Unraveling the unexpected aggregation behavior of Pyrazole-Based compounds Targeting Mycobacterium tuberculosis UDP-Galactopyranose mutase

Dalia M Ahmed; David A R Sanders

doi:10.1016/j.bmc.2023.117466

Unraveling the unexpected aggregation behavior of Pyrazole-Based compounds Targeting Mycobacterium tuberculosis UDP-Galactopyranose mutase

Bioorg Med Chem. 2023 Oct 30:94:117466. doi: 10.1016/j.bmc.2023.117466. Epub 2023 Sep 9.

Authors

Dalia M Ahmed¹, David A R Sanders²

Affiliations

¹ Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia 11566, Cairo, Egypt.
² Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan, S7N 5C9, Canada. Electronic address: david.sanders@usask.ca.

PMID: 37722298
DOI: 10.1016/j.bmc.2023.117466

Abstract

A pyrazole-based compound, MS208, was previously identified as an inhibitor of UDP-Galactopyranose Mutase from Mycobacterium tuberculosis (MtUGM). Targeting this enzyme is a novel therapeutic strategy for the development of new antituberculosis agents because MtUGM is an essential enzyme for the bacterial cell wall synthesis and it is not present in human. It was proposed that MS208 targets an allosteric site in MtUGM as MS208 followed a mixed inhibition model. DA10, an MS208 analogue, showed competitive inhibition rather than mixed inhibition. In this paper, we have used an integrated biophysical approach, including thermal shift assays, dynamic light scattering and nuclear magnetic resonance experiments, to show that MS208 and many analogues displayed unexpected aggregation behavior against MtUGM.

Keywords: Aggregation; Antituberculosis; Inhibitors; Pyrazole; UDP-galactopyranose mutase.