Novel pyrimidine-1,3,4-oxadiazole hybrids and their precursors as potential antimycobacterial agents.

Abstract

Background: Molecular hybridization and isostery are proven approaches in medicinal chemistry, and as suchwe used them to design novel compounds that weinvestigated as potential antimycobacterials to combat drug-resistant strains. Methods & results: Prepared N-alkyl-2-(pyrimidine-5-carbonyl)hydrazine-1-carboxamides were cyclized to N-alkyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amines along with their analogues. A total of 48 compounds were tested against Mycobacterium tuberculosisH37Rv, Mycobacterium avium and Mycobacterium kansasii, with oxadiazoles and C8-C12 alkyls being the most effective from aconcentration of 2μM. Multidrug-resistant strains were inhibited at same concentrations as the susceptible strain. For the most potent N-dodecyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amine, themechanism of action related to cell wall biosynthesis was investigated. Conclusion: Pyrimidine-1,3,4-oxadiazole hybrids are unique antimycobacterial agents inhibiting mainly M. tuberculosisstrains without cross-resistance to current drugs andare thus promising drug candidates.