90772-91-1Relevant academic research and scientific papers
Targeting Mycobacterium tuberculosis CoaBC through Chemical Inhibition of 4′-Phosphopantothenoyl- l -cysteine Synthetase (CoaB) Activity
Evans, Joanna C.,Murugesan, Dinakaran,Post, John M.,Mendes, Vitor,Wang, Zhe,Nahiyaan, Navid,Lynch, Sasha L.,Thompson, Stephen,Green, Simon R.,Ray, Peter C.,Hess, Jeannine,Spry, Christina,Coyne, Anthony G.,Abell, Chris,Boshoff, Helena I. M.,Wyatt, Paul G.,Rhee, Kyu Y.,Blundell, Tom L.,Barry, Clifton E.,Mizrahi, Valerie
, p. 1666 - 1679 (2021)
Coenzyme A (CoA) is a ubiquitous cofactor present in all living cells and estimated to be required for up to 9% of intracellular enzymatic reactions. Mycobacterium tuberculosis (Mtb) relies on its own ability to biosynthesize CoA to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the pathway to CoA biosynthesis is recognized as a potential source of novel tuberculosis drug targets. In prior work, we genetically validated CoaBC as a bactericidal drug target in Mtb in vitro and in vivo. Here, we describe the identification of compound 1f, a small molecule inhibitor of the 4′-phosphopantothenoyl-l-cysteine synthetase (PPCS; CoaB) domain of the bifunctional Mtb CoaBC, and show that this compound displays on-target activity in Mtb. Compound 1f was found to inhibit CoaBC uncompetitively with respect to 4′-phosphopantothenate, the substrate for the CoaB-catalyzed reaction. Furthermore, metabolomic profiling of wild-type Mtb H37Rv following exposure to compound 1f produced a signature consistent with perturbations in pantothenate and CoA biosynthesis. As the first report of a direct small molecule inhibitor of Mtb CoaBC displaying target-selective whole-cell activity, this study confirms the druggability of CoaBC and chemically validates this target.
Pyrazole and Triazole Derivatives as Mycobacterium tuberculosis UDP-Galactopyranose Inhibitors
Ahmed, Dalia M.,Chen, Jeffrey M.,Sanders, David A. R.
, (2022/02/11)
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.
A 1H and 13C NMR Study of the Structure and Tautomerism of 4-Pyrazolylpyrazolinones
Elguero, J.,Martinez, A.,Singh, S. P.,Grover, M.,Tarar, L. S.
, p. 865 - 870 (2007/10/02)
It has been established that the primary reactions products between dehydroacetic acid and p-chlorophenylhydrazine or 4-phenylthiazol-2-ylhydrazine are 4-acetylacetyl-5-hydroxypyrazoles.These compounds react with the above hydrazines to yield 4-(pyrazol-5
