|
Mammalian cell cytotoxicity test in chinese hamster V79 cells (clonogenic cytotoxicity)
|
None
|
500.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity.
Year : 1992
Volume : 35
Issue : 25
First Page : 4745
Last Page : 4750
Authors : Suto MJ, Domagala JM, Roland GE, Mailloux GB, Cohen MA.
Abstract : Fluoroquinolones are potent inhibitors of bacterial topoisomerase II (DNA gyrase). They can also inhibit eukaryotic topoisomerases, which could possibly lead to clastogenicity and/or cellular toxicity. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the fluoroquinolones and the potential of these compounds to induce micronuclei, a genetic toxicity endpoint. In an effort to identify potent nontoxic quinolone antibacterials, we have examined the structural features of the fluoroquinolones associated with mammalian cell cytotoxicity. An investigation of a wide variety of substituents at the 1, 5, 7, and 8 positions of a quinolone nucleus was conducted. The results indicate that no one position has a controlling effect on the observed cytotoxicity. Instead, a combination of the various substituents contributes to the effects seen. Certain trends were apparent, such as the fact that compounds with pyrrolidines at the R-7 position were more cytotoxic than those with piperazines, and halogens at R-8 (X-position) were associated with more cytotoxicity relative to hydrogen. A general trend also existed between the cytotoxicity of the compounds and their Gram-positive antibacterial activity. A detailed comparison between the various groups and positional variations as they controlled the cytotoxicity and antibacterial activity is presented.
|
Inhibitory effect on DNA gyrase supercoiling activity from Escherichia coli K-12 C600
|
Escherichia coli
|
0.59
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of thiazolo-, oxazolo-, and imidazolo[3,2-a][1,8]naphthyridinecarboxylic acids.
Year : 1990
Volume : 33
Issue : 7
First Page : 2012
Last Page : 2015
Authors : Kondo H, Taguchi M, Inoue Y, Sakamoto F, Tsukamoto G.
Abstract : It is known that thiazolo[3,2-a][1,8]naphthyridine derivatives (3a) exhibit good antibacterial activity. Accordingly, several analogues of 3a, viz. oxazolo- and imidazolo[3,2-a][1,8]naphthyridine derivatives 3b and 3c, were synthesized and evaluated for antibacterial activity in vitro and for inhibitory activity against DNA gyrase of Escherichia coli K-12 C600. Compound 3a exhibited antibacterial activity comparable to that of ofloxacin and enoxacin against Gram-positive and Gram-negative bacteria and displayed antibacterial activity superior to that of 3b and 3c. The antibacterial activities of 3b and 3c decreased in that order. DNA gyrase inhibitory activities of 3a-c in E. coli K-12 C600 paralleled their in vitro antibacterial activity. It was found that enhancement of the DNA gyrase inhibitory activity of 3a was dependent on a certain feature of the sulfur atom of the thiazole ring.
|
Inhibition of DNA gyrase supercoiling in Escherichia coli.
|
Escherichia coli
|
1.8
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : DNA gyrase inhibitory activity of ellagic acid derivatives.
Year : 1998
Volume : 8
Issue : 1
First Page : 97
Last Page : 100
Authors : Weinder-Wells MA, Altom J, Fernandez J, Fraga-Spano SA, Hilliard J, Ohemeng K, Barrett JF.
Abstract : Ellagic acid was found to inhibit E. coli DNA gyrase supercoiling with approximately the same potency as nalidixic acid. Tricyclic analogs of ellagic acid, which vary in the number and position of the hydroxy groups as well as their replacement with halogens, have been synthesized. The biological activity of these analogs is discussed.
|
Tested for inhibitory activity against DNA gyrase supercoiling in Escherichia coli (KL-16)
|
Escherichia coli
|
0.53
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and antibacterial activity of a new series of tetracyclic pyridone carboxylic acids.
Year : 1993
Volume : 36
Issue : 21
First Page : 3148
Last Page : 3153
Authors : Jinbo Y, Taguchi M, Inoue Y, Kondo H, Miyasaka T, Tsujishita H, Sakamoto F, Tsukamoto G.
