Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides as new antitubercular agents

Apeng Wang; Kai Lv; Linhu Li; Hongtao Liu; Zeyu Tao; Bin Wang; Mingliang Liu; Chao Ma; Xican Ma; Bing Han; Aoyu Wang; Yu Lu

doi:10.1016/j.ejmech.2019.06.038

Design, synthesis and biological activity of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides as new antitubercular agents

Eur J Med Chem. 2019 Sep 15:178:715-725. doi: 10.1016/j.ejmech.2019.06.038. Epub 2019 Jun 14.

Authors

Apeng Wang¹, Kai Lv¹, Linhu Li¹, Hongtao Liu², Zeyu Tao¹, Bin Wang³, Mingliang Liu⁴, Chao Ma¹, Xican Ma¹, Bing Han¹, Aoyu Wang¹, Yu Lu⁵

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; Department of Pharmacy, Hebei General Hospital, Hebei, Shijiazhuang, 050051, 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, 100149, China.
⁴ Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
⁵ 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, 100149, China. Electronic address: [email protected].

PMID: 31229874
DOI: 10.1016/j.ejmech.2019.06.038

Abstract

A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.

Keywords: Antimycobacterial activity; Design; Synthesis; imidazo[1,2-a]pyridine.

MeSH terms

Animals
Antitubercular Agents / administration & dosage
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Female
Imidazoles / administration & dosage
Imidazoles / chemistry
Imidazoles / pharmacology*
Mice
Mice, Inbred ICR
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Pyridines / administration & dosage
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Antitubercular Agents
Imidazoles
Pyridines