Khator_2025_Arch.Pharm.(Weinheim)_358_e70135

In the current study, a series of 22 prenylated arylidene appended thiazolidinedione derivatives were designed, synthesized, and evaluated for pancreatic lipase (PL) inhibitory activity. The study led to the identification of compounds exhibiting potent to moderate inhibitory activities with IC(50) values ranging between 6.18 +/- 0.46 and 52.75 +/- 2.34 microM. Among them, compound 22b demonstrated remarkable PL inhibitory activity with an IC(50) value of 6.18 +/- 0.46 microM. Enzyme kinetics studies revealed a reversible competitive mode of inhibition for 22b with a K(i) value of 4.1 microM. The results of in vitro findings further supported the outcome of in silico studies, which correlate the strong binding affinity of compound 22b for PL. Molecular docking studies confirmed satisfactory binding mode of compounds within the active site of PL by exhibiting various interactions such as H-bonding, Pi-Pi stacking, and hydrophobic interactions. A 100 ns molecular dynamics simulation study of protein-ligand complex with compound 22b revealed good binding and stability. The MM-GBSA analysis revealed strong binding affinity toward the active site of PL as compared with the reference ligand. Further, all derivatives were predicted to exhibit good pharmacokinetic properties, devoid of toxicity (toxicity class 4) and drug likeness.