Metronidazole derivatives as a new class of antiparasitic agents: Synthesis, prediction of biological activity, and molecular properties

Series of new metronidazole urea and thiourea derivatives have been prepared in good yields through reactions of 2-(2-methyl-5-nitroimidazolyl) ethylamine hydrochloride with various cyanates and isothiocyanates. Similarly, metronidazole hydroxybenzoic acid derivatives were synthesized by reacting 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl-4-methylbenzene sulfonate (4) with m- and p-hydroxybenzoic acids. Structures of the newly prepared compounds were confirmed through different spectroscopic methods such as ¹H-NMR, ¹³C-NMR, mass spectrometry and also by elemental analyses. The antigiardial and antitrichomonal activities of the prepared compounds were evaluated in vitro. Compounds 3a, 3b, 3c, 3d, 3f, 3g, 3j, 3l, 3m, and 6b exhibited remarkable antigiardial activity with IC₅₀ values ranging from 5.2 to 7.5 μg/mL and were found to be more active than metronidazole which has an IC₅₀ of 8.0 μg/mL. Similarly, several of the tested compounds showed significant antitrichomonal activity with IC₅₀ values ranging from 4.95 to 6.80 μg/mL compared with the standard drug, metronidazole which has an IC₅₀ of 8.0 μg/mL. Compound 6b was the most potent among the prepared compounds and was about 1.6 times more active than metronidazole. In addition, the newly synthesized products were subjected to Petra/Osiris/Molinspiration (POM) analyses to get insights on the degree of their toxicity.