Recent advances in antifungal drug development targeting lanosterol 14α-demethylase (CYP51): A comprehensive review with structural and molecular insights

Fungal infections are posing serious threat to healthcare system due to emerging resistance among available antifungal agents. Among available antifungal agents in clinical practice, azoles (diazole, 1,2,4-triazole and tetrazole) remained most effective and widely prescribed antifungal agents. Now their associated side effects and emerging resistance pattern raised a need of new and potent antifungal agents. Lanosterol 14a-demethylase (CYP51) is responsible for the oxidative removal of 14a-methyl group of sterol precursors lanosterol and 24(28)-methylene-24,25-dihydrolanosterol in ergosterol biosynthesis hence an essential component of fungal life cycle and prominent target for antifungal drug development. This review will shed light on various azole- as well as non-azoles-based derivatives as potential antifungal agents that target fungal CYP51. Review will provide deep insight about structure activity relationship, pharmacological outcomes, and interactions of derivatives with CYP51 at molecular level. It will help medicinal chemists working on antifungal development in designing more rational, potent, and safer antifungal agents by targeting fungal CYP51 for tackling emerging antifungal drug resistance.

Automated summary

Fungal infections are becoming a serious threat to the healthcare system due to the increased resistance to currently available antifungal drugs. Azoles have been the most effective and commonly used antifungal agents, but their side effects and emerging resistance have prompted the need for new and potent antifungal agents. This review focuses on azole and non-azole derivatives that target fungal lanosterol 14a-demethylase (CYP51) as potential antifungal agents. The review provides insights into the structure-activity relationship, pharmacological outcomes, and molecular interactions of these derivatives with CYP51, aiming to assist medicinal chemists in designing rational and effective antifungal agents to combat emerging drug resistance.