Antimycobacterial Activities of Novel 1-(Cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro- 6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic Acid

Fifty-one 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acids were synthesized and evaluated for antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug-resistant Mycobacter...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-11, Vol.50 (24), p.6232-6239
Main Authors: Sriram, Dharmarajan, Senthilkumar, Palaniappan, Dinakaran, Murugesan, Yogeeswari, Perumal, China, Arnab, Nagaraja, Valakunja
Format: Article
Language:English
Subjects:
Animals
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Biological and medical sciences
Cercopithecus aethiops
Drug Resistance, Multiple, Bacterial
Female
Light - adverse effects
Medical sciences
Mice
Microbial Sensitivity Tests
Mycobacterium smegmatis - drug effects
Mycobacterium smegmatis - enzymology
Mycobacterium tuberculosis - drug effects
Naphthyridines - chemical synthesis
Naphthyridines - chemistry
Naphthyridines - pharmacology
Pharmacology. Drug treatments
Structure-Activity Relationship
Topoisomerase II Inhibitors
Vero Cells
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Summary:Fifty-one 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acids were synthesized and evaluated for antimycobacterial in vitro and in vivo against Mycobacterium tuberculosis H37Rv (MTB), multi-drug-resistant Mycobacterium tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from M. smegmatis. Among the synthesized compounds, 1-tert-butyl-1,4-dihydro-7-(4,4-dimethyloxazolidin-3-yl)-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid (10q) was found to be the most active compound in vitro with an MIC of 0.1 μM against MTB and MDR-TB and was 3 and 455 times more potent than isoniazid against MTB and MDR-TB, respectively. In the in vivo animal model 10q decreased the bacterial load in lung and spleen tissues with 2.39 and 3.89-log10protections respectively at the dose of 50 mg/kg body weight.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm700999n