|
Inhibitory activity against Staphylococcus aureus ATCC 29213 wild type Topo 4
|
Staphylococcus aureus
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biological evaluation of isothiazoloquinolones containing aromatic heterocycles at the 7-position: In vitro activity of a series of potent antibacterial agents that are effective against methicillin-resistant Staphylococcus aureus.
Year : 2006
Volume : 16
Issue : 5
First Page : 1277
Last Page : 1281
Authors : Wiles JA, Song Y, Wang Q, Lucien E, Hashimoto A, Cheng J, Marlor CW, Ou Y, Podos SD, Thanassi JA, Thoma CL, Deshpande M, Pucci MJ, Bradbury BJ.
Abstract : We synthesized a diverse series of 9H-isothiazolo[5,4-b]quinoline-3,4-diones containing heteroaromatic groups at the 7-position via palladium-catalyzed cross-coupling. Many of these compounds demonstrated potent antistaphylococcal activity (MICs 2 microg/mL) against a multi-drug-resistant strain (ATCC 700699) and low cytotoxic activity (CC(50)>100 microM) against the human cell line Hep2 (laryngeal carcinoma).
|
Inhibitory activity against wild type Escherichia coli gyrase
|
Escherichia coli
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Isothiazoloquinolones containing functionalized aromatic hydrocarbons at the 7-position: synthesis and in vitro activity of a series of potent antibacterial agents with diminished cytotoxicity in human cells.
Year : 2006
Volume : 16
Issue : 5
First Page : 1272
Last Page : 1276
Authors : Wiles JA, Wang Q, Lucien E, Hashimoto A, Song Y, Cheng J, Marlor CW, Ou Y, Podos SD, Thanassi JA, Thoma CL, Deshpande M, Pucci MJ, Bradbury BJ.
Abstract : This report describes 9H-isothiazolo[5,4-b]quinoline-3,4-diones (ITQs) containing aromatic groups at the 7-position that were prepared using palladium-catalyzed cross-coupling and tested against a panel of susceptible and resistant bacteria. In general, these compounds were more effective against Gram-positive than Gram-negative organisms. Many of the ITQs were more potent than contemporary quinolones and displayed a particularly strong antistaphylococcal activity against a clinically important, multi-drug-resistant strain. In contrast with ITQs reported previously, several of the analogues described in this Letter demonstrated low cytotoxic activity against a human cell line.
|
Inhibitory activity against wild type Staphylococcus aureus topoisomerase 4
|
Staphylococcus aureus
|
800.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Isothiazoloquinolones containing functionalized aromatic hydrocarbons at the 7-position: synthesis and in vitro activity of a series of potent antibacterial agents with diminished cytotoxicity in human cells.
Year : 2006
Volume : 16
Issue : 5
First Page : 1272
Last Page : 1276
Authors : Wiles JA, Wang Q, Lucien E, Hashimoto A, Song Y, Cheng J, Marlor CW, Ou Y, Podos SD, Thanassi JA, Thoma CL, Deshpande M, Pucci MJ, Bradbury BJ.
Abstract : This report describes 9H-isothiazolo[5,4-b]quinoline-3,4-diones (ITQs) containing aromatic groups at the 7-position that were prepared using palladium-catalyzed cross-coupling and tested against a panel of susceptible and resistant bacteria. In general, these compounds were more effective against Gram-positive than Gram-negative organisms. Many of the ITQs were more potent than contemporary quinolones and displayed a particularly strong antistaphylococcal activity against a clinically important, multi-drug-resistant strain. In contrast with ITQs reported previously, several of the analogues described in this Letter demonstrated low cytotoxic activity against a human cell line.
|
Inhibition of Staphylococcus aureus topoisomerase 4 by decatenation assay
|
Staphylococcus aureus
|
800.0
nM
|
|
Journal : J. Med. Chem.
Title : Isothiazoloquinolones with enhanced antistaphylococcal activities against multidrug-resistant strains: effects of structural modifications at the 6-, 7-, and 8-positions.
Year : 2007
Volume : 50
Issue : 2
First Page : 199
Last Page : 210
Authors : Wang Q, Lucien E, Hashimoto A, Pais GC, Nelson DM, Song Y, Thanassi JA, Marlor CW, Thoma CL, Cheng J, Podos SD, Ou Y, Deshpande M, Pucci MJ, Buechter DD, Bradbury BJ, Wiles JA.
Abstract : We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 microg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.
|
Antiproliferative effect against primary human osteoblasts assessed as BrdU incorporation into DNA after 48 hrs
|
Homo sapiens
|
160.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines.
Year : 2007
Volume : 51
Issue : 1
First Page : 54
Last Page : 63
Authors : Duewelhenke N, Krut O, Eysel P.
Abstract : Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
|
Inhibition of metabolic activity in primary human osteoblasts assessed as MTT reduction after 48 hrs
|
Homo sapiens
|
400.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines.
Year : 2007
Volume : 51
Issue : 1
First Page : 54
Last Page : 63
Authors : Duewelhenke N, Krut O, Eysel P.
Abstract : Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
|
Antiproliferative effect against MG63 cells assessed as BrdU incorporation into DNA after 48 hrs after 48 hrs
|
Homo sapiens
|
230.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines.
Year : 2007
Volume : 51
Issue : 1
First Page : 54
Last Page : 63
Authors : Duewelhenke N, Krut O, Eysel P.
Abstract : Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
|
Inhibition of metabolic activity in MG63 cells assessed as MTT reduction after 48 hrs
|
Homo sapiens
|
170.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines.
Year : 2007
Volume : 51
Issue : 1
First Page : 54
Last Page : 63
Authors : Duewelhenke N, Krut O, Eysel P.
Abstract : Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
|
Antiproliferative effect against HeLa cells after 48 hrs
|
Homo sapiens
|
320.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines.
Year : 2007
Volume : 51
Issue : 1
First Page : 54
Last Page : 63
Authors : Duewelhenke N, Krut O, Eysel P.
Abstract : Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
|
Inhibition of metabolic activity in HeLa cells assessed as MTT reduction after 48 hrs
|
Homo sapiens
|
110.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Influence on mitochondria and cytotoxicity of different antibiotics administered in high concentrations on primary human osteoblasts and cell lines.
Year : 2007
Volume : 51
Issue : 1
First Page : 54
Last Page : 63
Authors : Duewelhenke N, Krut O, Eysel P.
Abstract : Osteomyelitis, osteitis, spondylodiscitis, septic arthritis, and prosthetic joint infections still represent the worst complications of orthopedic surgery and traumatology. Successful treatment requires, besides surgical débridement, long-term systemic and high-concentration local antibiotic therapy, with possible local antibiotic concentrations of 100 microg/ml and more. In this study, we investigated the effect of 20 different antibiotics on primary human osteoblasts (PHO), the osteosarcoma cell line MG63, and the epithelial cell line HeLa. High concentrations of fluoroquinolones, macrolides, clindamycin, chloramphenicol, rifampin, tetracycline, and linezolid during 48 h of incubation inhibited proliferation and metabolic activity, whereas aminoglycosides and inhibitors of bacterial cell wall synthesis did not. Twenty percent inhibitory concentrations for proliferation of PHO were determined as 20 to 40 microg/ml for macrolides, clindamycin, and rifampin, 60 to 80 microg/ml for chloramphenicol, tetracylin, and fluoroquinolones, and 240 microg/ml for linezolid. The proliferation of the cell lines was always less inhibited. We established the measurement of extracellular lactate concentration as an indicator of glycolysis using inhibitors of the respiratory chain (antimycin A, rotenone, and sodium azide) and glycolysis (iodoacetic acid) as reference compounds, whereas inhibition of the respiratory chain increased and inhibition of glycolysis decreased lactate production. The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations. This explains partly the observed inhibition of metabolic activity and proliferation in our experiments. Because of differences in the energy metabolism, PHO provided a more sensitive model for orthopedic antibiotic usage than stable cell lines.
|
Inhibition of Mycobacterium leprae recombinant DNA gyrase expressed in Escherichia coli assessed as inhibition of pBR322 DNA supercoiling
|
Mycobacterium leprae
|
2.0
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 Mycobacterium leprae wild type DNA gyrase A2B2 assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
6.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Mycobacterium leprae DNA gyrase subunit A G89C mutant assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
30.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Mycobacterium leprae DNA gyrase subunit A A91V mutant assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
25.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Mycobacterium leprae wild type DNA gyrase subunit B D205N mutant assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
6.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Are all the DNA gyrase mutations found in Mycobacterium leprae clinical strains involved in resistance to fluoroquinolones?
Year : 2008
Volume : 52
Issue : 2
First Page : 745
Last Page : 747
Authors : Matrat S, Cambau E, Jarlier V, Aubry A.
Abstract : Mycobacterium leprae DNA gyrases carrying various mutations, previously described in clinical strains, were investigated for quinolone susceptibility by inhibition of supercoiling and DNA cleavage promotion. We demonstrated that the gyrA mutations leading to G89C or A91V confer fluoroquinolone resistance whereas the gyrB mutation leading to D205N does not.
|
Inhibition of Staphylococcus aureus wild type DNA topoisomerase 4
|
Staphylococcus aureus
|
1.36
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
|
24.2
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
|
4.38
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.
|
Inhibition of Escherichia coli DNA gyrase-mediated supercoiling of pBR322 using bromothymol blue by electrophoresis
|
Escherichia coli
|
0.85
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents.
