|
Inhibitory activity against mammalian DNA topoisomerase II
|
None
|
600.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological testing of non-fluorinated analogues of levofloxacin.
Year : 2003
Volume : 13
Issue : 14
First Page : 2373
Last Page : 2375
Authors : Gray JL, Almstead JI, Gallagher CP, Hu XE, Kim NK, Taylor CJ, Twinem TL, Wallace CD, Ledoussal B.
Abstract : Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.
|
Inhibitory activity against quinolone resistant gyrase in Escherichia coli
|
Escherichia coli
|
12.8
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological testing of non-fluorinated analogues of levofloxacin.
Year : 2003
Volume : 13
Issue : 14
First Page : 2373
Last Page : 2375
Authors : Gray JL, Almstead JI, Gallagher CP, Hu XE, Kim NK, Taylor CJ, Twinem TL, Wallace CD, Ledoussal B.
Abstract : Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.
|
Inhibitory activity against wild type gyrase in Escherichia coli
|
Escherichia coli
|
3.2
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological testing of non-fluorinated analogues of levofloxacin.
Year : 2003
Volume : 13
Issue : 14
First Page : 2373
Last Page : 2375
Authors : Gray JL, Almstead JI, Gallagher CP, Hu XE, Kim NK, Taylor CJ, Twinem TL, Wallace CD, Ledoussal B.
Abstract : Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.
|
Gyrase inhibitory activity against Escherichia coli
|
Escherichia coli
|
1.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and bacterial DNA gyrase inhibitory properties of a spirocyclopropylquinolone derivative.
Year : 1988
Volume : 31
Issue : 9
First Page : 1694
Last Page : 1697
Authors : Wentland MP, Perni RB, Dorff PH, Rake JB.
Abstract : A novel conformationally restricted 1-cyclopropylquinolone (1) that incorporates structural features of both ofloxacin and ciprofloxacin has been prepared. Compound 1 was found to be a DNA gyrase inhibitor having potency similar to ofloxacin but less than ciprofloxacin. The cellular inhibitory and in vivo antibacterial potencies of 1 were found to be less than those of the two reference agents.
|
Inhibition constant against DNA Gyrase isolated from Escherichia coli
|
Escherichia coli
|
0.9
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin).
Year : 1987
Volume : 30
Issue : 12
First Page : 2283
Last Page : 2286
Authors : Mitscher LA, Sharma PN, Chu DT, Shen LL, Pernet AG.
Abstract : A short and efficient synthesis, starting with (R)- and (S)-alaninol, of the two optical antipodes of the quinolone antimicrobial agent ofloxacin has been devised. Testing in vitro of the products against a range of bacteria and in an assay system incorporating purified DNA gyrase from different bacterial species demonstrates that the S-(-) enantiomer is substantially the more active.
|
Inhibition constant against DNA Gyrase isolated from Micrococcus luteus
|
Micrococcus luteus
|
36.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin).
Year : 1987
Volume : 30
Issue : 12
First Page : 2283
Last Page : 2286
Authors : Mitscher LA, Sharma PN, Chu DT, Shen LL, Pernet AG.
Abstract : A short and efficient synthesis, starting with (R)- and (S)-alaninol, of the two optical antipodes of the quinolone antimicrobial agent ofloxacin has been devised. Testing in vitro of the products against a range of bacteria and in an assay system incorporating purified DNA gyrase from different bacterial species demonstrates that the S-(-) enantiomer is substantially the more active.
|
Displacement of [3H]dofetilide from human ERG at 300 uM
|
Homo sapiens
|
10.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological evaluation of novel series of nitrile-containing fluoroquinolones as antibacterial agents.
Year : 2007
Volume : 17
Issue : 8
First Page : 2150
Last Page : 2155
Authors : Murphy ST, Case HL, Ellsworth E, Hagen S, Huband M, Joannides T, Limberakis C, Marotti KR, Ottolini AM, Rauckhorst M, Starr J, Stier M, Taylor C, Zhu T, Blaser A, Denny WA, Lu GL, Smaill JB, Rivault F.
Abstract : Several novel series of nitrile-containing fluoroquinolones with weakly basic amines are reported which have reduced potential for hERG (human ether-a-go-go gene) channel inhibition as measured by the dofetilide assay. The new fluoroquinolones are potent against both Gram-positive and fastidious Gram-negative strains, including Methicillin resistant Staphylococcus aureus and fluoroquinolone-resistant Streptococcus pneumoniae. Several analogs also showed low potential for human genotoxicity as measured by the clonogenicity test. Compounds 22 and 37 (designated PF-00951966 and PF-02298732, respectively), which had good in vitro activity and in vitro safety profiles, also showed good pharmacokinetic properties in rats.
|
Inhibition of Mycobacterium leprae recombinant DNA gyrase expressed in Escherichia coli assessed as inhibition of pBR322 DNA supercoiling
|
Mycobacterium leprae
|
7.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Expression and purification of an active form of the Mycobacterium leprae DNA gyrase and its inhibition by quinolones.