Abstract : A novel tetracyclic pyridone carboxylic acid with a thiazolidine ring, 1,2-dihydro-9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo -5H- thiazolo[3,2-a]quinoline-4-carboxylic acid (4a), and variants with a nitrogen atom (4b) or carbonyl group (4c) in the place of the 10-position oxygen atom of 4a were prepared and tested for antibacterial activity and inhibitory activity on DNA gyrase from Escherichia coli KL-16. The in vitro antibacterial potency with regard to the 10-position atom was found to be of the following order; O > NCH3 = C = O. The IC50 values for DNA gyrase inhibition activity for the 4a, 4b, and 4c compounds were 0.33, 0.53, and 0.67 g/mL, respectively. The activity of 4a, in which the C-3 methyl group and C-5 of ofloxacin (2a) were connected with a sulfur atom to restrict the conformation of 2a, was more potent than that of 2a against both Gram-positive and -negative bacteria, except for Pseudomonas aeruginosa. Compared to the tetracyclic pyridone carboxylic acid 1a, which has a flat thiazole ring, compound 4a showed comparable or slightly more potent activity against both Gram-positive and -negative bacteria, except for P. aeruginosa.
|
Minimum concentration of the drug needed to produce linear DNA at an intensity relative to oxolinic acid(at 10 ug/mL)
|
Escherichia coli
|
2.25
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : New "ofloxacin" type antibacterial agents. Incorporation of the spiro cyclopropyl group at N-1.
Year : 1988
Volume : 31
Issue : 10
First Page : 2004
Last Page : 2008
Authors : Kiely JS, Schroeder MC, Sesnie JC.
Abstract : The first example incorporating a spiro cyclopropyl group into an "ofloxacin" type of quinolone antibacterial agent has been prepared by potassium fluoride mediated ring closure of the hydroxymethyl cyclopropyl intermediate to give 9'-fluoro-7'-oxo-10'-(1-piperazinyl)spiro[cyclopropane-1,3'(2'H)-[7H] pyrido[1,2,3-de][1,4]benzoxazine]-6'-carboxylic acid. Analogues were made by substitution at C-7 by various complex amines. Evaluation of these compounds for antibacterial activity was carried out. All examples prepared and examined showed in vitro minimum inhibitory values and in vivo mouse protection results to be diminished as compared to the parent, ofloxacin.
|
Inhibitory concentration in supercoiling inhibition Escherichia coli DNA gyrase assay
|
Escherichia coli
|
6.3
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : New structure-activity relationships of the quinolone antibacterials using the target enzyme. The development and application of a DNA gyrase assay.
Year : 1986
Volume : 29
Issue : 3
First Page : 394
Last Page : 404
Authors : Domagala JM, Hanna LD, Heifetz CL, Hutt MP, Mich TF, Sanchez JP, Solomon M.
Abstract : A series of 60 newly synthesized and known quinolone antibacterials, including quinoline- and 1,8-naphthyridine-3-carboxylic acids, pyrido[2,3-d]pyrimidine-6-carboxylic acids, and some monocyclic 4-pyridone-3-carboxylic acids, were tested and compared in a newly established, easy to perform, DNA gyrase assay. The results were correlated with minimum inhibitory concentrations (MICs) against a variety of organisms. Among the known quinolones were 14 clinically significant drugs (oxolinic acid, norfloxacin, ciprofloxacin, enoxacin, etc.) which were used as standards and compared side-by-side. The study focused on the changes in DNA gyrase inhibition brought about by certain features of the molecules, namely, the C6-fluorine or the nature of the C7 substituent. The intrinsic gyrase inhibition of the fused parent rings, quinoline vs. naphthyridine vs. pyrido[2,3-d]pyrimidine, was also explored. In all cases, loss of enzyme inhibition produced poor MICs, but some compounds with good DNA gyrase inhibition did not correspondingly inhibit bacterial growth. Possible explanations for this phenomena and the benefits of a DNA gyrase-MIC strategy for developing future structure-activity relationships are discussed.
|
50% inhibitory concentration against DNA-gyrase
|
Escherichia coli
|
7.5
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : 7-substituted 5-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3- quinolinecarboxylic acids: synthesis and biological activity of a new class of quinolone antibacterials.
