1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors.

Yanlin Jian,Hélène Munier-Lehmann,Helena I M Boshoff,Martijn D P Risseeuw,Serge Van Calenbergh,Fabian Hulpia,Guy Caljon,He Eun Forbes

doi:10.3390/molecules25122805

Abstract

A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).

Highlights

Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis)
After we found that it potently inhibited MtbTMPK, a SAR investigation demonstrated that it could be converted to the potently inhibited MtbTMPK, a SAR investigation demonstrated that it could be converted to the achiral achiral inhibitor 2 [14]
The envisioned analogs were synthesized according to a literature-reported procedure [14]

Summary

Introduction

Tuberculosis (TB) is an airborne infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). Still belonging to the top ten causes of death worldwide, TB was responsible for claiming 1.5 million lives in 2018, thereby preceding AIDS [1]. Patients with drug-sensitive TB are currently treated with a combination regimen, consisting of a two-month treatment with first-line agents rifampicin, isoniazid, pyrazinamide and ethambutol, followed by a four-month treatment with rifampicin and isoniazid. This schedule has decreased TB mortality, these gains are being threatened by the advent of coinfection with HIV/AIDS, poor patient adherence and a deficient health care system.

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Conclusion