Synthesis and evaluation of the antifungal activity of 2-(substituted-amino)-4,5-dialkyl-thiophene-3- carbonitrile derivatives

Fifteen 2-[(substituted-benzylidene)-amino]-5-methyl-thiophene-3-carbonitrile (3a-g) and 2-[(substituted-benzylidene)-amino]-4,5-cycloalkyl-thiophene-3-carbonitrile derivatives (4a-h) were synthesized and screened for their in vitro antifungal activity against 42 clinical isolates of Candida (representing 4 different species) and 2 isolates of Criptococcus. The antifungal activities of these compounds were compared to fluconazole and amphotericin B as standard agents. All compounds presented fungicidal activity at different doses, but a few compounds showed moderate or poor antifungal activity when compared with the standard drugs. The Cryptococcus strains were more sensitive than those of the genus Candida, and compound 4d was the most active, with MFC values varying between 100-800 μg/mL. A preliminary SAR study demonstrated that the presence of a cycloalkyl ring linked to the thiophene moiety is essential for antifungal activity, and that the best antifungal candidates are cyclohexyl compounds (4d-f). The results suggest that thiophene derivatives may be interesting compounds for the further development of antifungal drugs. Colegio de Farmacéuticos de la Provincia de Buenos Aires