Year : 1988
Volume : 31
Issue : 3
First Page : 503
Last Page : 506
Authors : Domagala JM, Hagen SE, Heifetz CL, Hutt MP, Mich TF, Sanchez JP, Trehan AK.
|
Gyrase inhibitory activity against Escherichia coli
|
Escherichia coli
|
1.0
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Synthesis and bacterial DNA gyrase inhibitory properties of a spirocyclopropylquinolone derivative.
Year : 1988
Volume : 31
Issue : 9
First Page : 1694
Last Page : 1697
Authors : Wentland MP, Perni RB, Dorff PH, Rake JB.
Abstract : A novel conformationally restricted 1-cyclopropylquinolone (1) that incorporates structural features of both ofloxacin and ciprofloxacin has been prepared. Compound 1 was found to be a DNA gyrase inhibitor having potency similar to ofloxacin but less than ciprofloxacin. The cellular inhibitory and in vivo antibacterial potencies of 1 were found to be less than those of the two reference agents.
|
In vitro antibacterial activity was determined as inhibitory concentration causing 50% DNA-gyrase supercoiling inhibition (SCI)
|
Escherichia coli
|
1.75
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : DNA gyrase inhibitory and antibacterial activity of some flavones(1)
Year : 1993
Volume : 3
Issue : 2
First Page : 225
Last Page : 230
Authors : Ohemeng K, Schwender C, Fu K, Barrett J
|
Inhibition constant against DNA Gyrase isolated from Escherichia coli
|
Escherichia coli
|
1.6
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin).
Year : 1987
Volume : 30
Issue : 12
First Page : 2283
Last Page : 2286
Authors : Mitscher LA, Sharma PN, Chu DT, Shen LL, Pernet AG.
Abstract : A short and efficient synthesis, starting with (R)- and (S)-alaninol, of the two optical antipodes of the quinolone antimicrobial agent ofloxacin has been devised. Testing in vitro of the products against a range of bacteria and in an assay system incorporating purified DNA gyrase from different bacterial species demonstrates that the S-(-) enantiomer is substantially the more active.
|
Inhibition constant against DNA Gyrase isolated from Micrococcus luteus
|
Micrococcus luteus
|
84.0
ug ml-1
|
|
Journal : J. Med. Chem.
Title : Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin).
Year : 1987
Volume : 30
Issue : 12
First Page : 2283
Last Page : 2286
Authors : Mitscher LA, Sharma PN, Chu DT, Shen LL, Pernet AG.
Abstract : A short and efficient synthesis, starting with (R)- and (S)-alaninol, of the two optical antipodes of the quinolone antimicrobial agent ofloxacin has been devised. Testing in vitro of the products against a range of bacteria and in an assay system incorporating purified DNA gyrase from different bacterial species demonstrates that the S-(-) enantiomer is substantially the more active.
|
Inhibition of Mycobacterium leprae recombinant DNA gyrase expressed in Escherichia coli assessed as inhibition of pBR322 DNA supercoiling
|
Mycobacterium leprae
|
10.0
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 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
21.1
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Inhibition of Mycobacterium leprae wild type DNA gyrase A2B2 assessed as DNA supercoiling inhibition
|
Mycobacterium leprae
|
15.0
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
|
160.0
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
|
80.0
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
|
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.
