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

Bioorg Med Chem. 2023 Sep 9;94:117466. doi: 10.1016/j.bmc.2023.117466. Online ahead of print.ABSTRACTA 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.PMID:37722298 | DOI:10.1016/j.bmc.2023.117466

Source: Bioorganic and Medicinal Chemistry - September 18, 2023 Category: Chemistry Authors: Dalia M Ahmed David A R Sanders Source Type: research