Abstract
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.
Highlights
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) continues to be one of the leading causes of death and morbidity globally, claiming 1.2 million lives in 2018.1 The emergence and spread of multi drug-resistant (MDR) and extensively drugresistant (XDR) strains of Mtb that are resistant to the first- and second-line drugs have further exacerbated the situation.2 The rise in anti-microbial resistance warrants the search for new drugs with unique modes of action that can bypass existing modes of resistance or can be used as adjunctive therapy to compensate for those that are vulnerable to promoting resistance
A highthroughput screen of a ∼530,000 diverse set of compounds from Medicines for Malaria Venture (MMV) compound library against Mtb was conducted at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIAID/NIH, U.S.)
We recognized that pyrazolylpyrimidinones potentially possess iron-chelating properties by virtue of their two sp2 heteroatoms in a 1,4-relationship on adjacent rings, which might play a crucial role in the structure−activity relationship (SAR) and mode of action
Summary
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) continues to be one of the leading causes of death and morbidity globally, claiming 1.2 million lives in 2018.1 The emergence and spread of multi drug-resistant (MDR) and extensively drugresistant (XDR) strains of Mtb that are resistant to the first- and second-line drugs have further exacerbated the situation. The rise in anti-microbial resistance warrants the search for new drugs with unique modes of action that can bypass existing modes of resistance or can be used as adjunctive therapy to compensate for those that are vulnerable to promoting resistance. As compound 12 with the CF3 group at R1 showed higher solubility and SI relative to 1, this modification was included in further explorations for potency and selectivity Overall, these SAR observations suggested the requirement for hydrophobic substitutions on the pyrimidinone ring for the retention of potent in vitro activity against Mtb. A few polar modifications on the pyrazole ring were attempted in order to evaluate the scope of reducing lipophilicity and improving drug-like properties. Compounds 38 and 39, with the neutral ether substituents like methoxyethylamino and pyranamino, respectively, at the R5 position, showed more potent activity (MIC 1.5−2 μM) as compared to 12 while the SI was about the same This is because of the toxic nature of heme to eukaryotic cells, which require specific heme-binding proteins to maintain a nontoxic homeostasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