Year : 2010
Volume : 18
Issue : 16
First Page : 5873
Last Page : 5884
Authors : Al-Trawneh SA, Zahra JA, Kamal MR, El-Abadelah MM, Zani F, Incerti M, Cavazzoni A, Alfieri RR, Petronini PG, Vicini P.
Abstract : A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a-e) and a structurally related 6-fluoro-4-oxothieno[2',3':4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a-f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c-f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC(50) 0.8 and 1.6muM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.
|
Inhibition of Escherichia coli DNA topoisomerase-4-mediated decatenation of pBR322 by electrophoresis
|
Escherichia coli
|
5.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents.
Year : 2010
Volume : 18
Issue : 16
First Page : 5873
Last Page : 5884
Authors : Al-Trawneh SA, Zahra JA, Kamal MR, El-Abadelah MM, Zani F, Incerti M, Cavazzoni A, Alfieri RR, Petronini PG, Vicini P.
Abstract : A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a-e) and a structurally related 6-fluoro-4-oxothieno[2',3':4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a-f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c-f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC(50) 0.8 and 1.6muM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.
|
Antimicrobial activity against extracellular Mycobacterium avium subsp. hominissuis ATCC 700898 after 7 days by CLSI method
|
Mycobacterium avium subsp. hominissuis
|
32.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Moxifloxacin pharmacokinetics/pharmacodynamics and optimal dose and susceptibility breakpoint identification for treatment of disseminated Mycobacterium avium infection.
Year : 2010
Volume : 54
Issue : 6
First Page : 2534
Last Page : 2539
Authors : Deshpande D, Srivastava S, Meek C, Leff R, Hall GS, Gumbo T.
Abstract : Organisms of the Mycobacterium avium-intracellulare complex (MAC) have been demonstrated to be susceptible to moxifloxacin. However, clinical data on how to utilize moxifloxacin to treat disseminated MAC are scanty. In addition, there have been no moxifloxacin pharmacokinetic-pharmacodynamic (PK/PD) studies performed for MAC infection. We utilized an in vitro PK/PD model of intracellular MAC to study moxifloxacin PK/PD for disseminated disease. Moxifloxacin doses, based on a serum half-life of 12 h, were administered, and the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to MIC ratios associated with 1.0 log(10) CFU/ml per week kill and 90% of maximal kill (EC(90)) were identified. The AUC(0-24)/MIC ratio associated with 1.0 log(10) CFU/ml kill was 17.12, and that with EC(90) was 391.56 (r(2) = 0.97). Next, the moxifloxacin MIC distribution in 102 clinical isolates of MAC was identified. The median MIC was 1 to 2 mg/liter. Monte Carlo simulations of 10,000 patients with disseminated MAC were performed to determine the probability that daily moxifloxacin doses of 400 and 800 mg/day would achieve or exceed 1.0 log(10) CFU/ml per week kill or EC(90). Doses of 400 and 800 mg/day achieved the AUC(0-24)/MIC ratio of 17.12 in 64% and 92% of patients, respectively. The critical concentration of moxifloxacin against MAC was identified as 0.25 mg/liter in Middlebrook media. The proposed susceptibility breakpoint means that a larger proportion of clinical isolates is resistant to moxifloxacin prior to therapy. For patients infected with susceptible isolates, however, 800 mg a day should be examined for safety and efficacy for disseminated M. avium disease.
|
Antimicrobial activity against intracellular Mycobacterium avium subsp. hominissuis ATCC 700898 after 7 days by CLSI method
|
Mycobacterium avium subsp. hominissuis
|
8.24
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Moxifloxacin pharmacokinetics/pharmacodynamics and optimal dose and susceptibility breakpoint identification for treatment of disseminated Mycobacterium avium infection.
Year : 2010
Volume : 54
Issue : 6
First Page : 2534
Last Page : 2539
Authors : Deshpande D, Srivastava S, Meek C, Leff R, Hall GS, Gumbo T.
