TY - JOUR
T1 - Antitubercular 2-Pyrazolylpyrimidinones
T2 - Structure-Activity Relationship and Mode-of-Action Studies
AU - Soares de Melo, Candice
AU - Singh, Vinayak
AU - Myrick, Alissa
AU - Simelane, Sandile B.
AU - Taylor, Dale
AU - Brunschwig, Christel
AU - Lawrence, Nina
AU - Schnappinger, Dirk
AU - Engelhart, Curtis A.
AU - Kumar, Anuradha
AU - Parish, Tanya
AU - Su, Qin
AU - Myers, Timothy G.
AU - Boshoff, Helena I. M.
AU - Barry, Clifton E.
AU - Sirgel, Frederick A.
AU - van Helden, Paul D.
AU - Buchanan, Kirsteen I.
AU - Bayliss, Tracy
AU - Green, Simon R.
AU - Ray, Peter C.
AU - Wyatt, Paul G.
AU - Basarab, Gregory S.
AU - Eyermann, Charles J.
AU - Chibale, Kelly
AU - Ghorpade, Sandeep R.
N1 - no funding
PY - 2021/1/14
Y1 - 2021/1/14
N2 - Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
AB - Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
KW - Electromagnetic radiation
KW - Structure activity relationship
KW - Ethanol
KW - Substituents
KW - Solubility
U2 - 10.1021/acs.jmedchem.0c01727
DO - 10.1021/acs.jmedchem.0c01727
M3 - Article
C2 - 33395287
SN - 0022-2623
VL - 64
SP - 719
EP - 740
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -