Editor-in-Chief İlkay Küçükgüzel Associate Editor Aslı Türe Online ISSN 2630-6344 Publisher Marmara University Frequency Bimonthly (Six issues / year) Abbreviation J.Res.Pharm. Former Name Marmara Pharmaceutical Journal
Journal of Research in Pharmacy 2020 , Vol 24 , Issue 5
Design, synthesis, antifungal activity, and QM/MM docking study of two azole derivatives with indole ring
Suat SARI1,Didem KART2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye 06100 Ankara, Turkey
2Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Hacettepe University, Sıhhiye 06100 Ankara, Turkey
DOI : 10.35333/jrp.2020.223 Systemic candidiasis is a major health issue for immunocompromised individuals due to the increase in drug-resistance among Candida spp., which are prevalent pathogenic fungi responsible for many types of fungal infections. Azoles are among the most preferred antifungal class for systemic candidiasis with broad antifungal spectrum and systemic availability. In this study, we synthesized and tested antifungal effects of two new indole derivatives to investigate the impact of indole on the activity of azole antifungal compounds and to find potent derivatives 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 activity against 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 showed promising biofilm inhibitory effect compared to amphotericin B. The importance of indole was demonstrated through molecular docking studies with the structure of C. albicans CYP51, the established target of azole antifungals, using different protocols. QM/MM docking approach yielded excellent results and accuracy, especially regarding metal interactions. As a result, indole could be a very useful fragment to design new and highly potent antifungal compounds in azole structure. Keywords : Azole; antifungal; biofilm; Candida albicans; CYP51; indole; induced fit docking; QM/MM docking
Marmara University