Abstract : Organisms of the Mycobacterium avium-intracellulare complex (MAC) have been demonstrated to be susceptible to moxifloxacin. However, clinical data on how to utilize moxifloxacin to treat disseminated MAC are scanty. In addition, there have been no moxifloxacin pharmacokinetic-pharmacodynamic (PK/PD) studies performed for MAC infection. We utilized an in vitro PK/PD model of intracellular MAC to study moxifloxacin PK/PD for disseminated disease. Moxifloxacin doses, based on a serum half-life of 12 h, were administered, and the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to MIC ratios associated with 1.0 log(10) CFU/ml per week kill and 90% of maximal kill (EC(90)) were identified. The AUC(0-24)/MIC ratio associated with 1.0 log(10) CFU/ml kill was 17.12, and that with EC(90) was 391.56 (r(2) = 0.97). Next, the moxifloxacin MIC distribution in 102 clinical isolates of MAC was identified. The median MIC was 1 to 2 mg/liter. Monte Carlo simulations of 10,000 patients with disseminated MAC were performed to determine the probability that daily moxifloxacin doses of 400 and 800 mg/day would achieve or exceed 1.0 log(10) CFU/ml per week kill or EC(90). Doses of 400 and 800 mg/day achieved the AUC(0-24)/MIC ratio of 17.12 in 64% and 92% of patients, respectively. The critical concentration of moxifloxacin against MAC was identified as 0.25 mg/liter in Middlebrook media. The proposed susceptibility breakpoint means that a larger proportion of clinical isolates is resistant to moxifloxacin prior to therapy. For patients infected with susceptible isolates, however, 800 mg a day should be examined for safety and efficacy for disseminated M. avium disease.
|
Antimicrobial activity against Mycobacterium avium subsp. hominissuis ATCC 700898 infected in human THP1 cells in presence of 2% FBS
|
Mycobacterium avium subsp. hominissuis
|
8.09
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Moxifloxacin pharmacokinetics/pharmacodynamics and optimal dose and susceptibility breakpoint identification for treatment of disseminated Mycobacterium avium infection.
Year : 2010
Volume : 54
Issue : 6
First Page : 2534
Last Page : 2539
Authors : Deshpande D, Srivastava S, Meek C, Leff R, Hall GS, Gumbo T.
Abstract : Organisms of the Mycobacterium avium-intracellulare complex (MAC) have been demonstrated to be susceptible to moxifloxacin. However, clinical data on how to utilize moxifloxacin to treat disseminated MAC are scanty. In addition, there have been no moxifloxacin pharmacokinetic-pharmacodynamic (PK/PD) studies performed for MAC infection. We utilized an in vitro PK/PD model of intracellular MAC to study moxifloxacin PK/PD for disseminated disease. Moxifloxacin doses, based on a serum half-life of 12 h, were administered, and the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to MIC ratios associated with 1.0 log(10) CFU/ml per week kill and 90% of maximal kill (EC(90)) were identified. The AUC(0-24)/MIC ratio associated with 1.0 log(10) CFU/ml kill was 17.12, and that with EC(90) was 391.56 (r(2) = 0.97). Next, the moxifloxacin MIC distribution in 102 clinical isolates of MAC was identified. The median MIC was 1 to 2 mg/liter. Monte Carlo simulations of 10,000 patients with disseminated MAC were performed to determine the probability that daily moxifloxacin doses of 400 and 800 mg/day would achieve or exceed 1.0 log(10) CFU/ml per week kill or EC(90). Doses of 400 and 800 mg/day achieved the AUC(0-24)/MIC ratio of 17.12 in 64% and 92% of patients, respectively. The critical concentration of moxifloxacin against MAC was identified as 0.25 mg/liter in Middlebrook media. The proposed susceptibility breakpoint means that a larger proportion of clinical isolates is resistant to moxifloxacin prior to therapy. For patients infected with susceptible isolates, however, 800 mg a day should be examined for safety and efficacy for disseminated M. avium disease.
|
Antimicrobial activity against Mycobacterium avium subsp. hominissuis ATCC 700898 infected in human THP1 cells in presence of 10% FBS
|
Mycobacterium avium subsp. hominissuis
|
5.07
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Moxifloxacin pharmacokinetics/pharmacodynamics and optimal dose and susceptibility breakpoint identification for treatment of disseminated Mycobacterium avium infection.
Year : 2010
Volume : 54
Issue : 6
First Page : 2534
Last Page : 2539
Authors : Deshpande D, Srivastava S, Meek C, Leff R, Hall GS, Gumbo T.
Abstract : Organisms of the Mycobacterium avium-intracellulare complex (MAC) have been demonstrated to be susceptible to moxifloxacin. However, clinical data on how to utilize moxifloxacin to treat disseminated MAC are scanty. In addition, there have been no moxifloxacin pharmacokinetic-pharmacodynamic (PK/PD) studies performed for MAC infection. We utilized an in vitro PK/PD model of intracellular MAC to study moxifloxacin PK/PD for disseminated disease. Moxifloxacin doses, based on a serum half-life of 12 h, were administered, and the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to MIC ratios associated with 1.0 log(10) CFU/ml per week kill and 90% of maximal kill (EC(90)) were identified. The AUC(0-24)/MIC ratio associated with 1.0 log(10) CFU/ml kill was 17.12, and that with EC(90) was 391.56 (r(2) = 0.97). Next, the moxifloxacin MIC distribution in 102 clinical isolates of MAC was identified. The median MIC was 1 to 2 mg/liter. Monte Carlo simulations of 10,000 patients with disseminated MAC were performed to determine the probability that daily moxifloxacin doses of 400 and 800 mg/day would achieve or exceed 1.0 log(10) CFU/ml per week kill or EC(90). Doses of 400 and 800 mg/day achieved the AUC(0-24)/MIC ratio of 17.12 in 64% and 92% of patients, respectively. The critical concentration of moxifloxacin against MAC was identified as 0.25 mg/liter in Middlebrook media. The proposed susceptibility breakpoint means that a larger proportion of clinical isolates is resistant to moxifloxacin prior to therapy. For patients infected with susceptible isolates, however, 800 mg a day should be examined for safety and efficacy for disseminated M. avium disease.
