title: 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.
abstract: 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 microM 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.
authors.affiliation: Medicinal Chemistry Research Laboratory, Pharmacy group, Birla Institute of Technology and Science, Pilani 333031, India. dsriram@bits-pilani.ac.in
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Senthilkumar
authors.forename: Murugesan
authors.initials: M
authors.lastname: Dinakaran
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Arnab
authors.initials: A
authors.lastname: China
authors.forename: Valakunja
authors.initials: V
authors.lastname: Nagaraja
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D008027:Light / Q000009:adverse effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014709:Vero Cells
chemical_list: C526821:1-tert-butyl-1,4-dihydro-7-(4,4-dimethyloxazolidin-3-yl)-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylic acid; D000995:Antitubercular Agents; D009287:Naphthyridines; D059005:Topoisomerase II Inhibitors