2. Academic Validation
  3. Synthesis and antitubercular evaluation of reduced lipophilic imidazo[1,2-a]pyridine-3-carboxamide derivatives

Synthesis and antitubercular evaluation of reduced lipophilic imidazo[1,2-a]pyridine-3-carboxamide derivatives

  • Eur J Med Chem. 2019 Mar 1:165:11-17. doi: 10.1016/j.ejmech.2018.12.071.
Hongjian Wang 1,  Apeng Wang 1,  Jian Gu 2,  Lei Fu 3,  Kai Lv 1,  Chao Ma 1,  Zeyu Tao 1,  Bin Wang 3,  Mingliang Liu 4,  Huiyuan Guo 1,  Yu Lu 5
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 College of Pharmacy, Southwest Minzu University, Chengdu, 610041, 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: lmllyx@126.com.
  • 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: luyu4876@hotmail.com.
PMID: 30654236 DOI: 10.1016/j.ejmech.2018.12.071
Abstract

A series of reduced lipophilic N-benzylic imidazo[1,2-a]pyridine carboxamides (IPAs) with various side chains were designed and synthesized as new anti-TB agents in this work. Five derivatives A2, A3, A4, B1 and B9 exhibit excellent in vitro activity (MIC: < 0.035 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains, and acceptable PK properties. Compound B1 bearing a cyclohexylmethyl piperazine moiety, the same side chain of PBTZ169, was found to have obviously greater AUC0-∞ and Cmax than Q203 and PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.

Keywords

Antitubercular agents; Pharmacokinetics; imidazo[1,2-a]pyridine carboxamides; structure−activity relationships.

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