Design and Synthesis of Imidazole and Benzimidazole Derivatives as Antifungal Agents

S.      Khabnadideh; Z.      Rezaei; A.      Khalafi-Nezhad; K.      Pakshir; A.      Roosta; Z.      Baratzadeh

Abstract

Two different series of N-substituted heteroaromatic compounds related to clotrimazole structure were synthesized. In one series ortho-cholortrityl moiety of clotrimazole was replaced by trityl, mono or dimethoxy trityl (series c). In the second series the imidazole ring of clotrimazole was also replaced by benzimidazole (series d). 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. They showed good affinity for the enzyme comparable to clotrimazole. Antifungal activities for these compounds were evaluated against Trichophyton mentagrophytes, Microsporum gypseum and Candida albicans using PDA as media, CHCl3 or DMSO as solvents and agar dilution assay as method. In this method 1-triphenylmethyl-imidazole (1c), 1-(bis-4-methoxyphenyl)-phenylmethyl-benzimidazole (6d) and 1-(4-methoxyphenyl)-diphenylmethyl-imidazole (2c) showed 100%, 90% and 70% activity respectively. 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. In this method 1-triphenylmethyl-imidazole (1c) and 1-(bis-4- methoxyphenyl)-phenylmethyl-benzimidazole (6d) showed 100% and 1-(4-methoxyphenyl)-diphenylmethyl-imidazole (2c) and 1-(bis-4-methoxyphenyl)-phenylmethyl-imidazole (3c) more than 75% activity against the fungi. Then the most active analogues (1c, 2c and 6d) were tested in RPMI 1640 medium which showed desirable biological activity in comparison to clotrimazole.

Keywords: Imidazole, benzimidazole, clotrimazole, antifungal activity

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