Design, synthesis, and biological evaluation of disubstituted thiazolidinedione derivatives as pancreatic lipase inhibitors for the management of obesity.

AIM: Inspired by our previous research findings and to explore the effect of N-3 and C-5 substitution in relation to pancreatic lipase (PL) inhibitory activity, the present study aims at the design and synthesis of a series of disubstituted thiazolidinedione (TZD) derivatives and to evaluate their PL inhibitory activity.

METHODS: A series of disubstituted TZD derivatives was synthesized by condensing various aldehydes on C-5 and substituting 4-fluorobenzyl on N-3 of TZD. The synthesized derivatives were screened for PL inhibitory activity. Further, kinetic study and various in silico studies were also performed.

RESULTS AND CONCLUSION: Compound 16f displayed most potent inhibitory activity with IC50 value of 4.58 μM. Kinetic studies revealed competitive mode of inhibition for 16f, 16g, and 16r with Ki values 1.479, 1.827, and 1.939 μM; while their Vmax values were found to be 0.611, 0.958, and 0.939 μM, respectively. Docking studies confirmed good binding affinities of synthesized derivatives toward the active site of PL. Molecular dynamic simulation of 16f revealed stability of the protein-ligand complex. Moreover, compound 16f was predicted to have a satisfactory drug likeness profile. Compound 16f can be used as a leading candidate for further structural optimization to identify more potent and efficacious PL inhibitors as anti-obesity agents.