inhibitors and as anti-Mycobacterium tuberculosis agents. Structure-activity relationships concerning the length and the location of the lipophilic chain around the azaisoindolinone framework, the suppression of the phenyl group, the bioisosteric substitution of ether link and alkylating of the tertiary hydroxyl and the hemiamidal nitrogen were also investigated, revealing insightful information and thereby enabling further diversification of the azaisoindolinone scaffold for new antitubercular agents.
|
Inhibition of Plasmodium falciparum enoyl-ACP reductase assessed as oxidation of NADH to NAD+ after 10 mins by spectrophotometric analysis
|
Plasmodium falciparum
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Methylenebissantin: a rare methylene-bridged bisflavonoid from Dodonaea viscosa which inhibits Plasmodium falciparum enoyl-ACP reductase.
Year : 2012
Volume : 22
Issue : 1
First Page : 610
Last Page : 612
Authors : Muhammad A, Anis I, Ali Z, Awadelkarim S, Khan A, Khalid A, Shah MR, Galal M, Khan IA, Iqbal Choudhary M.
Abstract : A new methylene-bridged bisflavonoid, methylenebissantin (1), and nine known compounds, including flavonoids (2-5), diterpenoids (6 and 7), and phenol derivatives (8-10) were isolated from the aerial parts of Dodonaea viscosa Jacq. The structure elucidation was based on spectroscopic data analyses. The isolated compounds were evaluated for the inhibition of Plasmodium falciparum enoyl-ACP reductase (PfENR). Methylenebissantin (1) exhibited a moderate inhibition (IC(50) 91.13 μM) against PfENR.
|
Inhibition of Staphylococcus aureus recombinant FabI using trans-2-octenoyl N-acetylcysteamine thioester as substrate preincubated for 60 mins
|
Staphylococcus aureus
|
59.0
nM
|
|
Journal : J. Med. Chem.
Title : From triclosan toward the clinic: discovery of nonbiocidal, potent FabI inhibitors for the treatment of resistant bacteria.
Year : 2012
Volume : 55
Issue : 22
First Page : 9914
Last Page : 9928
Authors : Gerusz V, Denis A, Faivre F, Bonvin Y, Oxoby M, Briet S, LeFralliec G, Oliveira C, Desroy N, Raymond C, Peltier L, Moreau F, Escaich S, Vongsouthi V, Floquet S, Drocourt E, Walton A, Prouvensier L, Saccomani M, Durant L, Genevard JM, Sam-Sambo V, Soulama-Mouze C.
Abstract : In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.
|
Inhibition of Escherichia coli FabI using crotonoyl-CoA as substrate preincubated for 90 mins
|
Escherichia coli
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : From triclosan toward the clinic: discovery of nonbiocidal, potent FabI inhibitors for the treatment of resistant bacteria.
Year : 2012
Volume : 55
Issue : 22
First Page : 9914
Last Page : 9928
Authors : Gerusz V, Denis A, Faivre F, Bonvin Y, Oxoby M, Briet S, LeFralliec G, Oliveira C, Desroy N, Raymond C, Peltier L, Moreau F, Escaich S, Vongsouthi V, Floquet S, Drocourt E, Walton A, Prouvensier L, Saccomani M, Durant L, Genevard JM, Sam-Sambo V, Soulama-Mouze C.
Abstract : In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.
|
Leishmanicidal activity against axenic amastigote stage of Leishmania panamensis MHOM/CO/87/UA140epir GFP assessed as parasite viability after 72 hr by MTT assay
|
Leishmania panamensis
|
11.3
ug.mL-1
|
|
Journal : Med Chem Res
Title : Synthesis and leishmanicidal activity of quinolinetriclosan and quinolineeugenol hybrids
Year : 2012
Volume : 21
Issue : 11
First Page : 3445
Last Page : 3454
Authors : Arango V, Dominguez JJ, Cardona W, Robledo SM, Munoz DL, Figadere B, Saez J
|
Inhibition of Toxoplasma gondii enoyl reductase assessed as conversion of trans-2-acyl-ACP to acyl-ACP
|
Toxoplasma gondii
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase.