|
Antimicrobial activity against Mycobacterium avium subsp. hominissuis ATCC 700898 infected in human THP1 cells in presence of 20% FBS
|
Mycobacterium avium subsp. hominissuis
|
5.21
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Moxifloxacin pharmacokinetics/pharmacodynamics and optimal dose and susceptibility breakpoint identification for treatment of disseminated Mycobacterium avium infection.
Year : 2010
Volume : 54
Issue : 6
First Page : 2534
Last Page : 2539
Authors : Deshpande D, Srivastava S, Meek C, Leff R, Hall GS, Gumbo T.
Abstract : Organisms of the Mycobacterium avium-intracellulare complex (MAC) have been demonstrated to be susceptible to moxifloxacin. However, clinical data on how to utilize moxifloxacin to treat disseminated MAC are scanty. In addition, there have been no moxifloxacin pharmacokinetic-pharmacodynamic (PK/PD) studies performed for MAC infection. We utilized an in vitro PK/PD model of intracellular MAC to study moxifloxacin PK/PD for disseminated disease. Moxifloxacin doses, based on a serum half-life of 12 h, were administered, and the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to MIC ratios associated with 1.0 log(10) CFU/ml per week kill and 90% of maximal kill (EC(90)) were identified. The AUC(0-24)/MIC ratio associated with 1.0 log(10) CFU/ml kill was 17.12, and that with EC(90) was 391.56 (r(2) = 0.97). Next, the moxifloxacin MIC distribution in 102 clinical isolates of MAC was identified. The median MIC was 1 to 2 mg/liter. Monte Carlo simulations of 10,000 patients with disseminated MAC were performed to determine the probability that daily moxifloxacin doses of 400 and 800 mg/day would achieve or exceed 1.0 log(10) CFU/ml per week kill or EC(90). Doses of 400 and 800 mg/day achieved the AUC(0-24)/MIC ratio of 17.12 in 64% and 92% of patients, respectively. The critical concentration of moxifloxacin against MAC was identified as 0.25 mg/liter in Middlebrook media. The proposed susceptibility breakpoint means that a larger proportion of clinical isolates is resistant to moxifloxacin prior to therapy. For patients infected with susceptible isolates, however, 800 mg a day should be examined for safety and efficacy for disseminated M. avium disease.
|
Inhibition of Escherichia coli DNA gyrase assessed as reduction of DNA supercoiling activity using pBR322 DNA substrate after 30 mins by electrophoresis
|
Escherichia coli
|
0.85
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of tetracyclic thienopyridones as antibacterial and antitumor agents.
Year : 2011
Volume : 19
Issue : 8
First Page : 2541
Last Page : 2548
Authors : Al-Trawneh SA, El-Abadelah MM, Zahra JA, Al-Taweel SA, Zani F, Incerti M, Cavazzoni A, Vicini P.
Abstract : A facile synthesis of model 4-oxopyrido[3',2':4,5]thieno[3,2-b]indole-3-carboxylic acids 9a-e was achieved via Stille arylation of 2-chloro-3-nitro-4-oxothieno[2,3-b]pyridine-5-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. Compounds 9a-c and 9e exhibited very high potency against Gram positive Bacillus subtilis and Bacillus megaterium at concentrations 0.000015-0.007 μg/mL. They also displayed excellent activity towards other Gram positive bacilli and staphylococci and Gram negative Haemophilus influenzae, being in most cases superior or equal to commercial fluoroquinolones. Both 9a and 9c were inhibitors of the DNA gyrase activity. As concerns antitumor properties, compounds 9b-e showed growth inhibition of MCF-7 breast tumor and A549 non-small cell lung cancer cells with IC(50) 1.6-2.8 μM and 2.6-6.9 μM, respectively, coupled with absence of cytotoxicity towards normal cells. These compounds are promising as dual acting chemotherapeutics.
|
Inhibition of Escherichia coli topoisomerase 4 assessed as decatenation of kDNA after 30 mins by electrophoresis
|
Escherichia coli
|
5.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of tetracyclic thienopyridones as antibacterial and antitumor agents.
