Design and Synthesis of 2-Methyl and 2-Methyl-4-Nitro Imidazole Derivatives as Antifungal Agents

Two series (a and b) of N-substituted heteroaromatic compounds related to clotrimazole were synthesized. Imidazole ring of the clotrimazole was replaced by 2-methylimidazole in series a, and by 2-methyl-4-nitroimidazole in series b. Ocholortrityl moiety of clotrimazole was also replaced by trityl, mono or dimethoxy trityl. Chemical structures of all the new compounds were confirmed by spectrophotometric methods. These compounds docked into the active site of MT-CYP51 (PDB code, 1E9X) using Autodock tools software which showed good affinity for the enzyme. Antifungal activities of these compounds were evaluated against Trichophyton mentagrophytes, Microsporum gypseum and Candida albicans using SC, SCC and PDA as media, CHCl3 and DMSO as solvents and agar dilution assay as method. In this method 1(4-methoxyphenyl-diphenylmethyl)-2-methyl imidazole (2), 1[bis-4-methoxyphenyl-phenylmethyl]-2-methyl imidazole (3) and 1[4-methoxyphenyl-diphenylmethyl]-2-methyl-4-nitroimidazole (5) showed more than 75% activity against fungi. In the second step all of the derivatives also were evaluated against Trichophyton rubrum, Microsporum canis and Epidermaphyton floccosum using PDA medium by agar dilution method. Compound 2 showed more than 75% activity by this method. Then the most active analogue (2) was tested in RPMI 1640 medium which showed desirable biological activity in comparison to clotrimazole.