Pyrazole and Triazole Derivatives as Mycobacterium tuberculosis UDP-Galactopyranose Inhibitors.

Dalia M Ahmed,Jeffrey M Chen,David A R Sanders

doi:10.3390/ph15020197

Dalia M Ahmed, Jeffrey M Chen + Show 1 more

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https://doi.org/10.3390/ph15020197

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Journal: Pharmaceuticals	Publication Date: Feb 4, 2022
Citations: 5	License type: CC BY 4.0

Affiliation: Ain Shams University, University of Saskatchewan

Abstract

UDP-galactopyranose mutase (UGM) is an essential enzyme involved in the bacterial cell wall synthesis, and is not present in mammalian cells. Thus, UGM from Mycobacterium tuberculosis (Mtb) represents a novel and attractive drug target for developing antituberculosis agents. A pyrazole-based compound, MS208, was previously identified as a mixed inhibitor of MtbUGM which targets an allosteric site. To understand more about the structure activity relationship around the MS208 scaffold as a MtbUGM inhibitor, thirteen pyrazoles and triazole analogues were synthesized and tested against both MtbUGM and Mycobacterium tuberculosis in vitro. While the introduced structural modifications to MS208 did not improve the antituberculosis activity, most of the compounds showed MtbUGM inhibitory activity. Interestingly, the pyrazole derivative DA10 showed a competitive model for MtbUGM inhibition with improved Ki value of 51 ± 4 µM. However, the same compound did not inhibit the growth of Mycobacterium tuberculosis.

Highlights

Inhibitors of UGMstudies can beinvolved classified according to theiranalogues resemblance to the natural submolecules, they were not tested against MtbUGM except for MS208 [10,11,12]
MS208 phenyl rings would increase the binding sis molecules, they were not tested against MtbUGM except for MS208 [10,11,12]
No inforvia polarisinteractions with the thestructure polar residues located at the periphery of the allosteric mation available about activity relationship (SAR) around the to test this proposed hypothesis, polar groups were introduced the anfold as MtbUGM inhibitor

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Tuberculosis (TB) is an infectious disease that remains one of the top ten causes of death worldwide [1]. Mycobacterium tuberculosis (Mtb), which is the causative agent of TB, has developed resistant strains against many of the clinically available antibacterial agents [1]. The crisis of multidrug-resistant Mtb has continued and there is an increasing demand to develop new potential drug candidates that target novel biosynthetic pathways of Mtb [1]

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