Pyrazole and Triazole Derivatives as <i>Mycobacterium tuberculosis</i> UDP-Galactopyranose Inhibitors

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 Mtb UGM which targets an allosteric site. To understand more about the structure activity relationship around the MS208 scaffold as a Mtb UGM inhibitor, thirteen pyrazoles and triazole analogues were synthesized and tested against both Mtb UGM and Mycobacterium tuberculosis in vitro. While the introduced structural modifications to MS208 did not improve the antituberculosis activity, most of the compounds showed Mtb UGM inhibitory activity. Interestingly, the pyrazole derivative DA10 showed a competitive model for Mtb UGM inhibition with improved Ki value of 51 ± 4 µM. However, the same compound did not inhibit the growth of Mycobacterium tuberculosis .