Synthesis of some novel coumarin-based heterocycles, elucidation of their antifungal behavior, molecular docking and computational studies

Abstract A novel series of coumarin–cyanoacetohydrazide hybrids was synthesized via efficient strategies that exploit the nucleophilic and electrophilic functionalities of the cyanoacetohydrazide scaffold. The designed framework incorporated a C-4 amino-substituted coumarin nucleus, enabling the construction of diverse fused and heteroannulated coumarin derivatives under mild conditions, affording moderate to excellent yields. The structures of all new compounds were confirmed by spectroscopic analyses (IR, MS, 1 H, and 13 C NMR). Selected derivatives were evaluated for antifungal activity against phytopathogenic fungi. Results revealed that compounds 2 , 3 , 6 , 7 , and 8 exhibited notable inhibition, while compound 8 showed the broadest antifungal spectrum and the highest inhibition potency (inhibition zones up to 4.00 ± 0.50 mm). IC 50 determination highlighted compounds 2 (0.35 mg/mL) and 3 (< 0.63 mg/mL) as the most potent. At the same time, molecular docking against five key fungal enzymes indicated strong, multi-target binding affinities for compounds 6–8, particularly 8, which showed ΔG values below -8.982 kcal/mol. Density Functional Theory (DFT) calculations established correlations between frontier orbital energies, energy gaps, softness, dipole moments, and antifungal performance, suggesting that reduced ΔE and enhanced softness favor the biological activity. These findings identify compound 8 as a promising broad-spectrum antifungal lead and provide valuable structure–activity insights for the rational design of coumarin-based antifungal agents.