Design, synthesis, biological evaluation, and in silico characterization of chalcone derivatives as antidiabetic hits

A series of 40 chalcone derivatives was synthesized through Claisen-Schmidt condensation and characterized by FT-IR and NMR spectroscopy. The compounds were evaluated for α-amylase inhibitory and DPPH radical-scavenging activities to identify chalcone-based hits with a dual in vitro profile relevant to postprandial glycemic control. The series displayed a broad range of activities, with α-amylase IC₅₀, values spanning 10.41 ± 1.23-1021.64 ± 2.75 µM and radical-scavenging IC₅₀ , values ranging from 31.34 ± 0.20 to 698.34 ± 14.56 µM. Among the evaluated compounds, 4, 17, 19, 31, 33, and 35 emerged as the most active α-amylase inhibitors, with compound 4 being the most potent member of the series (IC₅₀ = 10.41 ± 1.23 µM), outperforming acarbose (IC₅₀ = 73.12 ± 5.04 µM). Structure-activity relationship analysis indicated that hydroxy- and methoxy-substituted aryl motifs were generally favorable, whereas some heteroaryl replacements and heavily halogenated patterns were less well tolerated. To rationalize the experimental profile, an ensemble docking workflow coupled to Naive Bayes rescoring was applied to human pancreatic α-amylase. The predicted binding modes supported productive occupation of the catalytic groove and suggested a key interaction between compound 4 and Glu233, consistent with its superior inhibitory potency. In silico ADMET profiling of the leading compounds indicated acceptable lipophilicity, solubility, intestinal absorption, and low predicted cardiotoxicity, with compound 4 showing the most balanced overall profile. In summary, these findings identify this chalcone series as a promising starting point for hit-to-lead optimization toward multifunctional radical scavenging and α-amylase inhibitors.