Year : 2013
Volume : 23
Issue : 7
First Page : 2035
Last Page : 2043
Authors : Cheng G, Muench SP, Zhou Y, Afanador GA, Mui EJ, Fomovska A, Lai BS, Prigge ST, Woods S, Roberts CW, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Rice DW, McLeod R.
Abstract : Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.
|
Inhibition of Toxoplasma gondii enoyl reductase assessed as conversion of trans-2-acyl-ACP to acyl-ACP at 1 uM
|
Toxoplasma gondii
|
98.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and biological activity of diaryl ether inhibitors of Toxoplasma gondii enoyl reductase.
Year : 2013
Volume : 23
Issue : 7
First Page : 2035
Last Page : 2043
Authors : Cheng G, Muench SP, Zhou Y, Afanador GA, Mui EJ, Fomovska A, Lai BS, Prigge ST, Woods S, Roberts CW, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Rice DW, McLeod R.
Abstract : Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.
|
Inhibition of Escherichia coli FabI using 2-dodecenoyl-CoA as substrate at pH 8
|
Escherichia coli
|
5.0
nM
|
|
Journal : J. Nat. Prod.
Title : Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target.
Year : 2013
Volume : 76
Issue : 6
First Page : 1064
Last Page : 1070
Authors : Lauinger IL, Vivas L, Perozzo R, Stairiker C, Tarun A, Zloh M, Zhang X, Xu H, Tonge PJ, Franzblau SG, Pham DH, Esguerra CV, Crawford AD, Maes L, Tasdemir D.
Abstract : Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 μM, BS IC50 value 47.3 μM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.
|
Inhibition of Staphylococcus aureus FabI using dodecenoyl ACP at pH 7.8
|
Staphylococcus aureus
|
25.0
nM
|
|
Journal : J. Nat. Prod.
Title : Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target.
Year : 2013
Volume : 76
Issue : 6
First Page : 1064
Last Page : 1070
Authors : Lauinger IL, Vivas L, Perozzo R, Stairiker C, Tarun A, Zloh M, Zhang X, Xu H, Tonge PJ, Franzblau SG, Pham DH, Esguerra CV, Crawford AD, Maes L, Tasdemir D.
Abstract : Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 μM, BS IC50 value 47.3 μM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.
|
Inhibition of Plasmodium falciparum FabI using crotonoyl-CoA as substrate preincubated for 10 mins prior to substrate addition
|
Plasmodium falciparum
|
50.0
nM
|
|
Journal : J. Nat. Prod.
Title : Potential of lichen secondary metabolites against Plasmodium liver stage parasites with FAS-II as the potential target.
Year : 2013
Volume : 76
Issue : 6
First Page : 1064
Last Page : 1070
Authors : Lauinger IL, Vivas L, Perozzo R, Stairiker C, Tarun A, Zloh M, Zhang X, Xu H, Tonge PJ, Franzblau SG, Pham DH, Esguerra CV, Crawford AD, Maes L, Tasdemir D.
Abstract : Chemicals targeting the liver stage (LS) of the malaria parasite are useful for causal prophylaxis of malaria. In this study, four lichen metabolites, evernic acid (1), vulpic acid (2), psoromic acid (3), and (+)-usnic acid (4), were evaluated against LS parasites of Plasmodium berghei. Inhibition of P. falciparum blood stage (BS) parasites was also assessed to determine stage specificity. Compound 4 displayed the highest LS activity and stage specificity (LS IC50 value 2.3 μM, BS IC50 value 47.3 μM). The compounds 1-3 inhibited one or more enzymes (PfFabI, PfFabG, and PfFabZ) from the plasmodial fatty acid biosynthesis (FAS-II) pathway, a potential drug target for LS activity. To determine species specificity and to clarify the mechanism of reported antibacterial effects, 1-4 were also evaluated against FabI homologues and whole cells of various pathogens (S. aureus, E. coli, M. tuberculosis). Molecular modeling studies suggest that lichen acids act indirectly via binding to allosteric sites on the protein surface of the FAS-II enzymes. Potential toxicity of compounds was assessed in human hepatocyte and cancer cells (in vitro) as well as in a zebrafish model (in vivo). This study indicates the therapeutic and prophylactic potential of lichen metabolites as antibacterial and antiplasmodial agents.
