title: Novel ofloxacin derivatives: synthesis, antimycobacterial and toxicological evaluation.
abstract: Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC(2)) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 microM and 0.09 microM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91--log10 protections, respectively, at the dose of 50mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC(50) of 10.0 microg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.
authors: Medicinal Chemistry Research Laboratory, Pharmacy group, Birla Institute of Technology and Science, Pilani 333031, India.
authors: Murugesan
authors: M
authors: Dinakaran
authors: Palaniappan
authors: P
authors: Senthilkumar
authors: Perumal
authors: P
authors: Yogeeswari
authors: Arnab
authors: A
authors: China
authors: Valakunja
authors: V
authors: Nagaraja
authors: Dharmarajan
authors: D
authors: Sriram
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques; 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; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D015242:Ofloxacin / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000382:microbiology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D015242:Ofloxacin; D027081:DNA Gyrase; D000077734:Gatifloxacin