|
Clonogenic cytotoxicity against Chinese hamster V-79 cells
|
Cricetulus griseus
|
85.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : The synthesis, structure-activity, and structure-side effect relationships of a series of 8-alkoxy- and 5-amino-8-alkoxyquinolone antibacterial agents.
Year : 1995
Volume : 38
Issue : 22
First Page : 4478
Last Page : 4487
Authors : Sanchez JP, Gogliotti RD, Domagala JM, Gracheck SJ, Huband MD, Sesnie JA, Cohen MA, Shapiro MA.
Abstract : A series of 1-cyclopropyl-6-fluoro-8-alkoxy (8-methyoxy and 8-ethoxy)-quionoline-3-carboxylic acids and 1-cyclopropyl-5-amino-6-fluoro-8-alkoxyquinoline-3-carboxylic acids has been prepared and evaluated for antibacterial activity. In addition, they were also compared to quinolones with classic substitution at C8 (H, F, Cl) and the naphthyridine nucleus in a phototoxicity and mammalian cell cytotoxicity assay. The series of 8-methoxyquinolones had antibacterial activity against Gram-positive, Gram-negative, and anaerobic bacteria equivalent to the most active 8-substituted compounds (8-F and 8-Cl). There was also a concomitant reduction in several of the potential side effects (i.e., phototoxicity and clonogenicity) compared to the most active quinolones with classic substitution at C-8. The 8-ethoxy derivatives had an even better safety profile but were significantly less active (2-3 dilutions) in the antibacterial assay.
|
Inhibitory activity against wild type Escherichia coli gyrase
|
Escherichia coli
|
500.0
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 Mycobacterium tuberculosis DNA gyrase
|
Mycobacterium tuberculosis
|
4.0
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Gatifloxacin derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis DNA gyrase.
Year : 2006
Volume : 16
Issue : 11
First Page : 2982
Last Page : 2985
Authors : Sriram D, Aubry A, Yogeeswari P, Fisher LM.
Abstract : Sixteen 7-substituted gatifloxacin derivatives were synthesized and evaluated for antimycobacterial activity in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB), and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. tuberculosis. Among the synthesized compounds, 1-cyclopropyl-6-fluoro-8-methoxy-7-[[[N4-[1'-(5-isatinyl-beta-semicarbazo)]methyl]3-methyl]N1-piperazinyl]-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (3d) was found to be the most active compound in vitro with an MIC of 0.0125 microg/mL against MTB and MTR-TB. In the in vivo animal model 3d decreased the bacterial load in lung and spleen tissues with 3.62- and 3.76-log10 protections, respectively. Compound 3d was also found to be equally active as gatifloxacin in the inhibition of the supercoiling activity of wild-type M. tuberculosis DNA gyrase with an IC50 of 3.0 microg/mL. The results demonstrate the potential and importance of developing new quinolone derivatives against mycobacterial infections.
|
Cytotoxicity against Vero cell line
|
Chlorocebus sabaeus
|
62.5
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Discovery of new antitubercular oxazolyl thiosemicarbazones.
Year : 2006
Volume : 49
Issue : 12
First Page : 3448
Last Page : 3450
Authors : Sriram D, Yogeeswari P, Thirumurugan R, Pavana RK.
Abstract : Twenty 4-(5-cyclobutyloxazol-2-yl)thiosemicarbazones were synthesized and evaluated for preliminary in vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB) and multidrug-resistant Mycobacterium tuberculosis (MDR-TB). Among them, (4-bromophenyl)(phenyl)methanone N-(5-cyclobutyl-1,3-oxazol-2-yl)thiosemicarbazone 6q was found to be the most active compound in vitro with minimum inhibitory concentration of 0.05 microg/mL against MTB and MDR-TB. In the in vivo animal model 6q decreased the bacterial load in lung and spleen tissues with 2.1 log 10 and 3.72 log 10 protections, respectively, at 50 mg/kg body weight dose.
|
Inhibition of Escherichia coli gyrase
|
Escherichia coli
|
500.0
nM
|
|
Journal : J. Med. Chem.
Title : 3-aminoquinazolinediones as a new class of antibacterial agents demonstrating excellent antibacterial activity against wild-type and multidrug resistant organisms.
Year : 2006
Volume : 49
Issue : 22
First Page : 6435
Last Page : 6438
Authors : Ellsworth EL, Tran TP, Showalter HD, Sanchez JP, Watson BM, Stier MA, Domagala JM, Gracheck SJ, Joannides ET, Shapiro MA, Dunham SA, Hanna DL, Huband MD, Gage JW, Bronstein JC, Liu JY, Nguyen DQ, Singh R.
Abstract : The 3-aminoquinzolinediones represent a new series of antibacterial agents structurally related to the fluoroquinolones. They are inhibitors of bacterial gyrase and topoisomerase IV and demonstrate clinically useful antibacterial activity against fastidious Gram-negative and Gram-positive organisms, including multidrug- and fluoroquinolone-resistant organisms. These agents also demonstrate in vivo efficacy in murine systemic infection models.
|
Suppression of TNF alpha-stimulated IL8 secretion in human PC3 cells at 16 ug/ml added 30 mins after stimulation
|
Homo sapiens
|
25.0
%
|
|
Journal : Antimicrob. Agents Chemother.
Title : The 6-fluoro-8-methoxy quinolone gatifloxacin down-regulates interleukin-8 production in prostate cell line PC-3.