|
Inhibition of Toxoplasma gondii enoyl acyl-carrier protein reductase
|
Toxoplasma gondii
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides.
Year : 2013
Volume : 23
Issue : 12
First Page : 3551
Last Page : 3555
Authors : Muench SP, Stec J, Zhou Y, Afanador GA, McPhillie MJ, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Prigge ST, Rice DW, McLeod R.
Abstract : The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery.
|
Inhibition of Toxoplasma gondii enoyl acyl-carrier protein reductase at 1 uM
|
Toxoplasma gondii
|
98.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides.
Year : 2013
Volume : 23
Issue : 12
First Page : 3551
Last Page : 3555
Authors : Muench SP, Stec J, Zhou Y, Afanador GA, McPhillie MJ, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Prigge ST, Rice DW, McLeod R.
Abstract : The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery.
|
Inhibition of Francisella tularensis SCHU S4 FabI R96M mutant using CrCoA as substrate by UV-vis spectrophotometric analysis in presence of non pre-equilibrated NAD+
|
Francisella tularensis subsp. tularensis SCHU S4
|
300.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-substituted indole inhibitors against Francisella tularensis FabI identified by structure-based virtual screening.
Year : 2013
Volume : 56
Issue : 13
First Page : 5275
Last Page : 5287
Authors : Hu X, Compton JR, Abdulhameed MD, Marchand CL, Robertson KL, Leary DH, Jadhav A, Hershfield JR, Wallqvist A, Friedlander AM, Legler PM.
Abstract : In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bound the NAD(+) form of the enzyme and inhibited growth of F. tularensis SchuS4 at concentrations near that of their measured Ki. While 57 was species-specific, 54 showed a broader spectrum of growth inhibition against F. tularensis , Bacillus anthracis , and Staphylococcus aureus . Binding interaction analysis in conjunction with site-directed mutagenesis revealed key residues and elements that contribute to inhibitor binding and species specificity. Mutation of Arg-96, a poorly conserved residue opposite the loop, was unexpectedly found to enhance inhibitor binding in the R96G and R96M variants. This residue may affect the stability and closure of the flexible loop to enhance inhibitor (or substrate) binding.
|
Inhibition of Francisella tularensis SCHU S4 FabI R96G mutant using CrCoA as substrate by UV-vis spectrophotometric analysis in presence of non pre-equilibrated NAD+
|
Francisella tularensis subsp. tularensis SCHU S4
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-substituted indole inhibitors against Francisella tularensis FabI identified by structure-based virtual screening.
Year : 2013
Volume : 56
Issue : 13
First Page : 5275
Last Page : 5287
Authors : Hu X, Compton JR, Abdulhameed MD, Marchand CL, Robertson KL, Leary DH, Jadhav A, Hershfield JR, Wallqvist A, Friedlander AM, Legler PM.
Abstract : In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bound the NAD(+) form of the enzyme and inhibited growth of F. tularensis SchuS4 at concentrations near that of their measured Ki. While 57 was species-specific, 54 showed a broader spectrum of growth inhibition against F. tularensis , Bacillus anthracis , and Staphylococcus aureus . Binding interaction analysis in conjunction with site-directed mutagenesis revealed key residues and elements that contribute to inhibitor binding and species specificity. Mutation of Arg-96, a poorly conserved residue opposite the loop, was unexpectedly found to enhance inhibitor binding in the R96G and R96M variants. This residue may affect the stability and closure of the flexible loop to enhance inhibitor (or substrate) binding.
|
Inhibition of Plasmodium falciparum FabI using crotonoyl-CoA as substrate by UV-Vis spectrophotometric analysis in presence of NADH
|
Plasmodium falciparum
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).
