title: Synthesis, antimycobacterial activities and phototoxic evaluation of 5H-thiazolo[3,2-a]quinoline-4-carboxylic acid derivatives.
abstract: Thirty four novel 7-fluoro/nitro-1,2-dihydro-5-oxo-8-(sub)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acids were synthesized from 2,4-dichlorobenzoic acid and 2,4-dichloro-5-fluoroacetophenone by multi step reaction, evaluated for in vitro and in vivo antimycobacterial activities 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, 8-[6-[[(1,1-dimethylethoxy)carbonyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-1,2-dihydro-7-nitro-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid (10q) was found to be the most active compound in vitro with MIC of 0.08 microM and <0.08 microM against MTB and MDR-TB respectively. Compound 10q was found to be 4.5 and >570 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 2.51 and 3.71-log10 protections 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.
authors.forename: Murugesan
authors.initials: M
authors.lastname: Dinakaran
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Senthilkumar
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
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D027081:DNA Gyrase / Q000378:metabolism; D017484:Dermatitis, Phototoxic / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000187:drug effects* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects* / Q000382:microbiology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D011804:Quinolines; D013844:Thiazoles; C059924:quinoline-4-carboxylic acid; D027081:DNA Gyrase