Synthesis, Anti‐Fungal Potency and <i>In silico</i> Studies of Novel Steroidal 1,4‐Dihydropyridines

Abstract

Working principle of azoles as antifungals is the inhibition of fungal CYP51/lanosterol-14α-demethylase via selective coordination with heme iron. This interaction can also cause side effects by binding to host lanosterol-14α-demethylase. Hence, it is necessary to design, synthesize and test new antifungal agents that have different structures than those of azoles and other antifungal drugs of choice in clinical practice. Consequently, a series of steroidal 1,4-dihydropyridine analogs 16-21 were synthesized and screened for their in vitro anti-fungal activity against three Candida species as steroids-based medications have low toxicity, less vulnerability to multi-drug resistance, and high bioavailability by being capable of penetrating the cell wall and binding to specific receptors. Initially, Claisen-Schmidt condensation takes place between steroidal ketone (dehydroepiandrosterone) and an aromatic aldehyde forming steroidal benzylidene 8-13 followed by Hantzsch 1,4-dihydropyridine synthesis resulting in steroidal 1,4-dihydropyridine derivatives 16-21. The results exhibited that compound 17 has significant anti-fungal potential with an MIC value of 750 μg/ml for C. albicans and C. glabrata and 800 μg/ml for C. tropicalis. In silico molecular docking and ADMET studies were also performed for compounds 16-21.

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