Year : 2013
Volume : 56
Issue : 19
First Page : 7516
Last Page : 7526
Authors : Belluti F, Perozzo R, Lauciello L, Colizzi F, Kostrewa D, Bisi A, Gobbi S, Rampa A, Bolognesi ML, Recanatini M, Brun R, Scapozza L, Cavalli A.
Abstract : Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.
|
Inhibition of recombinant Plasmodium falciparum FabI using crotonoyl-CoA as substrate assessed as consumption of NADH after 10 mins
|
Plasmodium falciparum
|
50.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).
Year : 2013
Volume : 56
Issue : 19
First Page : 7516
Last Page : 7526
Authors : Belluti F, Perozzo R, Lauciello L, Colizzi F, Kostrewa D, Bisi A, Gobbi S, Rampa A, Bolognesi ML, Recanatini M, Brun R, Scapozza L, Cavalli A.
Abstract : Malaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium's life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (PfFAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.
|
Inhibition of wild type Mycobacterium tuberculosis inhA
|
Mycobacterium tuberculosis
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Methyl-thiazoles: a novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in Mycobacterium tuberculosis.
Year : 2013
Volume : 56
Issue : 21
First Page : 8533
Last Page : 8542
Authors : Shirude PS, Madhavapeddi P, Naik M, Murugan K, Shinde V, Nandishaiah R, Bhat J, Kumar A, Hameed S, Holdgate G, Davies G, McMiken H, Hegde N, Ambady A, Venkatraman J, Panda M, Bandodkar B, Sambandamurthy VK, Read JA.
Abstract : InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a Kd of ~13.7 nM, as against the NAD(+)-bound form of the enzyme.
|
Inhibition of Mycobacterium tuberculosis recombinant His6x-tagged InhA expressed in Escherichia coli BL21 at 50 uM
|
Mycobacterium tuberculosis
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of 3-heteryl substituted pyrrolidine-2,5-diones via catalytic Michael reaction and evaluation of their inhibitory activity against InhA and Mycobacterium tuberculosis.
Year : 2014
Volume : 71
First Page : 46
Last Page : 52
Authors : Matviiuk T, Mori G, Lherbet C, Rodriguez F, Pasca MR, Gorichko M, Guidetti B, Voitenko Z, Baltas M.
Abstract : In the present paper, we report the synthesis via catalytic Michael reaction and biological results of a series of 3-heteryl substituted pyrrolidine-2,5-dione derivatives as moderate inhibitors against Mycobacterium tuberculosis H37Rv growth. Some of them present also inhibition activities against InhA.
|
Inhibition of Mycobacterium tuberculosis InhA using dodecyl coA as substrate by LC-MS/MS analysis
|
Mycobacterium tuberculosis
|
630.0
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.
|
Inhibition of Plasmodium falciparum FabI
|
Plasmodium falciparum
|
0.015
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 2-Octadecynoic acid as a dual life stage inhibitor of Plasmodium infections and plasmodial FAS-II enzymes.
Year : 2014
Volume : 24
Issue : 17
First Page : 4151
Last Page : 4157
Authors : Carballeira NM, Bwalya AG, Itoe MA, Andricopulo AD, Cordero-Maldonado ML, Kaiser M, Mota MM, Crawford AD, Guido RV, Tasdemir D.
Abstract : The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50=0.34 μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80 μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites.
|
Inhibition of Staphylococcus aureus FabI assessed as reduction in inhibition of reduction of trans-2-octenoyl N-acetylcysteamine substrate by spectrophotometry
|
Staphylococcus aureus
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a potent enoyl-acyl carrier protein reductase (FabI) inhibitor suitable for antistaphylococcal agent.
