Gatifloxacin derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis DNA gyrase.
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.
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani-333031, India. dsriram@bits-pilani.ac.in
Dharmarajan
D
Sriram
Alexandra
A
Aubry
Perumal
P
Yogeeswari
L M
LM
Fisher
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024841:Fluoroquinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000077734:Gatifloxacin; D051379:Mice; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase; D000077734:Gatifloxacin