2. Academic Validation
  3. Design, synthesis and biological evaluation of 3-substituted-2-thioxothiazolidin-4-one (rhodanine) derivatives as antitubercular agents against Mycobacterium tuberculosis protein tyrosine phosphatase B

Design, synthesis and biological evaluation of 3-substituted-2-thioxothiazolidin-4-one (rhodanine) derivatives as antitubercular agents against Mycobacterium tuberculosis protein tyrosine phosphatase B

  • Eur J Med Chem. 2023 Oct 5;258:115571. doi: 10.1016/j.ejmech.2023.115571.
Shihao Cheng 1,  Yi Zou 2,  Xi Chen 3,  Jiahao Chen 2,  Bin Wang 3,  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: [email protected].
  • 6 School of Life Sciences, Sun Yat-sen University, 135 West Xingang Road, Guangzhou, Guangdong, 510275, PR China. Electronic address: [email protected].
  • 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: [email protected].
PMID: 37348296 DOI: 10.1016/j.ejmech.2023.115571
Abstract

Mycobacterium tuberculosis infections still pose a serious threat to human health. Combination therapies are effective medical solutions to the problem. Mycobacterium tuberculosis is an intracellular pathogen that mainly depends on a virulence factor (Mycobacterium tuberculosis protein tyrosine Phosphatase B, MptpB) for its survival in the host. Therefore, MptpB inhibitors are potential components of tuberculosis combination treatments. Herein, a new series of MptpB inhibitors bearing a rhodanine group were developed using a structure-based strategy based on the virtual screening hit. The new MptpB inhibitors displayed potent MptpB inhibitory activities and great improvements in cell membrane permeability. The optimal compounds reduced the Bacterial burden in a dose-dependent manner in a macrophage Infection model, especially, a combination of compound 20 and rifampicin led to a Bacterial burden reduction of more than 95%, greater than the reductions achieved with compound 20 or rifampicin alone. This research provides new insights into the rational design of new MptpB inhibitors and verifies that the MptpB inhibitor has a promising potential as a component of tuberculosis treatment.

Keywords

Molecular modeling; MptpB; Rhodanine derivatives; Structure-based strategy; Tuberculosis.

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