Year : 2007
Volume : 51
Issue : 5
First Page : 1643
Last Page : 1648
Authors : Matrat S, Petrella S, Cambau E, Sougakoff W, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae, the causative agent of leprosy, is noncultivable in vitro; therefore, evaluation of antibiotic activity against M. leprae relies mainly upon the mouse footpad system, which requires at least 12 months before the results become available. We have developed an in vitro assay for studying the activities of quinolones against the DNA gyrase of M. leprae. We overexpressed in Escherichia coli the M. leprae GyrA and GyrB subunits separately as His-tagged proteins by using a pET plasmid carrying the gyrA and gyrB genes. The soluble 97.5-kDa GyrA and 74.5-kDa GyrB subunits were purified by nickel chelate chromatography and were reconstituted as an enzyme with DNA supercoiling activity. Based on the drug concentrations that inhibited DNA supercoiling by 50% or that induced DNA cleavage by 25%, the 13 quinolones tested clustered into three groups. Analysis of the quinolone structure-activity relationship demonstrates that the most active quinolones against M. leprae DNA gyrase share the following structural features: a substituted carbon at position 8, a cyclopropyl substituent at N-1, a fluorine at C-6, and a substituent ring at C-7. We conclude that the assays based on DNA supercoiling inhibition and drug-induced DNA cleavage on purified M. leprae DNA gyrase are rapid, efficient, and safe methods for the screening of quinolone derivatives with potential in vivo activities against M. leprae.
|
Inhibition of Staphylococcus aureus MS5935 wild type DNA gyrase-mediated supercoiling activity
|
Staphylococcus aureus
|
9.31
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives carrying the 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl group as a C-10 substituent.
Year : 2008
Volume : 51
Issue : 11
First Page : 3238
Last Page : 3249
Authors : Asahina Y, Takei M, Kimura T, Fukuda Y.
Abstract : Novel pyrido[1,2,3- de][1,4]benzoxazine-6-carboxylic acid derivatives 5- 9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.
|
Inhibition of quinoline-resistant Staphylococcus aureus MS5935 DNA gyrase-mediated supercoiling activity
|
Staphylococcus aureus
|
772.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives carrying the 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl group as a C-10 substituent.
Year : 2008
Volume : 51
Issue : 11
First Page : 3238
Last Page : 3249
Authors : Asahina Y, Takei M, Kimura T, Fukuda Y.
Abstract : Novel pyrido[1,2,3- de][1,4]benzoxazine-6-carboxylic acid derivatives 5- 9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.
|
Inhibition of Staphylococcus aureus MS5935 wild type topoisomerase 4-mediated decatenation activity
|
Staphylococcus aureus
|
5.44
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives carrying the 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl group as a C-10 substituent.
Year : 2008
Volume : 51
Issue : 11
First Page : 3238
Last Page : 3249
Authors : Asahina Y, Takei M, Kimura T, Fukuda Y.
Abstract : Novel pyrido[1,2,3- de][1,4]benzoxazine-6-carboxylic acid derivatives 5- 9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.
|
Inhibition of quinoline-resistant Staphylococcus aureus MS5935 topoisomerase 4-mediated decatenation activity
|
Staphylococcus aureus
|
319.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives carrying the 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl group as a C-10 substituent.
Year : 2008
Volume : 51
Issue : 11
First Page : 3238
Last Page : 3249
Authors : Asahina Y, Takei M, Kimura T, Fukuda Y.
Abstract : Novel pyrido[1,2,3- de][1,4]benzoxazine-6-carboxylic acid derivatives 5- 9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.
|
Inhibition of Staphylococcus aureus wild type DNA topoisomerase 4
|
Staphylococcus aureus
|
2.67
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.
Year : 2009
Volume : 17
Issue : 19
First Page : 6879
Last Page : 6889
Authors : Miyauchi R, Kawakami K, Ito M, Matsuhashi N, Ohki H, Inagaki H, Takahashi H, Takemura M.
Abstract : A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.
|
Inhibition of Staphylococcus aureus DNA topoisomerase 4 Ser80Phe mutant
|
Staphylococcus aureus
|
57.1
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.
Year : 2009
Volume : 17
Issue : 19
First Page : 6879
Last Page : 6889
Authors : Miyauchi R, Kawakami K, Ito M, Matsuhashi N, Ohki H, Inagaki H, Takahashi H, Takemura M.
Abstract : A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.
|
Inhibition of Staphylococcus aureus wild type DNA gyrase
|
Staphylococcus aureus
|
9.41
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.
Year : 2009
Volume : 17
Issue : 19
First Page : 6879
Last Page : 6889
Authors : Miyauchi R, Kawakami K, Ito M, Matsuhashi N, Ohki H, Inagaki H, Takahashi H, Takemura M.
Abstract : A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.
|
Inhibition of Staphylococcus aureus DNA gyrase Ser84Leu mutant
|
Staphylococcus aureus
|
512.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.
Year : 2009
Volume : 17
Issue : 19
First Page : 6879
Last Page : 6889
Authors : Miyauchi R, Kawakami K, Ito M, Matsuhashi N, Ohki H, Inagaki H, Takahashi H, Takemura M.
