Design, synthesis and biological activity of N-(amino)piperazine-containing benzothiazinones against Mycobacterium tuberculosis

Apeng Wang; Shijie Xu; Yun Chai; Guimin Xia; Bin Wang; Kai Lv; Chao Ma; Dan Wang; Aoyu Wang; Xiaoyu Qin; Mingliang Liu; Yu Lu

doi:10.1016/j.ejmech.2021.113398

Design, synthesis and biological activity of N-(amino)piperazine-containing benzothiazinones against Mycobacterium tuberculosis

Eur J Med Chem. 2021 Jun 5:218:113398. doi: 10.1016/j.ejmech.2021.113398. Epub 2021 Mar 28.

Authors

Apeng Wang¹, Shijie Xu¹, Yun Chai², Guimin Xia³, Bin Wang⁴, Kai Lv¹, Chao Ma¹, Dan Wang¹, Aoyu Wang⁵, Xiaoyu Qin¹, Mingliang Liu⁶, Yu Lu⁷

Affiliations

¹ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
² Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, 710072, China.
³ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: xiaguimin@126.com.
⁴ 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.
⁵ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Hebei Medical University, Shijiazhuang, 050017, China.
⁶ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lmllyx@126.com.
⁷ 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. Electronic address: luyu4876@hotmail.com.

PMID: 33823392
DOI: 10.1016/j.ejmech.2021.113398

Abstract

A series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent in vitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: < 0.016 μg/mL), and good safety index (CC₅₀: >64 μg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compound for future antitubercular drug discovery.

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

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Piperazine / chemistry
Piperazine / pharmacology*
Structure-Activity Relationship
Thiazines / chemical synthesis
Thiazines / chemistry
Thiazines / pharmacology*

Substances

Anti-Bacterial Agents
Thiazines
Piperazine