In silico and in vitro evaluation of designed fluconazole analogues as lanosterol 14α-demethylase inhibitors

Abstract

The drugs fighting against aggressive fungal infections are in limited number, therefore, extensive research is obligatory to develop new therapeutic strategies. Fluconazole (FLZ) is a clinically approved drug, but resistant drug against most fungal pathogens, thus it is vital to identify more compounds that can better check the fungal growth. Analogue-based drug designing is a quick and economical way since it has inherent drug-like properties of marketed drugs. This study aims to generate and evaluate analogues of FLZ with better potency against fungal-borne infections. A total of 3307 analogues of FLZ were developed from six scaffold structures. Only 390 compounds passed Lipinski’s rule, of which 247 analogues exhibited lower docking scores than FLZ with 5FSA. These inhibitors were further subjected to pharmacokinetics property evaluation and cytotoxicity test and it was found that only 46 analogues were suitable for further evaluation. Based on the molecular docking score of the best two analogues, 6f (−12.7 kcal/mol) and 8f (−12.8 kcal/mol) were selected for molecular dynamics and in-vitro studies. Antifungal activities of both compounds against 4 strains of Candida albicans were evaluated by disc diffusion assay and micro broth dilution assay and Minimum inhibitory concentrations (MICs) for 6f and 8f were observed as 256 µg/ml against 4719, 4918 and 5480 strains but the MIC was extended to 512 µg/ml for strain 3719. Both analogues exhibited low antifungal activities as compared to FLZ (8–16 µg/ml). The interaction of 6f with Mycostatin was also performed using a chequerboard assay that was found additive.

Communicated by Ramaswamy H. Sarma

Keywords:

• Fluconazole
• analogue based drug designing
• molecular docking
• simulations
• combination studies

Acknowledgement

The authors acknowledge “DBT Builder Maharshi DayanandUniversity Interdisciplinary Life Science Programme forAdvance Research and Education” for providing the necessarysupport and facilities for the completion of this research work. We also want to acknowledge Department of Pharmaceutical Sciences, MDU for providing necessary support to carry out this research.

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No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.