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

Xiaomei Wu; Wenxin Wang; Giovanni Stelitano; Olga Riabova; Bin Wang; Wei Niu; Mario Cocorullo; Rui Shi; Laurent R Chiarelli; Vadim Makarov; Yu Lu; Chuan Li; Chunhua Qiao

doi:10.1016/j.ejmech.2023.115976

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

Eur J Med Chem. 2024 Jan 15:264:115976. doi: 10.1016/j.ejmech.2023.115976. Epub 2023 Nov 25.

Authors

Xiaomei Wu¹, Wenxin Wang², Giovanni Stelitano³, Olga Riabova⁴, Bin Wang⁵, Wei Niu⁶, Mario Cocorullo³, Rui Shi¹, Laurent R Chiarelli³, Vadim Makarov⁴, Yu Lu⁷, Chuan Li⁸, Chunhua Qiao⁹

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 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.

MeSH terms

Animals
Antitubercular Agents* / chemistry
Mice
Microbial Sensitivity Tests
Mycobacterium tuberculosis*
Structure-Activity Relationship

Substances

Antitubercular Agents