Synthesis and antitubercular evaluation of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 7; pp. 1373 - 1376
• Main Authors: Peng, Cui-Ting, Gao, Chao, Wang, Ning-Yu, You, Xin-Yu, Zhang, Li-Dan, Zhu, Yong-Xia, Xv, Ying, Zuo, Wei-Qiong, Ran, Kai, Deng, Hong-Xia, Lei, Qian, Xiao, Kun-Jie, Yu, Luo-Ting
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.04.2015; Elsevier
• Subjects: Animals; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Aqueous solubility; Benzothiazinones; Cercopithecus aethiops; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Life Sciences & Biomedicine; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis - drug effects; Pharmacology & Pharmacy; Physical Sciences; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Science & Technology; Structure-Activity Relationship; Structure–activity relationships (SAR); Thiazines - chemical synthesis; Thiazines - chemistry; Thiazines - pharmacology; Tuberculosis; Tuberculosis - drug therapy; Vero Cells; Benzothiazinones; Structure–activity relationships (SAR); Tuberculosis; Aqueous solubility; DRUG-RESISTANT; DPRE1; Structure-activity relationships (SAR); INHIBITORS; KILL MYCOBACTERIUM-TUBERCULOSIS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.02.061

[Display omitted] Tuberculosis (TB) remains a major human health problem. New therapeutic antitubercular agents are urgent needed to control the global tuberculosis pandemic. We synthesized a new series of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives and evaluated their anti-mycobacterial activities against Mycobacterium tuberculosis H37Ra as well as their druggabilities. The results showed that most of these derivatives, especially the compounds with simple alkyl side chains, exhibited good antitubercular activities and favorable aqueous solubilities with no obvious cytotoxicity. It suggested that the 4-carbonyl piperazine substituents in benzothiazinone scaffold were well tolerated, in which the compound 8h, with an antitubercular activity of MIC 0.008μM, exhibited an excellent aqueous solubility of 104μg/mL, which was 100-fold better than the potent DprE1 inhibitor Comp.1 (BTZ038), also more soluble than PBTZ169.