Year : 2011
Volume : 19
Issue : 8
First Page : 2541
Last Page : 2548
Authors : Al-Trawneh SA, El-Abadelah MM, Zahra JA, Al-Taweel SA, Zani F, Incerti M, Cavazzoni A, Vicini P.
Abstract : A facile synthesis of model 4-oxopyrido[3',2':4,5]thieno[3,2-b]indole-3-carboxylic acids 9a-e was achieved via Stille arylation of 2-chloro-3-nitro-4-oxothieno[2,3-b]pyridine-5-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. Compounds 9a-c and 9e exhibited very high potency against Gram positive Bacillus subtilis and Bacillus megaterium at concentrations 0.000015-0.007 μg/mL. They also displayed excellent activity towards other Gram positive bacilli and staphylococci and Gram negative Haemophilus influenzae, being in most cases superior or equal to commercial fluoroquinolones. Both 9a and 9c were inhibitors of the DNA gyrase activity. As concerns antitumor properties, compounds 9b-e showed growth inhibition of MCF-7 breast tumor and A549 non-small cell lung cancer cells with IC(50) 1.6-2.8 μM and 2.6-6.9 μM, respectively, coupled with absence of cytotoxicity towards normal cells. These compounds are promising as dual acting chemotherapeutics.
|
Inhibition of human ERG expressed in mammalian cells at 10 uM by patch clamp method
|
Homo sapiens
|
10.0
%
|
|
Journal : J. Med. Chem.
Title : Selenophene-containing inhibitors of type IIA bacterial topoisomerases.
Year : 2011
Volume : 54
Issue : 9
First Page : 3418
Last Page : 3425
Authors : Wiles JA, Phadke AS, Bradbury BJ, Pucci MJ, Thanassi JA, Deshpande M.
Abstract : We investigated compounds related to the previously reported antistaphyloccocal agent AVE6971 in an effort to attenuate inhibition of hERG potassium channel current that has been noted for this and related antibacterial drug classes. While most modifications of the original thiophene group compromised antibacterial activity, one selenophene analogue displayed (i) improved activity against the primary target enzyme DNA gyrase, (ii) similar activities against a panel of MRSA clinical isolates, and (iii) reduced hERG channel inhibition.
|
Antimicrobial activity against Mycobacterium tuberculosis H37Rv ATCC 27294 after 7 days by MABA
|
Mycobacterium tuberculosis H37Rv
|
100.0
%
|
|
Journal : Med Chem Res
Title : Synthesis, antibacterial, and antitubercular studies of some novel isatin derivatives
Year : 2012
Volume : 21
Issue : 12
First Page : 4335
Last Page : 4340
Authors : Murali K, Avinash R, Kirthiga R, Franzblau SG
|
Inhibition of human ERG expressed in CHOK1 cells at 100 uM
|
Homo sapiens
|
42.3
%
|
|
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
|
21.5
%
|
|
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 Mycobacterium leprae DNA gyrase GyrA/GyrB assessed as reduction of enzyme supercoiling activity using relaxed pBR322 DNA substrate incubated for 2 hrs at 30 degC by ethidium bromide based gel electrophoresis
|
Mycobacterium leprae
|
2.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis.
Year : 2013
Volume : 21
Issue : 4
First Page : 948
Last Page : 956
Authors : Gomez C, Ponien P, Serradji N, Lamouri A, Pantel A, Capton E, Jarlier V, Anquetin G, Aubry A.
Abstract : Novel 3'-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by (1)H, (13)C and (19)F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC(50)), or inducing 25% DNA cleavage by DNA gyrase (CC(25)). Compound 4 (with a methoxy in R(8) and a secondary carbamate in R(3)') and compound 5 (with a hydrogen in R(8) and an ethyl ester in R(3)') displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R(3)' substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase GyrA/GyrB assessed as reduction of enzyme supercoiling activity using relaxed pBR322 DNA substrate incubated for 1 hr at 37 degC by ethidium bromide based gel electrophoresis
|
Mycobacterium tuberculosis
|
2.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis of gatifloxacin derivatives and their biological activities against Mycobacterium leprae and Mycobacterium tuberculosis.
Year : 2013
Volume : 21
Issue : 4
First Page : 948
Last Page : 956
Authors : Gomez C, Ponien P, Serradji N, Lamouri A, Pantel A, Capton E, Jarlier V, Anquetin G, Aubry A.