Abstract : A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.
|
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
|
230.0
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
|
370.0
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
|
230.0
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
|
690.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Microorganism-Based Dose Response HTS to Identify Compounds Cytotoxic to Streptococcus. (Class of assay: confirmatory) [Related pubchem assays: 1900 (Counter Screen), 1677 (Project Summary), 1902 (Retest at Dose), 1662 (Primary HTS)]
|
Streptococcus
|
911.0
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
|
230.0
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
|
230.0
nM
|
|
Title : PubChem BioAssay data set
|
Bactericidal activity against Staphylococcus aureus ATCC 29213 assessed as eradication of pre-formed biofilm at 50 times MIC after 24 hrs
|
Staphylococcus aureus
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of DNase and antibiotics on biofilm characteristics.
Year : 2009
Volume : 53
Issue : 3
First Page : 1204
Last Page : 1209
Authors : Tetz GV, Artemenko NK, Tetz VV.
Abstract : The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community biomass, architecture, morphology, and the numbers of CFU in the presence of DNase. This effect seems to be common to biofilms established by various unrelated gram-positive and gram-negative bacteria. The cleavage of extracellular DNA leads to the formation of an altered biofilm that permits the increased penetration of antibiotics. Thus, the addition of DNase enhances the effect of antibiotics, resulting in decreased biofilm biomass and numbers of CFU.
|
Bactericidal activity against Streptococcus pyogenes VT 59 assessed as eradication of pre-formed biofilm at 50 times MIC after 24 hrs
|
Streptococcus pyogenes
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of DNase and antibiotics on biofilm characteristics.
Year : 2009
Volume : 53
Issue : 3
First Page : 1204
Last Page : 1209
Authors : Tetz GV, Artemenko NK, Tetz VV.
Abstract : The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community biomass, architecture, morphology, and the numbers of CFU in the presence of DNase. This effect seems to be common to biofilms established by various unrelated gram-positive and gram-negative bacteria. The cleavage of extracellular DNA leads to the formation of an altered biofilm that permits the increased penetration of antibiotics. Thus, the addition of DNase enhances the effect of antibiotics, resulting in decreased biofilm biomass and numbers of CFU.
|
Bactericidal activity against Acinetobacter baumannii VT 126 assessed as eradication of pre-formed biofilm at 50 times MIC after 24 hrs
|
Acinetobacter baumannii
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of DNase and antibiotics on biofilm characteristics.
Year : 2009
Volume : 53
Issue : 3
First Page : 1204
Last Page : 1209
Authors : Tetz GV, Artemenko NK, Tetz VV.
Abstract : The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community biomass, architecture, morphology, and the numbers of CFU in the presence of DNase. This effect seems to be common to biofilms established by various unrelated gram-positive and gram-negative bacteria. The cleavage of extracellular DNA leads to the formation of an altered biofilm that permits the increased penetration of antibiotics. Thus, the addition of DNase enhances the effect of antibiotics, resulting in decreased biofilm biomass and numbers of CFU.
|
Bactericidal activity against Haemophilus influenzae VT450-2006 assessed as eradication of pre-formed biofilm at 50 times MIC after 24 hrs
|
Haemophilus influenzae
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of DNase and antibiotics on biofilm characteristics.
Year : 2009
Volume : 53
Issue : 3
First Page : 1204
Last Page : 1209
Authors : Tetz GV, Artemenko NK, Tetz VV.
Abstract : The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community biomass, architecture, morphology, and the numbers of CFU in the presence of DNase. This effect seems to be common to biofilms established by various unrelated gram-positive and gram-negative bacteria. The cleavage of extracellular DNA leads to the formation of an altered biofilm that permits the increased penetration of antibiotics. Thus, the addition of DNase enhances the effect of antibiotics, resulting in decreased biofilm biomass and numbers of CFU.
|
Bactericidal activity against Klebsiella pneumoniae VT 1367 assessed as eradication of pre-formed biofilm at 50 times MIC after 24 hrs
|
Klebsiella pneumoniae
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of DNase and antibiotics on biofilm characteristics.
Year : 2009
Volume : 53
Issue : 3
First Page : 1204
Last Page : 1209
Authors : Tetz GV, Artemenko NK, Tetz VV.
Abstract : The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community biomass, architecture, morphology, and the numbers of CFU in the presence of DNase. This effect seems to be common to biofilms established by various unrelated gram-positive and gram-negative bacteria. The cleavage of extracellular DNA leads to the formation of an altered biofilm that permits the increased penetration of antibiotics. Thus, the addition of DNase enhances the effect of antibiotics, resulting in decreased biofilm biomass and numbers of CFU.
|
Bactericidal activity against Escherichia coli ATCC 25922 assessed as eradication of pre-formed biofilm at 50 times MIC after 24 hrs
|
Escherichia coli
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of DNase and antibiotics on biofilm characteristics.
Year : 2009
Volume : 53
Issue : 3
First Page : 1204
Last Page : 1209
Authors : Tetz GV, Artemenko NK, Tetz VV.
Abstract : The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community biomass, architecture, morphology, and the numbers of CFU in the presence of DNase. This effect seems to be common to biofilms established by various unrelated gram-positive and gram-negative bacteria. The cleavage of extracellular DNA leads to the formation of an altered biofilm that permits the increased penetration of antibiotics. Thus, the addition of DNase enhances the effect of antibiotics, resulting in decreased biofilm biomass and numbers of CFU.
|
Bactericidal activity against Pseudomonas aeruginosa ATCC 27853 assessed as eradication of pre-formed biofilm at 50 times MIC after 24 hrs
|
Pseudomonas aeruginosa
|
10.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : Effect of DNase and antibiotics on biofilm characteristics.
