title: Synthesis and structure-activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents.
abstract: N-Alkyl and heterocycle substituted 1,3-benzothiazin-4-one (BTZ) derivatives were synthesized. The anti-mycobacterial activities of these compounds were evaluated by determination of minimal inhibitory concentration (MIC) for Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv. It was found that an extended or branched alkyl chain analog could enhance the potency, and activities of N-alkyl substituted BTZs were not affected by either nitro or trifluoromethyl at 6-position. Trifluoromethyl plays an important role in maintaining anti-tubercular activity in the piperazine or piperidine analogs. Compound 8o, which contains an azaspirodithiolane group, showed a MIC of 0.0001 μM against M. tuberculosis H37Rv, 20-fold more potent than BTZ043 racemate. These results suggested that the volume and lipophilicity of the substituents were important in maintaining activity. In addition, compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Ting-Hong
authors.initials: TH
authors.lastname: Ye
authors.forename: Ning-Yu
authors.initials: NY
authors.lastname: Wang
authors.forename: Xiu-Xiu
authors.initials: XX
authors.lastname: Zeng
authors.forename: Li-Dan
authors.initials: LD
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: You
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Cui-Ting
authors.initials: CT
authors.lastname: Peng
authors.forename: Wei-Qiong
authors.initials: WQ
authors.lastname: Zuo
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy; D014709:Vero Cells
chemical_list: C540716:2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; D000995:Antitubercular Agents; D013141:Spiro Compounds; D013843:Thiazines
keywords: Benzothiazinone; DprE1; Structure–activity relationships (SAR); Tuberculosis