Design, synthesis and antimycobacterial activity of new benzothiazinones inspired by rifampicin/rifapentine

Apeng Wang; Yu Lu; Kai Lv; Chao Ma; Shijie Xu; Bin Wang; Aoyu Wang; Guimin Xia; Mingliang Liu

doi:10.1016/j.bioorg.2020.104135

Design, synthesis and antimycobacterial activity of new benzothiazinones inspired by rifampicin/rifapentine

Bioorg Chem. 2020 Sep:102:104135. doi: 10.1016/j.bioorg.2020.104135. Epub 2020 Jul 22.

Authors

Apeng Wang¹, Yu Lu², Kai Lv¹, Chao Ma¹, Shijie Xu¹, Bin Wang², Aoyu Wang³, Guimin Xia⁴, Mingliang Liu⁵

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
² Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital College of Pharmacy, Medical University, Beijing 100149, China.
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Hebei Medical University, Shijiazhuang 050017, China.
⁴ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
⁵ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].

PMID: 32736151
DOI: 10.1016/j.bioorg.2020.104135

Abstract

A series of novel benzothiazinone derivatives containing a N-((methylene)amino)piperazine moiety, inspired by rifampicin/rifapentine, were designed and synthesized. Seven compounds 1a and 1e-j show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates (MIC: <0.029-0.110 μM), and accepted selective index (>1100->4000). Compound 1h displays good safety and pharmacokinetic profiles, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Keywords: Antimycobacterial activity; Benzothiazinones; N-((methylene)amino)piperazine; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Anti-Bacterial Agents / administration & dosage
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Cell Proliferation / drug effects
Chlorocebus aethiops
Dose-Response Relationship, Drug
Drug Design*
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Rifampin / administration & dosage
Rifampin / analogs & derivatives*
Rifampin / chemistry
Rifampin / pharmacology*
Structure-Activity Relationship
Thiazines / administration & dosage
Thiazines / chemistry
Thiazines / pharmacology*
Vero Cells

Substances

Anti-Bacterial Agents
Thiazines
Rifampin
rifapentine