Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety

Kai Lv; Zeyu Tao; Qian Liu; Lu Yang; Bin Wang; Shuo Wu; Apeng Wang; Menghao Huang; Mingliang Liu; Yu Lu

doi:10.1016/j.ejmech.2018.03.060

Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety

Eur J Med Chem. 2018 May 10:151:1-8. doi: 10.1016/j.ejmech.2018.03.060. Epub 2018 Mar 23.

Authors

Kai Lv¹, Zeyu Tao¹, Qian Liu², Lu Yang¹, Bin Wang³, Shuo Wu¹, Apeng Wang¹, Menghao Huang⁴, Mingliang Liu⁵, Yu Lu⁶

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 Molecular Design and Synthesis, School of Pharmaceutical Science & Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China.
³ Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China.
⁴ Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indiana, 46202, USA.
⁵ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lmllyx@126.com.
⁶ Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China. Electronic address: luyu4876@hotmail.com.

PMID: 29601990
DOI: 10.1016/j.ejmech.2018.03.060

Abstract

We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way.

Keywords: Antimycobacterial activity; Benzothiazionones; PBTZ169; Synthesis.

MeSH terms

Animals
Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry*
Antitubercular Agents / pharmacokinetics
Antitubercular Agents / pharmacology*
Drug Design
Female
Humans
Mice, Inbred ICR
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects*
Piperidines / chemical synthesis
Piperidines / chemistry*
Piperidines / pharmacokinetics
Piperidines / pharmacology*
Thiazines / chemical synthesis
Thiazines / chemistry*
Thiazines / pharmacokinetics
Thiazines / pharmacology*
Tuberculosis / drug therapy

Substances

Antitubercular Agents
Piperidines
Thiazines