Identification of novel benzothiopyranones with ester and amide motifs derived from active metabolite as promising leads against Mycobacterium tuberculosis

Peng Li; Bin Wang; Lei Fu; Kaijing Guo; Chen Ma; Baolian Wang; Ziyun Lin; Gang Li; Haihong Huang; Yu Lu

doi:10.1016/j.ejmech.2021.113603

Identification of novel benzothiopyranones with ester and amide motifs derived from active metabolite as promising leads against Mycobacterium tuberculosis

Eur J Med Chem. 2021 Oct 15:222:113603. doi: 10.1016/j.ejmech.2021.113603. Epub 2021 Jun 5.

Authors

Peng Li¹, Bin Wang², Lei Fu², Kaijing Guo³, Chen Ma³, Baolian Wang³, Ziyun Lin¹, Gang Li⁴, Haihong Huang⁵, Yu Lu⁶

Affiliations

¹ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, 100050, PR China; 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 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.
⁴ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, 100050, PR China; 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.
⁵ Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing, 100050, PR China; 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 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.

PMID: 34126456
DOI: 10.1016/j.ejmech.2021.113603

Abstract

We reported three distinct series of novel benzothiopyranones, derived from an active metabolite (M-1) of anti-TB agent 6b. These small molecules were evaluated for their biological activities against a range of Mycobacterium tuberculosis (M. tuberculosis) strains. Preliminary druggability evaluation demonstrated that M-1 showed good aqueous solubility and hepatocyte stability. Benzothiopyranones with acyl, sulfonyl and phosphoryl groups exhibited potent in vitro inhibitory activity against M. tuberculosis H₃₇Rv and low cytotoxicity. In particular, compound 3d, containing a benzoate fragment, displayed marked metabolic stability and potent in vitro activity against drug-resistant tuberculosis clinical strains. Further druggability evaluation based on the identified compounds 3d, 4e and 5b is ongoing for the discovery of promising anti-TB agents.

Keywords: Active metabolite; Benzothiopyranones; Drug-resistant tuberculosis; Metabolic stability.

MeSH terms

Amides / chemistry
Amides / metabolism
Amides / pharmacology*
Antitubercular Agents / chemistry
Antitubercular Agents / metabolism
Antitubercular Agents / pharmacology*
Benzopyrans / chemistry
Benzopyrans / metabolism
Benzopyrans / pharmacology*
Dose-Response Relationship, Drug
Esters / chemistry
Esters / metabolism
Esters / pharmacology*
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Structure-Activity Relationship

Substances

Amides
Antitubercular Agents
Benzopyrans
Esters