Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, <i>in silico</i> studies and pharmacological investigations
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A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (<b>16a-e, 17a-d, 18a-c</b>) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential <i>via</i> inhibition of Pancreatic Lipase (PL). Compound <b>18a</b> presented the most potent PL inhibitory activity with IC<sub>50</sub> = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC<sub>50</sub> = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound <b>18a</b> with an inhibitory constant value of 1.19 µM. The most promising compound <b>18a</b> revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound <b>18a</b>, which showed potent inhibition according to the results of <i>in vitro</i> studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of <i>in vivo</i> studies confirmed the anti-obesity efficacy of compound <b>18a</b>, wherein oral treatment with compound <b>18a</b> (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound <b>18a</b> significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.
