Design, synthesis, antifungal activity, and QM/MM docking study of two azole derivatives with indole ring

Abstract

Systemic candidiasis is a major health issue for immunocompromised individuals due to the increase indrug-resistance among Candida spp., which are prevalent pathogenic fungi responsible for many types of fungalinfections. Azoles are among the most preferred antifungal class for systemic candidiasis with broad antifungalspectrum and systemic availability. In this study, we synthesized and tested antifungal effects of two new indolederivatives to investigate the impact of indole on the activity of azole antifungal compounds and to find potentderivatives against Candida spp. including resistant strains and biofilms. 1-(4-Chlorophenyl)-2-(1H-imidazol-1-yl)ethanol 1H-indole-2-carboxylate (4a) showed excellent antifungal profile with several times more potent activityagainst the tested species including a fluconazole-resistant C. tropicalis isolate. The minimum inhibitory concentration(MIC) of 4a was 0.03125 μg/ml against C. albicans, which was 0.5 μg/ml for fluconazole. The compound also showedpromising biofilm inhibitory effect compared to amphotericin B. The importance of indole was demonstrated throughmolecular docking studies with the structure of C. albicans CYP51, the established target of azole antifungals, usingdifferent protocols. QM/MM docking approach yielded excellent results and accuracy, especially regarding metalinteractions. As a result, indole could be a very useful fragment to design new and highly potent antifungal compoundsin azole structure.