Identification of a new series of benzothiazinone derivatives with excellent antitubercular activity and improved pharmacokinetic profiles. Issue 20 (21st March 2018)

• Record Type: Journal Article
• 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
• Is Part Of: RSC advances. Volume 8:Issue 20(2018)
• Page Start: 11163
• Page End: 11176
• Publication Date: 2018-03-21
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8ra00720a
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Nitrobenzothiazinone (BTZ) is a promising scaffold with potent activity against M. tuberculosis by inhibiting decaprenylphosphoryl-beta-d -ribose 2′-oxidase (DprE1). Abstract : Nitrobenzothiazinone (BTZ) is a promising scaffold with potent activity against M. tuberculosis 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 Mycobacterium tuberculosis H37Ra and were profiled for metabolic stability, plasma protein-binding capacity and pharmacokinetics in vivo . In general, these new BTZs containing N -piperazine, N -piperidine or N -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 compound3o, which maintained good anti-tuberculosis activity (MIC = 8 nM) and presented better in vitro ADME/T and in vivo pharmacokinetic profiles than reported BTZ compoundPBTZ169, which may serve as a candidate for the treatment of tuberculosis.