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

Abstract

Two series (<em>a</em> and <em>b</em>) of N- substituted heteroaromatic compounds related to clotrimazole were synthesized. Imidazole ring of the clotrimazole was replaced by 2-methylimidazole in series <em>a</em>, and by 2-methyl-4-nitroimidazole in series <em>b</em>. <em>O</em>-cholortrityl moiety of clotrimazole was also replaced by trityl, mono or dimethoxy trityl. Chemical structures of all the new compounds were confirmed by spec-trophotometric 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<em> Trichophyton mentagrophytes</em>,<em> Microsporum gypseum </em>and<em> Candida albicans </em>using<em> </em>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 <em>Trichophyton rubrum</em>, <em>Microsporum canis</em> and <em>Epidermaphyton</em> <em>floccosum </em>using PDA medium by agar dilution method. Compound<em> </em>2<em> </em>showed more<em> </em>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.