2. Academic Validation
  3. Benzothiozinone derivatives with anti-tubercular Activity-Further side chain investigation

Benzothiozinone derivatives with anti-tubercular Activity-Further side chain investigation

  • Eur J Med Chem. 2023 Nov 25:264:115976. doi: 10.1016/j.ejmech.2023.115976.
Xiaomei Wu 1,  Wenxin Wang 2,  Giovanni Stelitano 3,  Olga Riabova 4,  Bin Wang 5,  Wei Niu 6,  Mario Cocorullo 3,  Rui Shi 1,  Laurent R Chiarelli 3,  Vadim Makarov 4,  Yu Lu 7,  Chuan Li 8,  Chunhua Qiao 9
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, Jiangsu Province, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu Province, China.
  • 3 Department of Biology and Biotechnology, University of Pavia, Pavia, 27100, Italy.
  • 4 Research Center of Biotechnology, The Russian Academy of Sciences, Moscow, 119071, Russia.
  • 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, Beijing, 101149, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China. Electronic address: luyu4876@hotmail.com.
  • 8 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu Province, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Zhongshan Institute for Drug Discovery, Zhongshan, 528400, Guangdong Province, China. Electronic address: chli@simm.ac.cn.
  • 9 College of Pharmaceutical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, Jiangsu Province, China. Electronic address: qiaochunhua@suda.edu.cn.
PMID: 38039794 DOI: 10.1016/j.ejmech.2023.115976
Abstract

A series of novel benzothiozinone (BTZ) derivatives were designed, prepared and evaluated for antituberculosis activity. Specifically, the BTZ pharmacophore is retained and the previous heterocyclic ring linker is replaced by alkynyl or vinyl linker, the resulting compounds displayed about 5-fold improved antimycobacterial activity. We further revealed that the linker attached tail group affects the compound metabolic stability, potency and other drug like properties. This work led to the discovery of two compounds (A1 and A11) with acceptable low MICs and improved metabolic stability. The representative compound A11 demonstrated bactericidal efficacy in an acute TB Infection mouse model.

Keywords

Anti-tubercular activity; Benzothiazinone derivatives; DprE1 inhibitor; Structure activity relationship.

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