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

Background: Molecular hybridization and isostery are proven approaches in medicinal chemistry, and as such we used them to design novel compounds that we investigated 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 tuberculosis  H 37 Rv, Mycobacterium avium and Mycobacterium kansasii , with oxadiazoles and C 8 -C 12 alkyls being the most effective from a concentration of 2 μM. 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, the mechanism of action related to cell wall biosynthesis was investigated. Conclusion: Pyrimidine-1,3,4-oxadiazole hybrids are unique antimycobacterial agents inhibiting mainly M. tuberculosis  strains without cross-resistance to current drugs and are thus promising drug candidates.