|
Antimicrobial activity against Escherichia coli harboring DNA gyrase GyrA QRDR
|
Escherichia coli
|
0.3
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Pseudomonas aeruginosa harboring DNA gyrase GyrA QRDR
|
Pseudomonas aeruginosa
|
0.5
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Staphylococcus aureus harboring DNA gyrase GyrA QRDR
|
Staphylococcus aureus
|
10.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Streptococcus pneumoniae harboring DNA gyrase GyrA QRDR
|
Streptococcus pneumoniae
|
40.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Mycobacterium smegmatis harboring DNA gyrase GyrA QRDR
|
Mycobacterium smegmatis
|
10.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Mycobacterium tuberculosis harboring DNA gyrase GyrA QRDR
|
Mycobacterium tuberculosis
|
10.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Mycobacterium fortuitum harboring DNA gyrase GyrA QRDR
|
Mycobacterium fortuitum
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Escherichia coli harboring DNA gyrase GyrB QRDR
|
Escherichia coli
|
0.3
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Pseudomonas aeruginosa harboring DNA gyrase GyrB QRDR
|
Pseudomonas aeruginosa
|
0.5
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Staphylococcus aureus harboring DNA gyrase GyrB QRDR
|
Staphylococcus aureus
|
10.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Streptococcus pneumoniae harboring DNA gyrase GyrB QRDR
|
Streptococcus pneumoniae
|
40.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Mycobacterium smegmatis harboring DNA gyrase GyrB QRDR
|
Mycobacterium smegmatis
|
10.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Mycobacterium tuberculosis harboring DNA gyrase GyrB QRDR
|
Mycobacterium tuberculosis
|
10.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
Antimicrobial activity against Mycobacterium fortuitum harboring DNA gyrase GyrB QRDR
|
Mycobacterium fortuitum
|
1.0
ug.mL-1
|
|
Journal : Antimicrob. Agents Chemother.
Title : Mutagenesis in the alpha3alpha4 GyrA helix and in the Toprim domain of GyrB refines the contribution of Mycobacterium tuberculosis DNA gyrase to intrinsic resistance to quinolones.
Year : 2008
Volume : 52
Issue : 8
First Page : 2909
Last Page : 2914
Authors : Matrat S, Aubry A, Mayer C, Jarlier V, Cambau E.
Abstract : The replacement of M74 in GyrA, A83 in GyrA, and R447 in GyrB of Mycobacterium tuberculosis gyrase by their Escherichia coli homologs resulted in active enzymes as quinolone susceptible as the E. coli gyrase. This demonstrates that the primary structure of gyrase determines intrinsic quinolone resistance and was supported by a three-dimensional model of N-terminal GyrA.
|
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
|
560.0
nM
|
|
Title : PubChem BioAssay data set
|
PUBCHEM_BIOASSAY: A Counter Screen to identiry small molecule screen for inhibitors of the PhoP region in Salmonella Typhimurium. (Class of assay: confirmatory) [Related pubchem assays: 2253, 1863, 1981, 1874 ]
|
None
|
800.0
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
|
390.0
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
|
310.0
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
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
-8.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
24.5
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
18.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Antitubercular activity against Mycobacterium tuberculosis
|
Mycobacterium tuberculosis
|
0.5
ug.mL-1
|
|
Journal : Med Chem Res
Title : Quinolone derivatives as antitubercular drugs
Year : 2013
Volume : 22
Issue : 3
First Page : 1029
Last Page : 1042
Authors : Asif M, Siddiqui AA, Husain A
|
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
|
8.0
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
|
6.0
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 sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
65.85
%
|
|
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
|
89.51
%
|
|
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.
|
Antichlamydial activity against Chlamydia trachomatis serovar L2 infected in human HeLa 299 cells assessed as reduction in number of inclusion bodies measured after 44 to 48 hrs by DAPI staining-based HCS assay
|
Chlamydia trachomatis
|
666.0
nM
|
|
Journal : Eur J Med Chem
Title : Natural product inspired library synthesis - Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis.
Year : 2018
Volume : 143
First Page : 1077
Last Page : 1089
Authors : Saleeb M, Mojica S, Eriksson AU, Andersson CD, Gylfe Å, Elofsson M.
Abstract : A natural product inspired library was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3-dihydrobenzofuran scaffolds. The library of forty-eight compounds was prepared by utilizing Pd-catalyzed one-pot multicomponent reactions and ruthenium-catalyzed intramolecular carbenoid C-H insertions. The compounds were evaluated for antibacterial activity in a panel of test systems including phenotypic, biochemical and image-based screening assays. We identified several potent inhibitors that block intracellular replication of pathogenic Chlamydia trachomatis with IC50 ≤ 3 μM. These new C. trachomatis inhibitors can serve as starting points for the development of specific treatments that reduces the global burden of C. trachomatis infections.
|
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
|
-5.24
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
12.52
%
|
|
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
|
0.25
%
|
|
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
|
0.25
%
|
|
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.
