Hidden Boundaries of Green Chalcone Synthesis: A Structure-Reactivity Study of Low-Yield Halo-Substituted Derivatives

Abstract

Chalcones are privileged α, β-unsaturated ketone scaffolds possessing a wide range of pharmacological activities. In the present study, eighteen halo-substituted chalcone derivatives synthesized using green and solvent-minimized methodologies were systematically screened for enzymatic inhibitory potential and theoretical binding affinity despite their earlier classification as low-yield derivatives. All compounds were subjected to in-vitro enzymatic screening against α-amylase and trypsin enzymes while further assessing their binding behavior through molecular docking. Enzymatic assays resulted in uniform inhibitory activity across the compound library: inhibition of α-amylase in a range of 27.6–36.8% and trypsin in a range of 23.4–31.9%. Of note, the C9, C20, and C29 compounds exhibited the highest enzymatic inhibition activities and also the best docking affinities towards both enzymes. Molecular docking confirmed the binding energies were quite favorable between -5.6 to -6.7 kcal/mol with α-amylase and -5.0 to -6.0 kcal/mol with trypsin. Binding was driven by hydrophobic interaction, π–π stacking, and halogen-mediated interactions within enzyme active sites. These findings prove that a low synthetic yield does not compromise biological relevance and therefore delineates the need for inclusive biological screening in medicinal chemistry. The present study establishes halo-substituted chalcones as promising scaffolds for further structure–activity optimization under sustainable conditions of synthesis.