title: Antifungal agents. 9. 3-Aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]pyrroles: a new class of potent anti-Candida agents.
abstract: A new class of potent antifungal agents, namely, 3-aryl-4-[alpha-(1H-imidazol-1-yl)arylmethyl]-pyrroles, is described. These compounds are related to bifonazole and pyrrolnitrin, two compounds belonging to the class of antimycotic drugs. The synthesis of the title pyrroles has been performed starting from 1,3-diaryl-2-propen-1-ones, which were reacted with tosylmethyl isocyanide to give 3-aroyl-4-arylpyrroles. Reduction of the resulting compounds by lithium aluminum hydride furnished the related alcohols, which were treated with 1,1'-carbonyldimidazole to afford the required imidazole derivatives. Forty-four new pyrroles which incorporate an (arylmethyl)imidazole moiety in the 3-arylpyrrole structure were prepared by the above procedure and tested in vitro against Candida albicans and Candida spp. Among test compounds, 10 were found to be highly active against C. albicans. The most active derivative (27) was twice as potent (MIC90) as bifonazole, and its activity was 4 times greater than those of miconazole and ketoconazole. The other nine compounds showed antifungal activity of the same order of that of bifonazole and were ca. 2 times as active as miconazole and ketoconazole. Derivatives 21 and 27 tested in vivo against C. albicans A170 were shown to be highly effective in rabbit skin candidosis. Pharmacological studies on compounds 27 and other related pyrroles (19, 35, 36, 38, 39, and 49) are in progress to select one of them as a potential candidate for clinical experiments.
mesh_terms: D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002175:Candida / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy; D004352:Drug Resistance, Microbial; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: C096251:3-(4-chlorophenyl)-4-((1H-imidazol-1-yl)(2,4-dichlorophenyl)methyl)pyrrole; C096250:3-(4-chlorophenyl)-4-(alpha-(1H-imidazol-1-yl)phenylmethyl)pyrrole; D000935:Antifungal Agents; D007093:Imidazoles; D011758:Pyrroles