Abstract
We identified a di-substituted triazolopyrimidine with anti-tubercular activity against Mycobacterium tuberculosis. Three segments of the scaffold were examined rationally to establish a structure-activity relationship with the goal of improving potency and maintaining good physicochemical properties. A number of compounds displayed sub-micromolar activity against Mycobacterium tuberculosis with no cytotoxicity against eukaryotic cells. Non-substituted aromatic rings at C5 and a two-carbon chain connecting a terminal aromatic at C7 were preferred features; the presence of NH at C7 and a lack of substituent at C2 were essential for potency. We identified compounds with acceptable metabolic stability in rodent and human liver microsomes. Our findings suggest that the easily-synthesized triazolopyrimidines are a promising class of potent anti-tubercular agents and warrant further investigation in our search for new drugs to fight tuberculosis.
Highlights
Tuberculosis (TB) and its causative agent Mycobacterium tuberculosis present a serious threat to global health
Our structure-activity relationship (SAR) investigation began with the design and synthesis of novel analogs based on modifications of the core structure of compound 1
We initially evaluated the SAR associated with modifications at the C5
Summary
Tuberculosis (TB) and its causative agent Mycobacterium tuberculosis present a serious threat to global health. Taken together with the estimate that a third of the world’s population is infected with M. tuberculosis and the existence of drugresistant strains of M. tuberculosis, it is apparent there is a pressing need for new therapies. To address these needs, there has been an increased effort directed towards TB drug discovery in recent years and a pipeline of new anti-TB drug candidates has started to emerge. Triazolopyrimidines (TZPs) are a well-known scaffold in medicinal chemistry, and their utility is exemplified by the discovery and development of novel agents to fight a wide range of diseases. TZPs possess anticancer activity, and have been used as phosphodiesterase inhibitors for diabetes treatment. Recently, the first natural TZP, essramycin, was isolated and found to possess antibacterial activity. A considerable effort has been made to develop TZPs with antimalarial activity. Transition metal-containing TZPs have antiproliferative activity against Leishmania and Trypanosoma cruzi, the protozoa that cause leishmaniasis and Chagas disease, respectively. In addition TZP acylsulfonamides with anti-mycobacterial activity target acetohydroxyacid synthase. Similar compounds were identified in a phenotypic screening campaign against Mycobacterium bovis BCG.
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