Synthesis, homology modeling, molecular docking, dynamics, and antifungal screening of new 4-hydroxycoumarin derivatives as potential chitinase inhibitors

The inhibition of chitinase activity is considered of great importance for the development of novel antifungal agents. Here we explore 4-hydroxycoumarins as a novel natural product-derived scaffold for inhibiting chitinases. A new series of 4-hydoxycoumarin derivatives containing Schiff's base motif in the 3 position was synthesized and computationally predicted for chitinase binding affinity. Docking simulation study was carried out using the built homology models of specified fungal species and the top ranked molecules with promising binding affinity were subjected to further molecular dynamic simulation to evaluate their binding stability. The top compounds were then tested in vitro against three phytopathogenic fungi, including Fusarium solani, Fusarium oxysporium and Aspergillus niger in addition to three candida species including C. albicans, C. tropicalis and C. krusei. The active antifungal candidates were further assessed for chitinase inhibition effect. Most of the tested compounds displayed promising antifungal effects. The 2,4-dichlorophenyl Schiff's base 2e exhibited a wide range of antifungal activity against most of the tested fungi and yeast while the 3-fluorophenyl Schiff's base 2a showed the highest anti-candidal effects. Both Schiff's bases 2a and 2e displayed the highest chitinase inhibition effects (IC 50  = 1.0 mM) having the same potential as the previously described chitinase inhibitor CI-4 (IC 50  = 1.2 mM). The target compounds have high ligand efficiency and binding stability, and as such are promising leads for future development of chitinase inhibitors.