2. Academic Validation
  3. Discovery of biphenyls bearing thiobarbiturate fragment by structure-based strategy as Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors

Discovery of biphenyls bearing thiobarbiturate fragment by structure-based strategy as Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors

  • Bioorg Med Chem. 2022 Nov 1:73:117006. doi: 10.1016/j.bmc.2022.117006.
Shihao Cheng 1,  Qinglin Wang 2,  Xi Chen 3,  Jiahao Chen 2,  Bin Wang 3,  Dongni Chen 2,  Dong Shen 2,  Jinying Tian 4,  Fei Ye 4,  Yu Lu 3,  Haihong Huang 5,  Yongjun Lu 6,  Dongfeng Zhang 7
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 School of Life Sciences, Sun Yat-sen University, 135 West Xingang Road, Guangzhou, Guangdong 510275, PR 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, 97 Ma Chang Street, Beijing 101149, PR China.
  • 4 Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China.
  • 5 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 School of Life Sciences, Sun Yat-sen University, 135 West Xingang Road, Guangzhou, Guangdong 510275, PR China. Electronic address: luyj@mail.sysu.edu.cn.
  • 7 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: 36150342 DOI: 10.1016/j.bmc.2022.117006
Abstract

Mycobacterium tuberculosis protein tyrosine Phosphatase B (MptpB) is an important virulence factor that blocks the host immune response and facilitates M. tuberculosis growth in host cells. MptpB inhibitors are potential components of tuberculosis combination treatment. Herein, we present the development of new biphenyls MptpB inhibitors with greatly improved MptpB inhibition based on our reported thiobarbiturate lead 6 by rational design with the structure-based strategy. The eight biphenyls bearing thiobarbiturate fragment target compounds showed more potent MptpB inhibition (IC50: 1.18-14.13 μM) than the lead compound 6. Further molecular docking studies showed that compounds 13, 26, 27 and 28 had multiple interactions with active sites. Among them, compound 13 exhibited dose-dependent increased antituberculosis activity in mouse macrophages. The results displayed that the strategy of modification utilizing biphenyl scaffold was efficient. Our study identifies biphenyls bearing thiobarbiturate fragment as new MptpB inhibitors and verifies the therapeutic potential of antimycobacterial agent targeting MptpB.

Keywords

Biphenyls with thiobarbiturate fragment; MptpB; Structure-based molecular design strategy; Tuberculosis.

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