Identification of a new series of benzothiazinone derivatives with excellent antitubercular activity and improved pharmacokinetic profiles

• Published in: RSC advances Vol. 8; no. 20; pp. 11163 - 11176
• Main Authors: Xiong, Lu, Gao, Chao, Shi, Yao-Jie, Tao, Xin, Rong, Juan, Liu, Kun-Lin, Peng, Cui-Ting, Wang, Ning-Yu, Lei, Qian, Zhang, Yi-Wen, Yu, Luo-Ting, Wei, Yu-Quan
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 01.01.2018; The Royal Society of Chemistry
• Subjects: Binding; Biocompatibility; Chemistry; Pharmacokinetics; Pharmacology; Piperidine; Ribose; Stability; Toxicity; Tuberculosis
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/c8ra00720a

Nitrobenzothiazinone (BTZ) is a promising scaffold with potent activity against by inhibiting decaprenylphosphoryl-beta-d-ribose 2'-oxidase (DprE1). But unfavorable durability poses a challenge to further development of this class of agents. Herein, a series of BTZs bearing a variety of different substituents at the C-2 position were designed and synthesized. Compounds were screened for their antimycobacterial activity against H37Ra and were profiled for metabolic stability, plasma protein-binding capacity and pharmacokinetics . In general, these new BTZs containing -piperazine, -piperidine or -piperidone moiety have excellent antitubercular activity and low cytotoxicity. Several of the compounds showed improved microsomal stability and lower plasma protein-binding, opening a new direction for further lead optimization. And we obtained compound 3o, which maintained good anti-tuberculosis activity (MIC = 8 nM) and presented better ADME/T and pharmacokinetic profiles than reported BTZ compound PBTZ169, which may serve as a candidate for the treatment of tuberculosis.