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.
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: [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: 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.