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Novel ofloxacin derivatives: Synthesis, antimycobacterial and toxicological evaluation

Dinakaran, Murugesan and Senthilkumar, Palaniappan and Yogeeswari, Perumal and China, Arnab and Nagaraja, Valakunja and Sriram, Dharmarajan (2008) Novel ofloxacin derivatives: Synthesis, antimycobacterial and toxicological evaluation. In: Bioorganic & Medicinal Chemistry Letters, 18 (3). pp. 1229-1236.

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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-car-boxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activ-ities 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 mycobac-teria. 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 $0.19 \mu M$ and $0.09 \mu M$ 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 - log 10 protections, respectively, at the dose of 50 mg/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 $10.0 \mu g/mL$. The results demonstrate the potential and importance of developing new oxazino quin-olone derivatives against mycobacterial infections

Item Type: Journal Article
Publication: Bioorganic & Medicinal Chemistry Letters
Publisher: Elsevier
Additional Information: Copyright of this article belongs to Elsevier.
Keywords: Oxazino[2,3,4-ij]quinoline-6-carboxylic acids;Antimycobacterial activity;Tuberculosis.
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 25 Sep 2008 06:56
Last Modified: 19 Sep 2010 04:50
URI: http://eprints.iisc.ac.in/id/eprint/15936

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