Year : 2009
Volume : 53
Issue : 3
First Page : 1204
Last Page : 1209
Authors : Tetz GV, Artemenko NK, Tetz VV.
Abstract : The role of extracellular DNA in the maintenance of biofilms formed by gram-positive and gram-negative bacteria was studied. This study evaluated all the bacterial strains that were tested for the presence of extracellular DNA with an average size of 30 kb in the matrix. Our results indicate changes in community biomass, architecture, morphology, and the numbers of CFU in the presence of DNase. This effect seems to be common to biofilms established by various unrelated gram-positive and gram-negative bacteria. The cleavage of extracellular DNA leads to the formation of an altered biofilm that permits the increased penetration of antibiotics. Thus, the addition of DNase enhances the effect of antibiotics, resulting in decreased biofilm biomass and numbers of CFU.
|
Antimicrobial activity against Pseudomonas aeruginosa infected in Swiss-Webster mouse at 200 mg/kg, ip administered as single dose
|
Pseudomonas aeruginosa
|
3.15
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Pharmacodynamics of levofloxacin in a murine pneumonia model of Pseudomonas aeruginosa infection: determination of epithelial lining fluid targets.
Year : 2009
Volume : 53
Issue : 8
First Page : 3325
Last Page : 3330
Authors : Louie A, Fregeau C, Liu W, Kulawy R, Drusano GL.
Abstract : The dose choice for Pseudomonas aeruginosa remains a matter of debate. The actual exposure targets required for multilog killing of organisms at the primary infection site have not been delineated. We studied Pseudomonas aeruginosa PAO1 using a murine model of pneumonia. We employed a large mathematical model to fit all the concentration-time data in plasma and epithelial lining fluid (ELF) as well as colony counts in lung simultaneously for all drug doses. Penetration into ELF was calculated to be approximately 77.7%, as indexed to the ratio of the area under the concentration-time curve for ELF (AUC(ELF)) to the AUC(plasma). We determined the ELF concentration-time profile required to drive a stasis response as well as 1-, 2-, or 3-log(10)(CFU/g) kill. AUC/MIC ratios of 12.4, 31.2, 62.8, and 127.6 were required to drive these bacterial responses. Emergence of resistance was seen only at the two lowest doses (three of five animals at 50 mg/kg [body weight] and one of five animals at 100 mg/kg). The low exposure targets were likely driven by a low mutational frequency to resistance. Bridging to humans was performed using Monte Carlo simulation. With a 750-mg levofloxacin dose, target attainment rates fell below 90% at 4 mg/liter, 1 mg/liter, and 0.5 mg/liter for 1-, 2-, and 3-log kills, respectively. Given the low exposure targets seen with this strain, we conclude that levofloxacin at a 750-mg dose is not adequate for serious Pseudomonas aeruginosa pneumonia as a single agent. More isolates need to be studied to make these observations more robust.
|
Antimycobacterial activity against Mycobacterium tuberculosis H37Rv after 6 days by MTT colorimetric microassay
|
Mycobacterium tuberculosis H37Rv
|
800.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis of lipophilic dimeric C-7/C-7-linked ciprofloxacin and C-6/C-6-linked levofloxacin derivatives. Versatile in vitro biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or antimycobacterial agents.
Year : 2011
Volume : 46
Issue : 12
First Page : 6025
Last Page : 6038
Authors : Azéma J, Guidetti B, Korolyov A, Kiss R, Roques C, Constant P, Daffé M, Malet-Martino M.
Abstract : The synthesis of C-7/C-7-linked ciprofloxacin (CP) and C-6/C-6-linked levofloxacin (LV) derivatives with modulated lipophilicity is described herein. The synthesized compounds, along with the monomeric analogs described previously, were evaluated in vitro for (i) their growth inhibitory effect against five human cancer cell lines, (ii) their antibacterial activity against Gram-positive Staphylococcus aureus and Enterococcus hirae and Gram-negative Escherichia coli and Pseudomonas aeruginosa strains and (iii) their antimycobacterial activity. The most efficient derivatives as antiproliferative agents (C-7/C-7-linked CP 7e and C-6/C-6-linked LV 11f) displayed IC(50) values in the 0.1-8.7 and 0.2-0.7 μM ranges respectively while IC(50) values for parent CP and LV ranged from 89 to 476 μM and from 67 to 622 μM respectively depending on the cell line. A specific antibacterial activity against S. aureus was found for the monomeric and dimeric derivatives of CP. The most efficient derivative against S. aureus (monomeric oxoethyloctanoate CP derivative 3d) displayed MIC <1 nM. Monomeric alkanoyloxymethyl LV esters (9a,c,e,f) and C-6/C-6-linked LV derivatives (11f-h) were the most efficient derivatives as antimycobacterial agents with MIC and IC(50) values in the 2.5-5 μM and 1.3-≤ 2.5 μM ranges respectively while MIC and IC(50) values for parent LV were 2.5 and 0.8 μM, respectively.
|
Inhibition of human MATE1-mediated ASP+ uptake expressed in HEK293 cells at 20 uM after 1.5 mins by fluorescence assay
|
Homo sapiens
|
26.0
%
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
Year : 2013
Volume : 56
Issue : 3
First Page : 781
Last Page : 795
Authors : Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM.
