2. Academic Validation
  3. Design, synthesis and antimycobacterial activity of less lipophilic Q203 derivatives containing alkaline fused ring moieties

Design, synthesis and antimycobacterial activity of less lipophilic Q203 derivatives containing alkaline fused ring moieties

  • Bioorg Med Chem. 2019 Mar 1;27(5):813-821. doi: 10.1016/j.bmc.2019.01.022.
Apeng Wang 1,  Hongjian Wang 1,  Yunhe Geng 2,  Lei Fu 3,  Jian Gu 4,  Bin Wang 3,  Kai Lv 1,  Mingliang Liu 5,  Zeyu Tao 1,  Chao Ma 1,  Yu Lu 6
Affiliations

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; College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang 050024, China.
  • 3 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Parmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China.
  • 4 College of Pharmacy, Southwest Minzu University, Chengdu 610041, China.
  • 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 Parmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China. Electronic address: luyu4876@hotmail.com.
PMID: 30692025 DOI: 10.1016/j.bmc.2019.01.022
Abstract

We report herein the design and synthesis of a series of less lipophilic Q203 derivatives containing an alkaline fused ring moiety. Most of them show considerable potency against MTB H37Rv strain (MIC < 0.25 μM). Nine compounds (13, 15, 19, 21, 23, 25, 29, 35, 36) have the same excellent activity against both drug-sensitive and -resistant strains (MIC < 0.035 μM) as Q203 and PBTZ169. Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Keywords

Imidazo[1,2-a]pyridine-3-carboxamides; Pharmacokinetics; Structure-activity relationship; Tuberculosis; hERG K(+) channel inhibition.

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