ABSTRACT Diabetes mellitus is a progression involves worsening insulin resistance and β‐cell dysfunction, culminating in severe metabolic complications. In this work, chalcone‐based aryloxyethylamines were synthesized and evaluated for their antihyperglycemic activity using glucose tolerance test (GTT) and STZ‐induced DM rat models. Compounds 12 , 10 , 8 , 7 , 5, and 3 exhibited moderate to good anti‐DM activity ranging from 18.5% to 39.8% in GTT and 11.6% to 28.3% in STZ in vivo models. The most promising compounds 10 and 12 exhibited 31.1% and 39.8% glucose lowering in GTT and 28.3% and 22.9% in STZ‐induced DM rat model, respectively. Molecular docking for β3‐AR revealed strong binding affinity of the identified compounds to β3‐AR, with docking scores in the range of −7.8 to −8.9 kcal/mol and comparable to co‐crystallized ligand carazolol. Key interactions included hydrogen bonds with Asn312 and hydrophobic contacts with Val118, Val121, and Phe309. The most promising compound 10 and 12 displayed the binding score of −8.9 and −8.1 kcal/mol, respectively. The binding mode analysis showed that carbonyl oxygen of 10 and 12 displayed hydrogen bond with Asn312, in addition to hydrogen bond with Ser209 in 10 . Further, ring A of 10 and 12 occupied the aromatic hydrophobic core created by residues Phe308, Phe309, Val118, and Val121. The ethylamine side chain on ring B of 10 displayed hydrophobic interactions with Val205, Ala316, and Arg315, while ring B itself engages in a carbon hydrogen bond with Tyr204. The ethylamine side chain of 12 displayed carbon hydrogen bond with Asn332. Overall, the work resulted in the identification of 10 and 12 as potential β3‐AR binders.
Srivastava et al. (Sat,) studied this question.