Year : 2015
Volume : 25
Issue : 20
First Page : 4481
Last Page : 4486
Authors : Kim YG, Seo JH, Kwak JH, Shin KJ.
Abstract : We report the discovery, synthesis, and biological activities of phenoxy-4-pyrone and phenoxy-4-pyridone derivatives as novel inhibitors of enoyl-acyl carrier protein reductase (FabI). Pyridone derivatives showed better activities than pyrone derivatives against FabI and Staphylococcus aureus strains, including methicillin-resistant Staphylococcus aureus (MRSA). Among the pyridone derivatives, compound 16l especially exhibited promising activities against the MRSA strain and good pharmacokinetic profiles.
|
Inhibition of Mycobacterium tuberculosis His6-tagged InhA expressed in Escherichia coli BL21 using trans-2-dodecenoyl-coA as substrate at 50 uM
|
Mycobacterium tuberculosis
|
99.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, antimycobacterial screening and ligand-based molecular docking studies on novel pyrrole derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties.
Year : 2016
Volume : 107
First Page : 133
Last Page : 152
Authors : Joshi SD, Dixit SR, Kirankumar MN, Aminabhavi TM, Raju KV, Narayan R, Lherbet C, Yang KS.
Abstract : We report here the synthesis, antibacterial and antitubercular evaluation of 61 novel pyrrolyl derivatives bearing pyrazoline, isoxazole and phenyl thiourea moieties. Molecular docking was carried out on enoyl ACP reductase from Mycobacterium tuberculsosis using Surflex-Dock, which is one of the key enzymes involved in type II fatty acid biosynthetic pathway of Mycobacterium tuberculosis, an attractive target for designing novel antitubercular agents. Docking analysis of the crystal structure of ENR performed using Surflex-Dock in Sybyl-X 2.0 software indicates the occupation of substituted pyrrolyl derivatives into hydrophobic pocket of InhA enzyme. Compounds 9b and 9d exhibited the highest antitubercular activity almost close to isoniazid (0.4 μg/mL) with a MIC value of 0.8 μg/mL. All other compounds showed the good activity with a MIC value of 6.25-100 μg/mL. The compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) and were nontoxic. Some compounds exhibited inhibition activities against InhA.
|
Inhibition of His6-tagged recombinant Mycobacterium tuberculosis InhA expressed in protease-deficient Escherichia coli (BL21) using trans-2-dodecenoyl-coenzyme A as substrate assessed as NADH oxidation at 50 uM relative to control
|
Mycobacterium tuberculosis
|
99.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis, characterization and antitubercular activities of novel pyrrolyl hydrazones and their Cu-complexes.
Year : 2016
Volume : 121
First Page : 21
Last Page : 39
Authors : Joshi SD, Kumar D, Dixit SR, Tigadi N, More UA, Lherbet C, Aminabhavi TM, Yang KS.
Abstract : Novel pyrrolyl hydrazones and their copper complexes have been synthesized and characterized using analytical and spectral techniques to show the tetrahedral geometry for Cu(II) complexes. Biological activities of hydrazones have been assessed to understand the role of metal ion on their biological activity and the effect of pyrrolyl hydrazones. In vitro antitubercular activity against Mycobacterium tuberculosis of the metal complexes (13b and 13r) exhibited the highest antitubercular activity that are quite close to rifampicin (0.4 μg/mL), giving a MIC of 0.8 μg/mL. All other compounds showed good activity with the MIC values ranging from 1.6 to 100 μg/mL. A comparative study of inhibition values of the ligands and their complexes showed higher antimicrobial activity of the complexes than the ligands. Some compounds have a good activity against InhA and in particular, compounds 12r, 13b and 13r exhibited more than 60% binding with the enzyme even at 5 μM (exhibited good IC50 upto 2.4 μM). Most of the active molecules have a very less cytotoxicity against the human lung cancer cell-line A549. The docking and 3D-QSAR studies have been carried out to provide some insights into the mechanism of action for this class of compounds.
|
Inhibition of Mycobacterium tuberculosis His6-tagged wild type InhA expressed in Escherichia coli BL21 at 50 uM using DDCoA as substrate relative to control
|
Mycobacterium tuberculosis
|
99.0
%
|
|
Journal : Eur J Med Chem
Title : Synthesis, biological evaluation and in silico molecular modeling of pyrrolyl benzohydrazide derivatives as enoyl ACP reductase inhibitors.
Year : 2017
Volume : 126
First Page : 286
Last Page : 297
Authors : Joshi SD, Dixit SR, Kulkarni VH, Lherbet C, Nadagouda MN, Aminabhavi TM.
Abstract : In efforts to develop lead anti-TB compounds, a novel series of 19 pyrrolyl benzohydrazides were synthesized and screened to target enoyl-ACP reductase enzyme, which is one of the important enzymes involved in type II fatty acid biosynthetic pathway of M. tuberculosis. Pharmacophores were constructed using GALAHAD to generate alignment of data sets and calculated by Pareto ranking. The pharmacophore features were then filtered by Surflex-dock study using enoyl ACP reductase from M. tuberculosis. Compounds 5b and 5d showed H-bonding interactions with Tyr158, Thr196 and co-factor NAD+ that fitted well within the binding pocket of InhA. All the synthesized compounds were screened for preliminary antibacterial activities against Gram-positive S. aureus and Gram-negative E. coli and M. tuberculosis H37Rv to evaluate their antitubercular activities. Some representative compounds were further tested for mammalian cell toxicity using human lung cancer cell-line (A549) that was found to be nontoxic. These compounds exhibited moderate inhibition activities against InhA.
|
Inhibition of Mycobacterium tuberculosis InhA
|
Mycobacterium tuberculosis
|
220.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview on crystal structures of InhA protein: Apo-form, in complex with its natural ligands and inhibitors.
Year : 2018
Volume : 146
First Page : 318
Last Page : 343
Authors : Chollet A, Maveyraud L, Lherbet C, Bernardes-Génisson V.
Abstract : The enoyl-ACP reductase InhA from the mycobacterial fatty acid biosynthesis pathway has become a target of interest for the development of new anti-tubercular drugs. This protein has been identified as essential for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis, and as the main target of two pro-drugs: isoniazid, the frontline anti-tubercular drug, and ethionamide, a second-line medicine. Since most cases of resistance to isoniazid and ethionamide result from mutations in the mycobacterial activating enzyme (KatG for isoniazid and EthA for ethionamide), research of direct InhA inhibitors, avoiding the activation step, has emerged as a promising strategy for combating tuberculosis. Thereby, InhA is drawing much attention and its three-dimensional structure has been particularly studied. A better understanding of key sites of interactions responsible for InhA inhibition arises thus as an essential tool for the rational design of new potent inhibitors. In this paper, we propose an overview of the 80 available crystal structures of wild-type and mutant InhA, in its apo form, in complex with its cofactor, with an analogue of its natural ligands (C16 fatty acid and/or NADH) or with inhibitors. We will first discuss structural and mechanistic aspects in order to highlight key features of the protein before delivering thorough inventory of structures of InhA in the presence of synthetic ligands to underline the key interactions implicated in high affinity inhibition.
|
Uncompetitive inhibition of Mycobacterium tuberculosis InhA using trans-2-dodecenoyl-CoA as substrate in presence of NADH
|
Mycobacterium tuberculosis
|
200.0
nM
|
|
Journal : Eur J Med Chem
Title : An overview on crystal structures of InhA protein: Apo-form, in complex with its natural ligands and inhibitors.
Year : 2018
Volume : 146
First Page : 318
Last Page : 343
Authors : Chollet A, Maveyraud L, Lherbet C, Bernardes-Génisson V.
