<p>Inhibition of carbohydrate digesting enzymes like pancreatic α-amylase has proven to be an effective strategy in countering postprandial hyperglycaemia. However, unwanted adverse effects associated with current therapies, such as ACB, voglibose, and miglitol, have necessitated the development of safer and more effective alternatives. These challenges have prompted growing interest in natural product scaffolds, particularly phenolic compounds, which exhibit favourable safety profiles and multifaceted enzyme inhibition. In this context, the strategic design of molecular conjugates integrating bioactive phenolics offers a promising route to enhance inhibitory potency, binding specificity, and therapeutic relevance. Reportedly, molecular hybrids with chalcone, phenolic acid, coumarin and polyphenol backbone exhibited impressive antioxidant and potent inhibition against digestive enzymes. In the quest of developing novel anti-hyperglycaemic agents, we report in vitro and in silico evaluation of the novel TPAC as potential pancreatic α-amylase inhibitors in the present work. Among the ten conjugates, T5 (IC₅₀ = 50.65 ± 0.76 µM) exhibited strong inhibition against PPA which was comparable to positive control ACB (24.81 ± 0.98 µM). Computational binding analysis revealed binding of T5 to HPA (PDB ID: 2QV4) by interacting with the amino acid residues and distorting the receptor’s catalytic site conformation. Furthermore, the conformational dynamic studies and electron density driven simulations established the stability and high reactivity of T5 within the ligand-receptor complex. The in silico studies corroborated the in vitro enzyme inhibition results, reinforcing the mechanistic insights into ligand–receptor interactions. Taken together, the experimental and computational results indicate that T5 merits further investigation as a candidate molecule targeting pancreatic α-amylase for the management of T2D .</p>