New Triazolopyrimidines with Improved Activity against Mycobacterium tuberculosis

Tuberculosis is a major health crisis, and new drugs are required. We previously identified a triazolopyrimidine series with antitubercular activity acting via inhibition of the terminal cytochrome oxidase (QcrB). We conducted further exploration of the series to improve the potency and physicochemical properties. We synthesized new analogues using a 3-step synthesis: (i) condensation of an amino-pyrazole with 1,3-diketones or β-ketoester; (ii) conversion of the hydroxyl group to chloride; and (iii) S_NAr with a variety of amines. Analogues with modifications of the triazolopyrimidine core and novel 5-member heteroaromatic rings at the C-5 position were tested for activity and cytotoxicity. We identified several potent molecules (MIC < 1 μM) with a methyl furan or thiophene moiety at the C-5 position of the triazolopyrimidine ring. These analogues had excellent selectivity with no cytotoxicity (CC₅₀ > 100 μM) against the human HepG2 cell line. We identified new analogues with improved metabolic stability in both human and mouse liver microsomes.