Abstract : The enoyl-ACP reductase InhA from the mycobacterial fatty acid biosynthesis pathway has become a target of interest for the development of new anti-tubercular drugs. This protein has been identified as essential for the survival of Mycobacterium tuberculosis, the causative agent of tuberculosis, and as the main target of two pro-drugs: isoniazid, the frontline anti-tubercular drug, and ethionamide, a second-line medicine. Since most cases of resistance to isoniazid and ethionamide result from mutations in the mycobacterial activating enzyme (KatG for isoniazid and EthA for ethionamide), research of direct InhA inhibitors, avoiding the activation step, has emerged as a promising strategy for combating tuberculosis. Thereby, InhA is drawing much attention and its three-dimensional structure has been particularly studied. A better understanding of key sites of interactions responsible for InhA inhibition arises thus as an essential tool for the rational design of new potent inhibitors. In this paper, we propose an overview of the 80 available crystal structures of wild-type and mutant InhA, in its apo form, in complex with its cofactor, with an analogue of its natural ligands (C16 fatty acid and/or NADH) or with inhibitors. We will first discuss structural and mechanistic aspects in order to highlight key features of the protein before delivering thorough inventory of structures of InhA in the presence of synthetic ligands to underline the key interactions implicated in high affinity inhibition.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-1.82
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
2.41
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
4.443
%
|
|
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
|
0.09
%
|
|
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
|
-0.01
%
|
|
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
|
0.09
%
|
|
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
|
-0.01
%
|
|
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.
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Inhibition of Mycobacterium tuberculosis InhA assessed as effect on NADH oxidation incubated for 10 mins by spectrophotometry
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None
|
460.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Mycobacterium tuberculosis InhA Inhibitors by Binding Sites Comparison and Ligands Prediction.
Year : 2016
Volume : 59
Issue : 24.0
First Page : 11069
Last Page : 11078
Authors : Štular T,Lešnik S,Rožman K,Schink J,Zdouc M,Ghysels A,Liu F,Aldrich CC,Haupt VJ,Salentin S,Daminelli S,Schroeder M,Langer T,Gobec S,Janežič D,Konc J
Abstract : Drug discovery is usually focused on a single protein target; in this process, existing compounds that bind to related proteins are often ignored. We describe ProBiS plugin, extension of our earlier ProBiS-ligands approach, which for a given protein structure allows prediction of its binding sites and, for each binding site, the ligands from similar binding sites in the Protein Data Bank. We developed a new database of precalculated binding site comparisons of about 290000 proteins to allow fast prediction of binding sites in existing proteins. The plugin enables advanced viewing of predicted binding sites, ligands' poses, and their interactions in three-dimensional graphics. Using the InhA query protein, an enoyl reductase enzyme in the Mycobacterium tuberculosis fatty acid biosynthesis pathway, we predicted its possible ligands and assessed their inhibitory activity experimentally. This resulted in three previously unrecognized inhibitors with novel scaffolds, demonstrating the plugin's utility in the early drug discovery process.
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Inhibition of wild type InhA in Mycobacterium tuberculosis H37Rv using trans-2-dodecenoyl-coenzyme A as substrate at 50 uM
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Mycobacterium tuberculosis H37Rv
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99.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of hydrazone containing thiadiazoles as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.
Year : 2020
Volume : 188
First Page : 112035
Last Page : 112035
Authors : Doğan H,Doğan ŞD,Gündüz MG,Krishna VS,Lherbet C,Sriram D,Şahin O,Sarıpınar E
Abstract : Tuberculosis, caused by Mycobacterium tuberculosis, is a serious infectious disease and remains a global health problem. There is an increasing need for the discovery of novel therapeutic agents for its treatment due to the emerging multi-drug resistance. Herein, we present the rational design and the synthesis of eighteen new thiadiazolylhidrazones (TDHs) which were synthesized by intramolecular oxidative N-S bond formation reaction of 2-benzylidene-N-(phenylcarbamothioyl)hydrazine-1-carboximidamide derivatives by phenyliodine(III) bis(trifluoroacetate) (PIFA) under mild conditions. The compounds were characterized by various spectral techniques including FTIR, H NMR, C NMR and HRMS. Furthermore, the proposed structure of TDH12 was resolved by single-crystal X-ray analysis. The compounds were evaluated for their in vitro antitubercular activity against M. tuberculosis H37Rv. Among them, some compounds exhibited remarkable antimycobacterial activity, MIC = 0.78-6.25 μg/mL, with low cytotoxicity. Additionally, the most active compounds were screened for their biological activities against M. tuberculosis in the nutrient starvation model. Enzyme inhibition assays and molecular docking studies revealed enoyl acyl carrier protein reductase (InhA) as the possible target enzyme of the compounds to show their antitubercular activities.
