Synthesis and structure–activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents

摘要: N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds evaluated by determination minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra M. H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, N-alkyl BTZs not affected either nitro trifluoromethyl at 6-position. Trifluoromethyl plays important role in maintaining anti-tubercular activity piperazine piperidine analogs. Compound 8o, which contains azaspirodithiolane group, showed a MIC 0.0001 μM against H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested volume lipophilicity substituents activity. In addition, compound 8o nontoxic to Vero cells orally bioavailable preliminary pharmacokinetics study.