Year : 2007
Volume : 51
Issue : 1
First Page : 162
Last Page : 168
Authors : Takeyama K, Mitsuzawa H, Nishitani C, Shimizu T, Sano H, Kunishima Y, Takahashi S, Hotta H, Matsukawa M, Shibata K, Tsukamoto T, Kuroki Y.
Abstract : Fluoroquinolones exhibit immunomodulatory effects on monocytes and macrophages, in addition to their bactericidal activities. It remains unknown even whether the quinolones act directly on the prostate. This study was based on the understanding of the molecular mechanisms of the actions of the fluoroquinolones that can be used for the treatment of chronic prostatitis/chronic pelvic pain syndrome. We investigated whether the 6-fluroro-8-methoxy quinolone gatifloxacin (GFLX) affected the production and secretion of interleukin-8 (IL-8) in the prostate cell line PC-3. GFLX decreased the level of IL-8 release from unstimulated PC-3 cells. GFLX also attenuated IL-8 secretion from PC-3 cells stimulated with peptidoglycan, Mycoplasma hominis, phorbol ester, and tumor necrosis factor alpha (TNF-alpha), indicating that GFLX exhibits an anti-inflammatory effect on the prostate cell line. However, GFLX failed to alter activation of the NF-kappaB and AP-1 elicited by these stimulants. GFLX significantly attenuated the expression of IL-8 mRNA in TNF-alpha-stimulated PC-3 cells and down-regulated the transcriptional activity of the 5'-flanking region of the IL-8 gene from -1481 to +44 bp. The deletion construct without the 5'-flanking region from -1481 to -170 bp but not the construct without the region from -1481 to -188 bp reversed the suppressive effect of GFLX on IL-8 promoter activity. These results demonstrate that GFLX suppresses IL-8 expression in the prostate cell line by decreasing the promoter activity of the IL-8 gene.
|
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
|
3.5
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
|
20.0
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
|
20.0
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
|
4.5
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
|
1.85
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
|
22.5
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
|
3.22
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
|
287.0
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
|
440.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: High Throughput Screen to Identify Inhibitors of Mycobacterium tuberculosis H37Rv. (Class of assay: confirmatory)
|
None
|
195.0
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
|
580.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Microorganism-Based Dose Confirmation HTS to Identify Compounds Cytotoxic to SK(-)GAS Group A Streptococcus. (Class of assay: confirmatory) [Related pubchem assays: 1677 (Project Summary), 1662 (Primary HTS)]
|
Streptococcus
|
660.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: Luminescence Microorganism-Based Dose Confirmation HTS to Identify Inhibitors of Streptokinase Promotor Activity. (Class of assay: confirmatory) [Related pubchem assays: 1677 (Project Summary), 1662 (Primary HTS)]
|
Streptococcus pyogenes M1 GAS
|
668.0
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
|
290.0
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
|
Anti-inflammatory activity in Homo sapiens (human) T lymphocytes assessed as inhibition of PHA-induced [3H] thymidine uptake incubated for 72 hr prior to [3H]thymidine addition measured after 18 hr by liquid scintillation method
|
Homo sapiens
|
50.0
ug.mL-1
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
Anti-inflammatory activity in Homo sapiens (human) T lymphocytes assessed as inhibition of PHA-induced [3H] thymidine uptake at 3.12 ug/ml incubated for 72 hr prior to [3H]thymidine addition measured after 18 hr by liquid scintillation method
|
Homo sapiens
|
-71.1
%
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
Anti-inflammatory activity in Homo sapiens (human) T lymphocytes assessed as inhibition of PHA-induced [3H] thymidine uptake at 12.5 ug/ml incubated for 72 hr prior to [3H]thymidine addition measured after 18 hr by liquid scintillation method
|
Homo sapiens
|
-97.9
%
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
Anti-inflammatory activity in Homo sapiens (human) T lymphocytes assessed as inhibition of PHA-induced [3H] thymidine uptake at 50 ug/ml incubated for 72 hr prior to [3H]thymidine addition measured after 18 hr by liquid scintillation method
|
Homo sapiens
|
-25.2
%
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
Antioxidant activity in Homo sapiens (human) whole blood assessed as inhibition of ROS production after 30 min by luminol-enhanced chemiluminescence assay
|
Homo sapiens
|
31.0
ug.mL-1
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
Antioxidant activity in Homo sapiens (human) whole blood assessed as inhibition of ROS production at 12.5 ug/ml after 30 min by luminol-enhanced chemiluminescence assay
|
Homo sapiens
|
19.7
%
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
Antioxidant activity in Homo sapiens (human) whole blood assessed as inhibition of ROS production at 50 ug/ml after 30 min by luminol-enhanced chemiluminescence assay
|
Homo sapiens
|
66.0
%
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
Antioxidant activity in Homo sapiens (human) whole blood assessed as inhibition of ROS production at 100 ug/ml after 30 min by luminol-enhanced chemiluminescence assay
|
Homo sapiens
|
84.7
%
|
|
Journal : Med Chem Res
Title : Synthesis, characterization, antibacterial, antifungal, and immunomodulating activities of gatifloxacin derivatives
Year : 2010
Volume : 19
Issue : 9
First Page : 1210
Last Page : 1221
Authors : Sultana N, Naz A, Khan B, Arayne MS, Mesaik MA
|
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
|
3.0
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
|
3.0
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.
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Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
121.89
%
|
|
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
|
96.61
%
|
|
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.
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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
|
-3.99
%
|
|
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.
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Inhibition of Mycobacterium tuberculosis DNA gyrase
|
Mycobacterium tuberculosis
|
5.0
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
|
22.31
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.909
%
|
|
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
|
0.15
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.09
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.15
%
|
|
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.