Abstract : The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.
|
Inhibition of human ERG expressed in CHOK1 cells at 100 uM
|
Homo sapiens
|
4.2
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluations of novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-8-methoxyquinolines with potent antibacterial activity against respiratory pathogens.
Year : 2013
Volume : 56
Issue : 5
First Page : 1974
Last Page : 1983
Authors : Odagiri T, Inagaki H, Sugimoto Y, Nagamochi M, Miyauchi RN, Kuroyanagi J, Kitamura T, Komoriya S, Takahashi H.
Abstract : Novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2a and 2b were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound 2a possessing (S)-configuration for the asymmetrical carbon on the pyrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens including gram-positive (Streptococcus pneumoniae and Staphylococcus aureus), gram-negative (Haemophilus influenzae and Moraxcella catarrhalis), and atypical strains (Chalmydia pneumoniae and Mycoplasma pneumoniae), as well as multidrug-resistant Streptococcus pneumoniae and quinolone-resistant and methicillin-resistant Staphylococcus aureus). Furthermore, compound 2a showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant Streptococcus pneumoniae (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies.
|
Inhibition of human ERG expressed in CHOK1 cells at 30 uM
|
Homo sapiens
|
-0.9
%
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological evaluations of novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-8-methoxyquinolines with potent antibacterial activity against respiratory pathogens.
Year : 2013
Volume : 56
Issue : 5
First Page : 1974
Last Page : 1983
Authors : Odagiri T, Inagaki H, Sugimoto Y, Nagamochi M, Miyauchi RN, Kuroyanagi J, Kitamura T, Komoriya S, Takahashi H.
Abstract : Novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2a and 2b were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound 2a possessing (S)-configuration for the asymmetrical carbon on the pyrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens including gram-positive (Streptococcus pneumoniae and Staphylococcus aureus), gram-negative (Haemophilus influenzae and Moraxcella catarrhalis), and atypical strains (Chalmydia pneumoniae and Mycoplasma pneumoniae), as well as multidrug-resistant Streptococcus pneumoniae and quinolone-resistant and methicillin-resistant Staphylococcus aureus). Furthermore, compound 2a showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant Streptococcus pneumoniae (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
117.4
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
95.07
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Antibacterial activity against methicillin-sensitive Staphylococcus aureus ATCC 29213 after 18 hrs by broth microdilution method
|
Staphylococcus aureus
|
250.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against methicillin-resistant Staphylococcus aureus ATCC 33591 after 18 hrs by broth microdilution method
|
Staphylococcus aureus
|
250.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against methicillin-sensitive Staphylococcus aureus 15 after 18 hrs by broth microdilution method
|
Staphylococcus aureus
|
125.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against methicillin-sensitive Staphylococcus aureus 12-28 after 18 hrs by broth microdilution method
|
Staphylococcus aureus
|
250.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against methicillin-sensitive Staphylococcus epidermidis ATCC 12228 after 18 hrs by broth microdilution method
|
Staphylococcus epidermidis
|
250.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against methicillin-sensitive Staphylococcus epidermidis 12-6 after 18 hrs by broth microdilution method
|
Staphylococcus epidermidis
|
250.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against extended spectrum beta-lactamase-deficient Escherichia coli ATCC 25922 after 18 hrs by broth microdilution method
|
Escherichia coli
|
30.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against extended spectrum beta-lactamase-deficient Escherichia coli 1515 after 18 hrs by broth microdilution method
|
Escherichia coli
|
125.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against extended spectrum beta-lactamase-deficient Klebsiella pneumoniae 7 after 18 hrs by broth microdilution method
|
Klebsiella pneumoniae
|
250.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Antibacterial activity against extended spectrum beta-lactamase-deficient Klebsiella pneumoniae 12-4 after 18 hrs by broth microdilution method
|
Klebsiella pneumoniae
|
125.0
nM
|
|
Journal : J. Nat. Prod.
Title : Spiromastixones A-O, antibacterial chlorodepsidones from a deep-sea-derived Spiromastix sp. fungus.
Year : 2014
Volume : 77
Issue : 4
First Page : 1021
Last Page : 1030
Authors : Niu S, Liu D, Hu X, Proksch P, Shao Z, Lin W.
