ANTIFUNGAL AGENTS .9. RYL-4-[ALPHA-(1H-IMIDAZOL-1-YL)ARYLMETHYL]PYRROLES - A NEW CLASS OF POTENT ANTICANDIDA AGENTS

A new class of potent antifungal agents, namely, l-4-[alpha-(1H-imidaz ol-1-yl)arylmethyl]-pyrroles, is described. These compounds are relate d to bifonazole and pyrrolnitrin, two compounds belonging to the class of antimycotic drugs. The synthesis of the title pyrroles has been pe rformed starting from 1,3-diaryl-2-propen-1-ones, which were reacted w ith tosylmethyl isocyanide to give 3-aroyl-4-arylpyrroles. Reduction o f the resulting compounds by lithium alumium hydride furnished the rel ated alcohols, which were treated with 1,1'-carbonyldiimidazole to aff ord the required imidazole derivatives. Forty-four new pyrroles which incorporate an (arylmethyl)imidazole moiety in the 3-arylpyrrole struc ture 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 (2 7) was twice as potent (MIC(90)) as bifonazole, and its activity was 4 times greater than those of miconazole and ketoconazole. The other ni ne compounds showed antifungal activity of the same order of that of b ifonazole and were ca. 2 times as active as miconazole and ketoconazol e. Derivatives 21 and 27 tested in vivo against C. albicans A(170) wer e shown to be highly effective in rabbit skin candidosis. Pharmacologi cal studies on compounds 27;7 and other related pyrroles (19, 35, 36, 38, 39, and 49) are in progress to select one of them as a potential c andidate for clinical experiments.