New acetophenone scaffolds: Synthesis, antifungal activities, biocompatibility, molecular docking, ADMET analysis and dynamic simulations

Abstract

In this work, the chemical reactivity of 2-cyano-N′-(1-phenylethylidene)acetohydrazide (3) towards different aldehydes is utilized to synthesize binary and fused heterocyclic compounds, including arylidenes 6, 7, 12, 13, 14, 18a-c, 19a,b, 20, chromone 23, and chromene derivatives 24, 26a-c, 29, and 30. The capability of newly synthesized compounds to inhibit fungal growth of Aspergillus niger ATCC 16404, A. flavus ATCC 9643, Penicillium chrysogenum ATCC 10106, and Rhizopus oryazae ATCC 96382 are assessed. It is observed that compound 29 had strong antifungal activity against all fungi with MFIC values varying from 250 to 1000 µg/ml, while compound 18a demonstrated potent antifungal effect against A. niger and A. flavus. In addition, it is found that compound 29 was cytotoxic to Vero cells at doses of 1000–500 µg/ml; however, no discernible variation was observed between the concentrations of 250–31.25 µg/ml. Moreover, the interactions between the promising compounds 18a, 19b, and 29 and antifungal target proteins are assessed using molecular docking. The results of the docking simulations demonstrated that these compounds demonstrated optimal binding energies and effectively engaged with the active sites of FDC1 protein in A. niger, UDP-N-acetylglucosamine in A. fumigatus, Adenosine 5′-phosphosulfate kinase in P. chrysogenum, and protease in Rhizopus oryazae. These interactions involved various types of molecular interactions, indicating that these compounds have the ability to impede enzymes and exhibit strong antimicrobial effects. Furthermore, the in-silico ADMET profiles of compounds 18a, 19b, and 29 reveal that they adhere to the Lipinski rules, suggesting favorable physicochemical properties. Also, MD simulations revealed stable complexes of 29 with anti-fungal receptors including fdc1, UDP-N-acetylglucosamine, APS kinase, and protease with RMSD (0.1–0.8, 0.19–0.25, 0.20–0.30, and 0.20–0.35 nm), RMSF (0.1–0.8 nm), SASA (140–155, 130–140, 135–145, and 120–130 nm2), and Rg (1.90–2.00, 1.80–1.90, 2.40–2.50, and 2.10–2.20 nm) respectively. Our results provide potential and promising compounds for fungal infection diseases.