Abstract : Fifteen new depsidone-based analogues named spiromastixones A-O (1-15) were isolated from the fermentation broth of a deep-sea Spiromastix sp. fungus. Their structures were elucidated on the basis of extensive NMR and mass spectroscopic analysis in association with chemical conversion. Spiromastixones A-O are classified into two subtypes based on the orientation of ring C relative to ring A, while the n-propyl substituents on rings A and C are rarely seen in natural products. Most analogues are substituted by various numbers of chlorine atoms. All compounds exhibited significant inhibition against Gram-positive bacteria including Staphylococcus aureus, Bacillus thuringiensis, and Bacillus subtilis with MIC values ranging from 0.125 to 8.0 μg/mL. In addition, compounds 6-10 displayed potent inhibitory effects against methicillin-resistant bacterial strains of S. aureus (MRSA) and S. epidermidis (MRSE), while 10 also inhibited the growth of the vancomycin-resistant bacteria Enterococcus faecalis and E. faecium (VRE). The structure-activity relationships are discussed.
|
Time dependent inhibition of CYP1A2 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2B6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C9 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C19 in human liver microsomes at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2D6 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP3A4 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Time dependent inhibition of CYP2C8 (unknown origin) at 100 uM by LC/MS system
|
Homo sapiens
|
10.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Combination of GSH trapping and time-dependent inhibition assays as a predictive method of drugs generating highly reactive metabolites.
Year : 2011
Volume : 39
Issue : 7
First Page : 1247
Last Page : 1254
Authors : Nakayama S, Takakusa H, Watanabe A, Miyaji Y, Suzuki W, Sugiyama D, Shiosakai K, Honda K, Okudaira N, Izumi T, Okazaki O.
Abstract : Covalent binding (CB) of reactive metabolites (RMs) is potentially involved in severe adverse drug reactions. Because the CB assay is of low throughput and costly, a qualitative trapping assay using agents such as [(35)S]GSH is often performed in the early stages of drug discovery. However, trapping methods alone cannot replace the CB assay. We hypothesized that the time-dependent inhibition (TDI) assay might be complementary to the [(35)S]GSH trapping assay in detecting RMs. We performed CB assays, [(35)S]GSH trapping assays, and TDI assays for 42 structurally diverse compounds. First, we showed that the [(35)S]GSH trapping assay alone does not correlate with the extent of CB. Four compounds that the [(35)S]GSH trapping assay failed to detect but that showed high extent of CB were inactivators of the enzyme in the TDI assay. There was a tendency for compounds judged as positive in the TDI assay to show a high degree of CB irrespective of the result of the [(35)S]GSH trapping assay. Finally, to combine parameters from the two assays, we introduced intrinsic clearance to describe the formation of RMs (CL(int, RMs)). The Spearman rank correlation coefficient between the extent of CB and CL(int, RMs) was 0.77 (p < 0.0001), which was better than that for the formation rates of [(35)S]GSH adducts. Therefore, we demonstrated that a combination of the [(35)S]GSH trapping and TDI assays is an effective method for detecting compounds potentially capable of generating highly reactive metabolites in the early stages of drug discovery.
|
Inhibition of Escherichia coli DNA gyrase preincubated for 5 mins at 37 degC before addition of relaxed pBR322 as substrate by supercoiling assay
|
Escherichia coli
|
0.17
ug.mL-1
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of WQ-3810: Design, synthesis, and evaluation of 7-(3-alkylaminoazetidin-1-yl)fluoro-quinolones as orally active antibacterial agents.
Year : 2015
Volume : 103
First Page : 354
Last Page : 360
Authors : Itoh K, Kuramoto Y, Amano H, Kazamori D, Yazaki A.
Abstract : Novel 7-(3-alkylaminoazetidin-1-yl)fluoroquinolones were designed, synthesized, and evaluated for their antibacterial activities and oral absorption rates. Against Gram-negative bacteria, 10a-e, which have various alkyl groups containing different numbers of carbon atoms (C0-C3) at the C-7 alkylaminoazetidine position, showed potent and similar antibacterial activities, whereas the activity of 10f (C4, t-Bu) was significantly lower than those of 10a-e. Conversely, the oral absorption rates of 10a-e in rats increased depending on the number of carbon atoms in the alkyl groups; 10d (C3, n-Pr) and 10e (C3, i-Pr) had high oral absorption rates (>90% at 10 mg/kg). These results demonstrated that the introduction of alkyl groups onto C-7 aminoazetidine is useful for the improvement of the oral absorption rates of these drugs while maintaining their antibacterial activities. As a conclusion, from this series of fluoroquinolones, WQ-3810 (10e), having 3-isopropylaminoazetidine as the C-7 substituent, was identified as an orally active antibacterial agent with a potent in vitro activity.
|
Inhibition of Staphylococcus aureus DNA gyrase assessed as reduction in pNO1 supercoiling at 0.5 ug/mL by fluorescent dye-based assay
|
Staphylococcus aureus
|
57.9
%
|
|
Journal : J Med Chem
Title : Triaryl Benzimidazoles as a New Class of Antibacterial Agents against Resistant Pathogenic Microorganisms.
Year : 2017
Volume : 60
Issue : 14
First Page : 6045
Last Page : 6059
Authors : Picconi P, Hind C, Jamshidi S, Nahar K, Clifford M, Wand ME, Sutton JM, Rahman KM.
