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

Area of Science:

• Medicinal Chemistry
• Computational Drug Design
• Antimicrobial Research

Background:

• Limited therapeutic options exist for aggressive fungal infections, necessitating new drug discovery.
• Fluconazole (FLZ), a common antifungal, faces increasing resistance, driving the need for alternative treatments.
• Analogue-based drug design offers an efficient strategy by leveraging existing drug properties.

Purpose of the Study:

• To design and evaluate novel fluconazole (FLZ) analogues with improved antifungal potency.
• To identify drug candidates with favorable pharmacokinetic and cytotoxicity profiles.
• To assess the in vitro antifungal activity and mechanism of action of lead analogues.

Main Methods:

• Computational methods including Lipinski's rule, molecular docking, and molecular dynamics simulations were employed.
• In vitro assays such as disc diffusion, micro broth dilution, and chequerboard assays were performed.
• Pharmacokinetic properties and cytotoxicity of selected analogues were evaluated.

Main Results:

• 3307 FLZ analogues were generated, with 46 selected after in silico and preliminary in vitro screening.
• Lead analogues 6f and 8f showed promising docking scores but exhibited lower Minimum Inhibitory Concentrations (MICs) than FLZ against Candida albicans strains.
• Analogue 6f demonstrated additive interaction with Mycostatin, indicating potential for combination therapy.

Conclusions:

• Novel FLZ analogues were successfully designed and screened, yielding potential leads for further development.
• The identified analogues require further structural modification to enhance their antifungal potency.
• The study highlights the potential of analogue-based design and combination strategies in combating fungal infections.