Abstract : Novel 3'-piperazinyl derivatives of the 8-hydrogeno and 8-methoxy-6-fluoro-1-cyclopropyl-4-quinolone-3-carboxylic acid scaffolds were designed, synthesized and characterized by (1)H, (13)C and (19)F NMR, and HRMS. The activity of these derivatives against pathogenic mycobacteria (M. leprae and M. tuberculosis), wild-type (WT) strains or strains harboring mutations implicated in quinolone resistance, were determined by measuring drug concentrations inhibiting cell growth (MIC) and/or DNA supercoiling by DNA gyrase (IC(50)), or inducing 25% DNA cleavage by DNA gyrase (CC(25)). Compound 4 (with a methoxy in R(8) and a secondary carbamate in R(3)') and compound 5 (with a hydrogen in R(8) and an ethyl ester in R(3)') displayed biological activities close to those of ofloxacin but inferior to those of gatifloxacin and moxifloxacin against M. tuberculosis and M. leprae WT DNA gyrases, whereas all of the compounds were less active in inhibiting M. tuberculosis growth and M. leprae mutant DNA gyrases. Since R(3)' substitutions have been poorly investigated previously, our results may help to design new quinolone derivatives in the future.
|
Inhibition of Mycobacterium tuberculosis GyrA/GyrB using relaxed pBR322 as substrate at 0.97 uM after 30 mins by DNA supercoiling assay
|
Mycobacterium tuberculosis
|
60.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Extending the N-linked aminopiperidine class to the mycobacterial gyrase domain: pharmacophore mapping from known antibacterial leads.
Year : 2014
Volume : 85
First Page : 593
Last Page : 604
Authors : Bobesh KA, Renuka J, Jeankumar VU, Shruti SK, Sridevi JP, Yogeeswari P, Sriram D.
Abstract : Bacterial DNA gyrase is a well-established and clinically validated target to develop novel antibacterial. Our effort was designated to search for synthetically better compounds with possibility of hit to lead development. With this as objective, a series of 1-(2-(4-aminopiperidin-1-yl)ethyl)-1,5-naphthyridin-2(1H)-one derivatives were designed by molecular hybridization strategy and synthesized following nine step reaction to yield activity in low nanomolar range and commendable antibacterial activities. Compound 1-(4-fluorophenyl)-3-(1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)urea (35) emerged as the most promising inhibitor with an IC50 of 78 nM against Mycobacterium tuberculosis DNA gyrase enzyme, with MTB MIC of 0.62 μM, and not cytotoxic at 50 μM in eukaryotic cell line.
|
Cytotoxicity against mouse RAW264.7 cells assessed as inhibition of cell growth at 50 uM after 72 hrs by MTT assay
|
Mus musculus
|
1.26
%
|
|
Journal : Bioorg. Med. Chem.
Title : Development of acridine derivatives as selective Mycobacterium tuberculosis DNA gyrase inhibitors.
Year : 2016
Volume : 24
Issue : 4
First Page : 877
Last Page : 885
Authors : Medapi B, Meda N, Kulkarni P, Yogeeswari P, Sriram D.
Abstract : In this study we have designed p-phenylene diamine linked acridine derivative from our earlier reported quinoline-aminopiperidine hybrid MTB DNA gyrase inhibitors with aiming more potency and less cardiotoxicity. We synthesized thirty six compounds using four step synthesis from 2-chloro benzoic acid. Among them compound 4-chloro-N-(4-((2-methylacridin-9-yl)amino)phenyl)benzenesulphonamide (6) was found to be more potent with MTB DNA gyrase super coiling IC50 of 5.21±0.51μM; MTB MIC of 6.59μM and no zHERG cardiotoxicity at 30μM and 11.78% inhibition at 50μM against mouse macrophage cell line RAW 264.7.
|
Cytotoxicity against mouse NIH/3T3 cells assessed as reduction in cell proliferation after 24 hrs by MTT assay
|
Mus musculus
|
379.82
ug.mL-1
|
|
Journal : Bioorg Med Chem Lett
Title : New 1,4-dihydro[1,8]naphthyridine derivatives as DNA gyrase inhibitors.
Year : 2017
Volume : 27
Issue : 5
First Page : 1162
Last Page : 1168
Authors : Gençer HK, Levent S, Acar Çevik U, Özkay Y, Ilgın S.
Abstract : Owing to the growing need for novel antibacterial agents, we synthesized a novel series of fluoroquinolones including 7-substituted-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid derivatives, which were tested against clinically relevant Gram positive and Gram negative bacteria. Chemical structures of the synthesized compounds were identified using spectroscopic methods. In vitro antimicrobial effects of the compounds were determined via microdilution assay. Microbiological examination revealed that compounds 13 and 14 possess a good antibacterial profile. Compound 14 was the most active and showed an antibacterial profile comparable to that of the reference drugs trovafloxacin, moxifloxacin, and ciprofloxacin. A significant MIC90 value (1.95μg/mL) against S. aureus ATCC 25923, E. coli ATCC 35218, and E. coli ATCC 25922 was recorded for compound 14. We observed reduced metabolic activity associated with compounds 13 and 14 in the relevant bacteria via a luminescence ATP assay. Results of this assay supported the antibacterial potency of compounds 13 and 14. An E. coli DNA gyrase inhibitory assay indicated that compound 14 is a potent inhibitor of E. coli DNA gyrase. Docking studies revealed that there is a strong interaction between compound 14 and the E. coli DNA gyrase enzyme. Genotoxicity and cytotoxicity evaluations of compounds 13 and 14 showed that compound 14 is non-genotoxic and less cytotoxic compared to the reference drugs (trovafloxacin, moxifloxacin, and ciprofloxacin), which increases its biological importance.
