Design and Synthesis of 2-En-4-Ynedioate Compounds as Novel and Potential Antifungal Agents.

In this investigation, we focused on generating innovative antifungal agents inspired by terbinafine, a prominent allylamine that inhibits squalene epoxidase and is a crucial enzyme in the biosynthesis of fungal ergosterol. Utilizing computational methods such as molecular docking and molecular dynamics (MD) simulations, we designed and synthesized a collection of enyne derivatives featuring aromatic side chains. The choice of these compounds was influenced by their anticipated interactions with squalene epoxidase, informed by comprehensive in silico assessments. The synthesized derivatives were analyzed using 1H-NMR, 13C-NMR, and mass spectrometry techniques. Among the synthesized series, Compound 2b (1,6-bis[(4-methylphenyl)methyl] (2E)-hex-2-en-4-ynedioate) exhibited potent antifungal activity, demonstrating a minimum inhibitory concentration (MIC) of 0.0391-0.7176 μM/mL against Candida albicans, Saccharomyces cerevisiae, and Aspergillus niger. These findings highlight the promising strategy of applying these novel compounds, based on the structural design of terbinafine, as viable candidates for antifungal treatment. This approach demonstrates a significant advancement in the design of antifungal agents targeting squalene epoxidase and suggests promising avenues for further development.