New Materials, Compounds and Applications

Aryl- and heteroaryl-hydrazone derivatives are recognized scaffolds with diverse biological activities, including antimicrobial, anti-inflammatory and antiviral effects. In this study, four α-keto acid-based arylhydrazone esters were evaluated using an integrated in silico workflow combining molecular docking, multitarget activity prediction, drug-repositioning analysis and toxicity assessment to explore their potential as SARS-CoV-2 main protease (Mpro) inhibitors. Docking simulations using SwissDock indicated that all compounds interacted with key catalytic residues, forming recurrent hydrogen bonds with Glu166 and Gly143 and hydrophobic contacts within the S1/S2 subsites. The 3,5-dimethyl-substituted derivative showed the most favorable docking score (ΔG = -5.17 kcal/mol), although the differences among the series were modest and should be interpreted cautiously. Multitarget profiling suggested additional interactions with enzymes related to inflammation and metabolic regulation, while toxicity predictions indicated generally acceptable acute oral risk with some route-dependent variability. Taken together, the results support these hydrazone esters as hypothesis-generating leads rather than confirmed antivirals. The contrasting outcomes between broader antiviral prediction models and SARS-CoV-2-specific QSAR tools highlight the importance of model specificity and the need for experimental validation. Overall, the present findings provide a computational basis for prioritizing arylhydrazone scaffolds for further optimization and biological testing.