FURAN-BASED CHALCONES DERIVATIVES: SYNTHESIS, ANTIOXIDANT EVALUATION, DFT CALCULATIONS AND ADME PREDICTIONS

Heteroaromatic chalcones have attracted attention due to their structural versatility and redox-related properties. In this study, five ortho-substituted furanochalcones were synthesized by ultrasound-assisted Claisen–Schmidt condensation and characterized by 1H and 13C NMR spectroscopy. Their antioxidant activity was evaluated using DPPH• radical scavenging and phosphomolybdenum assays, while pharmacokinetic properties and electronic features were investigated through SwissADME and Density Functional Theory (DFT) calculations. Among the synthesized derivatives, compound 5 (2-OH,5-NO2) showed the highest antioxidant activity in both assays, showing the highest antioxidant activity among the synthesized derivatives. The results support that substitution patterns strongly influence antioxidant performance by modulating hydrogen atom transfer (HAT) and electron-transfer (SET) mechanisms. DFT calculations suggested that compounds 5, 3, and 2 exhibit electronic profiles favorable to charge transfer, including lower global hardness, higher softness, increased electrophilicity, and smaller HOMO–LUMO energy gaps. Compound 5 also showed enhanced spin density delocalization and greater stabilization of the phenoxyl radical formed after hydrogen abstraction, explaining its superior antioxidant activity despite O–H bond dissociation energies similar to compound 2. Molecular electrostatic potential maps and frontier molecular orbital analyses further support the importance of substituent effects and electronic delocalization in modulating redox behavior. In silico ADME predictions indicated that all furanochalcones satisfy classical drug-likeness criteria, with favorable lipophilicity, acceptable polar surface area, and predicted gastrointestinal absorption. Overall, the combined experimental and computational results suggest that furanochalcones are useful for future antioxidant-oriented investigations.