Biaryl carboxamide-based peptidomimetics analogs as potential pancreatic lipase inhibitors for treating obesity

A series of 1,1'-biphenyl-3-carboxamide and furan-phenyl-carboxamide analogs were synthesized using an optimized scheme and confirmed by ¹H and ¹³C nuclear magnetic resonance and high-resolution mass spectrometry techniques. The synthesized peptidomimetics analogs were screened in vitro to understand the inhibitory potential of pancreatic lipase (PL). Analogs were assessed for the PL inhibitory activity based on interactions, geometric complementarity, and docking score. Among the synthesized analogs, 9, 29, and 24 were found to have the most potent PL inhibitory activity with IC₅₀ values of 3.87, 4.95, and 5.34 µM, respectively, compared to that of the standard drug, that is, orlistat, which inhibits PL with an IC₅₀ value of 0.99 µM. The most potent analog, 9, exhibited a competitive-type inhibition with an inhibition constant (K_i) of 2.72 µM. In silico molecular docking of analog 9 with the PL (PDB ID:1LPB) showed a docking score of -11.00 kcal/mol. Analog 9 formed crucial hydrogen bond interaction with Ser152, His263, π-cation interaction with Asp79, Arg256, and π-π stacking with Phe77, Tyr114 at the protein's active site. The molecular dynamic simulation confirmed that analog 9 forms stable interactions with PL at the end of 200 ns with root mean square deviation values of 2.5 and 6 Å. No toxicity was observed for analog 9 (concentration range of 1-20 µM) when tested by MTT assay in RAW 264.7 cells.