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Inhibition of recombinant Mycobacterium tuberculosis His6-tagged InHA expressed in Escherichia coli BL21 using trans-2-dodecenoyl-Coenzyme A as substrate at 50 uM relative to control
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Mycobacterium tuberculosis
|
99.0
%
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.
Year : 2020
Volume : 199
First Page : 112402
Last Page : 112402
Authors : Doğan ŞD,Gündüz MG,Doğan H,Krishna VS,Lherbet C,Sriram D
Abstract : Tuberculosis remains the most deadly infectious disease worldwide due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Hence, there is a great need for more efficient treatment regimens. Herein, we carried out rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) (PDB code: 5OIL). Although this compound fulfills all structural requirements to interact with InhA, it does not inhibit the enzyme effectively. With the aim of improving the inhibition value, we synthesized thiourea-based derivatives by one-pot reaction of the amines with corresponding isothiocyanates. After the structural characterization using H NMR, C NMR, FTIR and HRMS, the obtained compounds were initially tested for their abilities to inhibit Mycobacterium tuberculosis growth. The results revealed that some compounds exhibited promising antitubercular activity, MIC values at 0.78 and 1.56 μg/mL, combined with low cytotoxicity. Moreover, the most active compounds were tested against latent as well as dormant forms of the bacteria utilizing nutrient starvation model and Mycobacterium tuberculosis infected macrophage assay. Enzyme inhibition assay against enoyl-acyl carrier protein reductase identified InhA as the important target of some compounds. Molecular docking studies were performed to correlate InhA inhibition data with in silico results. Finally, theoretical calculations were established to predict the physicochemical properties of the most active compounds.
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Inhibition of recombinant Mycobacterium tuberculosis His6-tagged InHA expressed in Escherichia coli BL21 using trans-2-dodecenoyl-Coenzyme A as substrate at 5 uM relative to control
|
Mycobacterium tuberculosis
|
95.0
%
|
|
Journal : Eur J Med Chem
Title : Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors.
Year : 2020
Volume : 199
First Page : 112402
Last Page : 112402
Authors : Doğan ŞD,Gündüz MG,Doğan H,Krishna VS,Lherbet C,Sriram D
Abstract : Tuberculosis remains the most deadly infectious disease worldwide due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Hence, there is a great need for more efficient treatment regimens. Herein, we carried out rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) (PDB code: 5OIL). Although this compound fulfills all structural requirements to interact with InhA, it does not inhibit the enzyme effectively. With the aim of improving the inhibition value, we synthesized thiourea-based derivatives by one-pot reaction of the amines with corresponding isothiocyanates. After the structural characterization using H NMR, C NMR, FTIR and HRMS, the obtained compounds were initially tested for their abilities to inhibit Mycobacterium tuberculosis growth. The results revealed that some compounds exhibited promising antitubercular activity, MIC values at 0.78 and 1.56 μg/mL, combined with low cytotoxicity. Moreover, the most active compounds were tested against latent as well as dormant forms of the bacteria utilizing nutrient starvation model and Mycobacterium tuberculosis infected macrophage assay. Enzyme inhibition assay against enoyl-acyl carrier protein reductase identified InhA as the important target of some compounds. Molecular docking studies were performed to correlate InhA inhibition data with in silico results. Finally, theoretical calculations were established to predict the physicochemical properties of the most active compounds.
