Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

Rongfei Qin; Pengxu Wang; Bin Wang; Lei Fu; Sarah M Batt; Gurdyal S Besra; Chengwei Wu; Yanan Wang; Haihong Huang; Yu Lu; Gang Li

doi:10.1016/j.ejmech.2022.114145

Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

Rongfei Qin, Pengxu Wang, Bin Wang, Lei Fu, Sarah M Batt, Gurdyal S Besra, Chengwei Wu, Yanan Wang, Haihong Huang, Yu Lu, Gang Li

Biosciences

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Abstract

A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 μg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log10 CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.

Original language	English
Article number	114145
Number of pages	17
Journal	European Journal of Medicinal Chemistry
Volume	231
Early online date	22 Jan 2022
DOIs	https://doi.org/10.1016/j.ejmech.2022.114145
Publication status	Published - 5 Mar 2022

Bibliographical note

Funding Information:
The research is supported in part by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences ( 2018PT35026 ) and CAMS Innovation Fund for Medical Sciences ( CAMS-2016-I2M-1-010 ).

Publisher Copyright:
© 2022 Elsevier Masson SAS

Keywords

Thiophene-benzenesulfonamide
Drug-resistant tuberculosis
SAR exploration
Druggability evaluation

ASJC Scopus subject areas

Drug Discovery
Pharmacology
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis",

abstract = "A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 μg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log10 CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.",

keywords = "Thiophene-benzenesulfonamide, Drug-resistant tuberculosis, SAR exploration, Druggability evaluation",

author = "Rongfei Qin and Pengxu Wang and Bin Wang and Lei Fu and Batt, {Sarah M} and Besra, {Gurdyal S} and Chengwei Wu and Yanan Wang and Haihong Huang and Yu Lu and Gang Li",

note = "Funding Information: The research is supported in part by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences ( 2018PT35026 ) and CAMS Innovation Fund for Medical Sciences ( CAMS-2016-I2M-1-010 ). Publisher Copyright: {\textcopyright} 2022 Elsevier Masson SAS",

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AU - Qin, Rongfei

AU - Wang, Pengxu

AU - Wang, Bin

AU - Fu, Lei

AU - Batt, Sarah M

AU - Besra, Gurdyal S

AU - Wu, Chengwei

AU - Wang, Yanan

AU - Huang, Haihong

AU - Lu, Yu

AU - Li, Gang

N1 - Funding Information: The research is supported in part by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences ( 2018PT35026 ) and CAMS Innovation Fund for Medical Sciences ( CAMS-2016-I2M-1-010 ). Publisher Copyright: © 2022 Elsevier Masson SAS

PY - 2022/3/5

Y1 - 2022/3/5

N2 - A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 μg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log10 CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.

AB - A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 μg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log10 CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.

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Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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