2. Academic Validation
  3. Optimization of pyrrole-2-carboxamide to develop a potent antituberculosis agent with improved physicochemical property and druggability

Optimization of pyrrole-2-carboxamide to develop a potent antituberculosis agent with improved physicochemical property and druggability

  • Bioorg Chem. 2025 Oct:165:109016. doi: 10.1016/j.bioorg.2025.109016.
Yanan Wu 1,  Hongyi Zhao 1,  Bin Wang 2,  Xi Chen 2,  Bo Jin 3,  Yixuan Zheng 1,  Chen Ma 3,  Li Sheng 3,  Yu Lu 4,  Haihong Huang 5,  Dongfeng Zhang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Respiratory Health and Multimorbidity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; 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 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.
  • 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 State Key Laboratory of Respiratory Health and Multimorbidity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; 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.
  • 6 State Key Laboratory of Respiratory Health and Multimorbidity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China; 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: zdf@imm.ac.cn.
PMID: 41037866 DOI: 10.1016/j.bioorg.2025.109016
Abstract

MmpL3, a mycobacterial membrane protein, is essential for the transport of trehalose monomycolate, which is crucial for the formation of the M. tuberculosis outer membrane and the survival of the bacterium. Herein, we optimize our lead MmpL3 inhibitor bearing pyrrole-2-carboxamide scaffold to develop antituberculosis agents with improved physicochemical properties. Compound 27b, an optimized analog of our lead MmpL3 inhibitor, exhibited enhanced antituberculosis activity along with reduced cytotoxicity, improved microsomal stability, and high Caco-2 permeability. Significantly, the water solubility and pharmacokinetic profile of compound 27b was markedly improved compared to the lead compound 2. This compound demonstrated potent efficacy in decreasing the intracellular M. tuberculosis load within mouse macrophages. The results of this study indicated that incorporating an oxygen-containing group in pyrrole-2-carboxamide scaffold can improve the compound's LogP value, thereby achieving a balance between lipophilicity and antituberculosis activity.

Keywords

Antituberculosis activity; Druggability; MmpL3; Optimization; Physicochemical property.

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