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Inhibition of human ERG expressed in CHOK1 cells at 30 uM
|
Homo sapiens
|
22.0
%
|
|
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
|
42.0
%
|
|
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.
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Antimycobacterial activity against Mycobacterium marinum NCTC 2275 by resazurin dye based fluorimetric assay
|
Mycobacterium marinum
|
140.0
nM
|
|
Journal : Eur J Med Chem
Title : The synthesis and in vitro biological evaluation of novel fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones against Mycobacterium tuberculosis.
Year : 2019
Volume : 181
First Page : 111549
Last Page : 111549
Authors : Cappoen D, Torfs E, Meiresonne T, Claes P, Semina E, Holvoet F, de Macedo MB, Cools F, Piller T, Matheeussen A, Van Calster K, Caljon G, Delputte P, Maes L, Neyrolles O, De Kimpe N, Mangelinckx S, Cos P.
Abstract : Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase.
|
Antimycobacterial activity against Mycobacterium avium subsp. avium ATCC 25291 by resazurin dye based fluorimetric assay
|
Mycobacterium avium subsp. avium
|
190.0
nM
|
|
Journal : Eur J Med Chem
Title : The synthesis and in vitro biological evaluation of novel fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones against Mycobacterium tuberculosis.
Year : 2019
Volume : 181
First Page : 111549
Last Page : 111549
Authors : Cappoen D, Torfs E, Meiresonne T, Claes P, Semina E, Holvoet F, de Macedo MB, Cools F, Piller T, Matheeussen A, Van Calster K, Caljon G, Delputte P, Maes L, Neyrolles O, De Kimpe N, Mangelinckx S, Cos P.
Abstract : Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase.
|
Antimycobacterial activity against Mycobacterium bovis BCG ATCC 35737 by resazurin dye based fluorimetric assay
|
Mycobacterium bovis BCG
|
30.0
nM
|
|
Journal : Eur J Med Chem
Title : The synthesis and in vitro biological evaluation of novel fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones against Mycobacterium tuberculosis.
Year : 2019
Volume : 181
First Page : 111549
Last Page : 111549
Authors : Cappoen D, Torfs E, Meiresonne T, Claes P, Semina E, Holvoet F, de Macedo MB, Cools F, Piller T, Matheeussen A, Van Calster K, Caljon G, Delputte P, Maes L, Neyrolles O, De Kimpe N, Mangelinckx S, Cos P.
Abstract : Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase.
|
Inhibition of Mycobacterium tuberculosis DNA gyrase
|
Mycobacterium tuberculosis
|
5.5
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of moxifloxacin-acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against both drug-susceptible and drug-resistant Mycobacterium tuberculosis strains.
Year : 2019
Volume : 180
First Page : 648
Last Page : 655
Authors : Gao F, Chen Z, Ma L, Fan Y, Chen L, Lu G.
Abstract : Herein, synthesis and biological evaluation of fourteen moxifloxacin-acetyl-1,2,3-1H-triazole-methylene-isatin hybrids as potential anti-tubercular agents against both drug-susceptible (MTB H<sub>37</sub>Rv), rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains were reported, and cytotoxicity towards VERO cells as well as inhibitory activity against MTB DNA gyrase were also discussed in this paper. The structure-activity relationship and structure-cytotoxicity relationship demonstrated that substituents on the C-3 and C-5/C-7 positions of isatin framework were closely related with the anti-mycobacterial activity and cytotoxicity. The most active hybrids 8h and 8l (MIC: 0.12-0.5 μg/mL) showed excellent activity which was no inferior to the parent moxifloxacin against the tested drug-susceptible, rifampicin-resistant and multidrug-resistant Mycobacterium tuberculosis strains, demonstrating their potential application as novel anti-tubercular candidates.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
29.02
%
|
|
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
|
-0.07
%
|
|
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
|
-0.07
%
|
|
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.
|
Antibacterial activity against Mycobacterium tuberculosis H37Ra ATCC2517 assessed as inhibition of bacterial growth measured after 17 hrs by resazurin based flourimetric assay
|
Mycobacterium tuberculosis
|
250.0
nM
|
|
