2. Academic Validation
  3. Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

  • Eur J Med Chem. 2022 Mar 5;231:114145. doi: 10.1016/j.ejmech.2022.114145.
Rongfei Qin 1,  Pengxu Wang 1,  Bin Wang 2,  Lei Fu 2,  Sarah M Batt 3,  Gurdyal S Besra 3,  Chengwei Wu 1,  Yanan Wang 1,  Haihong Huang 4,  Yu Lu 5,  Gang Li 6
Affiliations

Affiliations

  • 1 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 School of Biosciences, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
  • 4 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.
  • 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, 97 Ma Chang Street, Beijing, 101149, PR China. Electronic address: luyu4876@hotmail.com.
  • 6 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: ligang@imm.ac.cn.
PMID: 35101648 DOI: 10.1016/j.ejmech.2022.114145
Abstract

A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 μg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log10 CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.

Keywords

Drug-resistant tuberculosis; Druggability evaluation; SAR exploration; Thiophene-benzenesulfonamide.

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