Abstract : A new class of nontoxic triaryl benzimidazole compounds, derived from existing classes of DNA minor groove binders, were designed, synthesized, and evaluated for their antibacterial activity against multidrug resistant (MDR) Gram-positive and Gram-negative species. Molecular modeling experiments suggest that the newly synthesized class cannot be accommodated within the minor groove of DNA due to a change in the shape of the molecules. Compounds 8, 13, and 14 were found to be the most active of the series, with MICs in the range of 0.5-4 μg/mL against the MDR Staphylococci and Enterococci species. Compound 13 showed moderate activity against the MDR Gram-negative strains, with MICs in the range of 16-32 μg/mL. Active compounds showed a bactericidal mode of action, and a mechanistic study suggested the inhibition of bacterial gyrase as the mechanism of action (MOA) of this chemical class. The MOA was further supported by the molecular modeling study.
|
Cytotoxicity against African green monkey Vero cells assessed as reduction in cell viability incubated for 24 hrs by trypan blue staining based assay
|
Chlorocebus sabaeus
|
293.16
ug.mL-1
|
|
Journal : Bioorg Med Chem
Title : meso-Dihydroguaiaretic acid derivatives with antibacterial and antimycobacterial activity.
Year : 2017
Volume : 25
Issue : 20
First Page : 5247
Last Page : 5259
Authors : Reyes-Melo K, García A, Romo-Mancillas A, Garza-González E, Rivas-Galindo VM, Miranda LD, Vargas-Villarreal J, Favela-Hernández JMJ, Camacho-Corona MDR.
Abstract : Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium. Additionally, nineteen meso-DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50µg/mL. Seven meso-DGA derivatives bearing amino-ethers (26-31 and 33) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25µg/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N-ethylpiperidine moieties in meso-31) resulted essential to significantly increase the antimycobacterial properties of parent meso-DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies.
|
Inhibition of human ERG expressed in CHOK1 cells at 30 uM
|
Homo sapiens
|
-0.9
%
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Novel 7-[(3 aS,7 aS)-3 a-Aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens.
Year : 2018
Volume : 61
Issue : 16
First Page : 7234
Last Page : 7244
Authors : Odagiri T, Inagaki H, Nagamochi M, Kitamura T, Komoriya S, Takahashi H.
Abstract : Novel 7-[(3 aS,7 aS)-3 a-aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-6-fluoro-1-[(1 R,2 S)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 (DS21412020) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound 5 possessing a trans-fused pyranose ring on the pyrrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens, including quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR- MRSA) and quinolone-resistant Escherichia coli (QR- E. coli). Furthermore, compound 5 showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae ( PRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound 5 as compared to those of the previously synthesized carba-type compound 4 resulted in a significant reduction in the human ether-a-go-go (hERG) related gene channel inhibition, which have the potential to prolong the QT interval.
|
Inhibition of human ERG expressed in CHOK1 cells at 100 uM
|
Homo sapiens
|
4.2
%
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of Novel 7-[(3 aS,7 aS)-3 a-Aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens.
Year : 2018
Volume : 61
Issue : 16
First Page : 7234
Last Page : 7244
Authors : Odagiri T, Inagaki H, Nagamochi M, Kitamura T, Komoriya S, Takahashi H.
Abstract : Novel 7-[(3 aS,7 aS)-3 a-aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-6-fluoro-1-[(1 R,2 S)-2- fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 5 (DS21412020) was designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Compound 5 possessing a trans-fused pyranose ring on the pyrrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens, including quinolone-resistant and methicillin-resistant Staphylococcus aureus (QR- MRSA) and quinolone-resistant Escherichia coli (QR- E. coli). Furthermore, compound 5 showed in vivo activity against the experimental murine pneumonia model due to penicillin-resistant Streptococcus pneumoniae ( PRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies. In particular, the reduced lipophilicity and basicity of compound 5 as compared to those of the previously synthesized carba-type compound 4 resulted in a significant reduction in the human ether-a-go-go (hERG) related gene channel inhibition, which have the potential to prolong the QT interval.
|
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
|
13.51
%
|
|
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.
|
Inhibition of Staphylococcus aureus DNA gyrase subunit A2B2 using relaxed pBR322 DNA as substrate measured after 30 mins in presence of ATP by ethidium bromide-based gel electrophoresis
|
Staphylococcus aureus
|
8.71
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies.
Year : 2019
Volume : 178
First Page : 500
Last Page : 514
Authors : Masci D, Hind C, Islam MK, Toscani A, Clifford M, Coluccia A, Conforti I, Touitou M, Memdouh S, Wei X, La Regina G, Silvestri R, Sutton JM, Castagnolo D.
Abstract : Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
|
Inhibition of Staphylococcus aureus DNA gyrase S84L mutant
|
Staphylococcus aureus
|
196.9
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies.
Year : 2019
Volume : 178
First Page : 500
Last Page : 514
Authors : Masci D, Hind C, Islam MK, Toscani A, Clifford M, Coluccia A, Conforti I, Touitou M, Memdouh S, Wei X, La Regina G, Silvestri R, Sutton JM, Castagnolo D.
Abstract : Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
|
Inhibition of Staphylococcus aureus topoisomerase-4 expressed in Escherichia coli assessed as relaxation of pBR322 substrate measured after 4 hrs by SDS-PAGE
|
Staphylococcus aureus
|
3.65
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Switching on the activity of 1,5-diaryl-pyrrole derivatives against drug-resistant ESKAPE bacteria: Structure-activity relationships and mode of action studies.
Year : 2019
Volume : 178
First Page : 500
Last Page : 514
Authors : Masci D, Hind C, Islam MK, Toscani A, Clifford M, Coluccia A, Conforti I, Touitou M, Memdouh S, Wei X, La Regina G, Silvestri R, Sutton JM, Castagnolo D.
