1,5-Diarylidene-4-Piperidones as Promising Antifungal Candidates Against Cryptococcus neoformans

Area of Science:

• Medicinal Chemistry
• Mycology
• Drug Discovery

Background:

• Cryptococcus neoformans is a critical priority pathogen identified by the WHO.
• Emerging drug-resistant fungal infections necessitate novel therapeutic agents.
• 1,5-diarylidene-4-piperidones are a class of compounds with unexplored biological activities.

Purpose of the Study:

• To investigate the antifungal potential of synthesized 1,5-diarylidene-4-piperidones.
• To explore structure-activity relationships for optimizing antifungal efficacy.
• To evaluate the safety and mechanism of action of these novel compounds.

Main Methods:

• Synthesis of 1,5-diarylidene-4-piperidones via Claisen-Schmidt condensation.
• Antifungal efficacy testing against Cryptococcus neoformans using minimum inhibitory concentration (MIC).
• Selectivity index (SI) assessment and molecular docking analysis targeting sterol 14-demethylase.

Main Results:

• Tetrabutozy-substituted piperidones demonstrated potent activity (MIC 7.8 µM), outperforming fluconazole.
• Compounds exhibited a favorable safety profile with high selectivity index values.
• Mechanism of action involves targeting sterol 14-demethylase, inhibiting ergosterol synthesis.
• Broad-spectrum activity observed against Candida, Aspergillus species, and fluconazole-resistant strains.

Conclusions:

• 1,5-diarylidene-4-piperidones represent a promising class of novel antifungal agents.
• The identified compounds possess a favorable safety profile for therapeutic development.
• These piperidones offer potential against resistant fungal infections and critical pathogens.