Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities.

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

doi:10.1021/acs.jmedchem.1c00263

Abstract

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.

Highlights

Tuberculosis (TB) is a chronic infectious disease caused primarily by pathogen Mycobacterium tuberculosis (M. tuberculosis)
DprE1 has emerged as a promising target for the treatment of tuberculosis, and previous studies have been indicated that the inhibition of DprE1 causes loss of its ability to construct the bacterial cell wall
Based on the crystal structure of the TCA1− DprE1 complex, we have reported the design, synthesis, and structure−activity relationship (SAR) study of a series of novel thiophene-arylamide compounds

Summary

Introduction

Tuberculosis (TB) is a chronic infectious disease caused primarily by pathogen Mycobacterium tuberculosis (M. tuberculosis). TB is one of the top 10 causes of death and the leading cause of mortality stemming from a single infectious agent. In 2020, the World Health Organization (WHO) reported that approximately 1.2 million human immunodeficiency virus (HIV)-negative people had died and 10 million new TB cases were identified. The TB incidence rate is falling but not fast enough to reach the 2020 milestone of a 20% reduction between 2015 and 2020.1 The COVID-19 pandemic threatens to reverse the recent progress in reducing the global burden of TB disease. The requirement for prolonged treatment with firstline drugs coupled with often difficult-to-manage side effects routinely leads to poor patient compliance and results in the accelerated emergence of drug-resistant strains of M. tuberculosis. Research focusing on the development of novel small molecules with activity against multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDRTB) remains a significant challenge.[2,3]

Methods

Results

Conclusion