Abstract : Antibiotic resistance represents a major threat worldwide. Gram-positive and Gram-negative opportunistic pathogens are becoming resistant to all known drugs mainly because of the overuse and misuse of these medications and the lack of new antibiotic development by the pharmaceutical industry. There is an urgent need to discover structurally innovative antibacterial agents for which no pre-existing resistance is known. This work describes the identification, synthesis and biological evaluation of a novel series of 1,5-diphenylpyrrole compounds active against a panel of ESKAPE bacteria. The new compounds show high activity against both wild type and drug-resistant Gram + ve and Gram-ve pathogens at concentrations similar or lower than levofloxacin. Microbiology studies revealed that the plausible target of the pyrrole derivatives is the bacterial DNA gyrase, with the pyrrole derivatives displaying similar inhibitory activity to levofloxacin against the wild type enzyme and retaining activity against the fluoroquinolone-resistant enzyme.
|
Antitubercular activity against Mycobacterium tuberculosis H37Rv INH-R1 harboring katG Y155 mutant after 5 days
|
Mycobacterium tuberculosis
|
640.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents.
Year : 2016
Volume : 7
Issue : 7
First Page : 686
Last Page : 691
Authors : Hampannavar GA, Karpoormath R, Palkar MB, Shaikh MS, Chandrasekaran B.
Abstract : Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = <0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.
|
Antitubercular activity against Mycobacterium tuberculosis H37Rv INH-R2 ATCC 35822 after 5 days
|
Mycobacterium tuberculosis
|
840.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents.
Year : 2016
Volume : 7
Issue : 7
First Page : 686
Last Page : 691
Authors : Hampannavar GA, Karpoormath R, Palkar MB, Shaikh MS, Chandrasekaran B.
Abstract : Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = <0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.
|
Antitubercular activity against Mycobacterium tuberculosis H37Rv RIF-R1 harboring nrpoB S522L mutant after 5 days
|
Mycobacterium tuberculosis
|
590.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents.
Year : 2016
Volume : 7
Issue : 7
First Page : 686
Last Page : 691
Authors : Hampannavar GA, Karpoormath R, Palkar MB, Shaikh MS, Chandrasekaran B.
Abstract : Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = <0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.
|
Antitubercular activity against Mycobacterium tuberculosis H37Rv RIF-R2 ATCC 35828 after 5 days
|
Mycobacterium tuberculosis
|
600.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Dehydrozingerone Inspired Styryl Hydrazine Thiazole Hybrids as Promising Class of Antimycobacterial Agents.
Year : 2016
Volume : 7
Issue : 7
First Page : 686
Last Page : 691
Authors : Hampannavar GA, Karpoormath R, Palkar MB, Shaikh MS, Chandrasekaran B.
Abstract : Series of styryl hydrazine thiazole hybrids inspired from dehydrozingerone (DZG) scaffold were designed and synthesized by molecular hybridization approach. In vitro antimycobacterial activity of synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv strain. Among the series, compound 6o exhibited significant activity (MIC = 1.5 μM; IC50 = 0.48 μM) along with bactericidal (MBC = 12 μM) and intracellular antimycobacterial activities (IC50 = <0.098 μM). Furthermore, 6o displayed prominent antimycobacterial activity under hypoxic (MIC = 46 μM) and normal oxygen (MIC = 0.28 μM) conditions along with antimycobacterial efficiency against isoniazid (MIC = 3.2 μM for INH-R1; 1.5 μM for INH-R2) and rifampicin (MIC = 2.2 μM for RIF-R1; 6.3 μM for RIF-R2) resistant strains of Mtb. Presence of electron donating groups on the phenyl ring of thiazole moiety had positive correlation for biological activity, suggesting the importance of molecular hybridization approach for the development of newer DZG clubbed hydrazine thiazole hybrids as potential antimycobacterial agents.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
93.65
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
22.85
%
|
|
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.
|
Chymotrypsin inhibition percentage at 10 µM by FRET kind of response from peptide substrate
|
Homo sapiens
|
1.29
%
|
|
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
|
0.12
%
|
|
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
|
-0.06
%
|
|
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
|
0.12
%
|
|
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
|
-0.06
%
|
|
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.
|
Growth inhibiting activity of Naegleria gruberi in vitro
|
Naegleria gruberi
|
0.0
%
|
|
Title : Naegleria gruberi Pathogen Box compounds screening
Authors : Sarink, M; Mykytyn, A; Tielens, A; van Hellemond, J
Abstract : 400 compounds from the Pathogen box were screened for inhibitory activity against Naegleria gruberi strain NEG-M. N. gruberi was grown in modified PYNFH medium in 96-wells plates. Compounds were added in 10 uM concentrations in triplicate wells. Optical density was measured daily, after 6 days area under the curve was calculated and compared to 0.1 % DMSO control.
|
Inhibition of biofilm formation in methicillin-resistant Staphylococcus aureus assessed as decrease in biofilm mass at 10 uM upon exposure to UV light irradiation and measured after 48 hrs by dilution plate coating method
|
Staphylococcus aureus
|
19.0
%
|
|
