Discovery of novel thiophene-arylamide derivatives as DprE1 inhibitors with potent antimycobacterial activities

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

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In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds 23j, 24f, 25a, and 25b exhibited potent in vitro activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02-0.12 μg/mL) and drug-resistant (MIC = 0.031-0.24 μg/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC50) = 0.2-0.9 μg/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-à-go-go related gene (hERG) channel. The representative compound 25a with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound 23j provides new insight into the discovery of novel antitubercular agents targeting DprE1.

Original languageEnglish
Pages (from-to)6241-6261
Number of pages21
JournalJournal of Medicinal Chemistry
Issue number9
Early online date14 Apr 2021
Publication statusPublished - 13 May 2021

Bibliographical note

Funding Information:
The research is supported in part by the National Science & Technology Major Project of China (2015ZX09102007-011) and CAMS Innovation Fund for Medical Sciences (CAMS-2016-I2M-1-010). G.S.B. acknowledges support in the form of a personal research chair from the James Bardrick Award and the Medical Research Council, U.K. (MR/R001154/1 and MR/S000542/1).

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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