Design, synthesis and biological evaluation of alkynyl-containing maleimide derivatives for the treatment of drug-resistant tuberculosis

Peng Li; Bin Wang; Xi Chen; Ziyun Lin; Gang Li; Yu Lu; Haihong Huang

doi:10.1016/j.bioorg.2022.106250

Design, synthesis and biological evaluation of alkynyl-containing maleimide derivatives for the treatment of drug-resistant tuberculosis

Bioorg Chem. 2023 Feb:131:106250. doi: 10.1016/j.bioorg.2022.106250. Epub 2022 Nov 15.

Authors

Peng Li¹, Bin Wang², Xi Chen², Ziyun Lin¹, Gang Li³, Yu Lu⁴, Haihong Huang⁵

Affiliations

¹ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China.
² Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, PR China.
³ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China. Electronic address: ligang@imm.ac.cn.
⁴ Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, PR China. Electronic address: luyu4876@hotmail.com.
⁵ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China. Electronic address: joyce@imm.ac.cn.

PMID: 36423487
DOI: 10.1016/j.bioorg.2022.106250

Abstract

A series of alkynyl-containing maleimides with potent anti-tuberculosis (TB) activity was developed through a rigid group substitution strategy based on our previous study. Systematic optimization of the two side chains flanking the maleimide core led to new compounds with potent activity against Mycobacterium tuberculosis (MIC < 1 μg/mL) and low cytotoxicity (IC₅₀ > 64 μg/mL). Among them, compound 29 not only possessed good activity against extensively drug-resistant TB and favorable hepatocyte stability, but also displayed good intracellular antimycobacterial activity in macrophages. This study lays a good foundation for identifying new alkynyl-containing maleimides as promising leads for treating drug-resistant TB.

Keywords: Drug-resistant tuberculosis; Lead compound; Maleimides; Rigid group substitution.

Publication types

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

MeSH terms

Antitubercular Agents / chemistry
Humans
Maleimides / pharmacology
Microbial Sensitivity Tests
Mycobacterium tuberculosis*
Tuberculosis, Multidrug-Resistant*

Substances

Antitubercular Agents
maleimide
VP1-001
Maleimides