Investigating the Role of Indole and Quinazolinone-Based Hybrid Analogues with Ketoamide Fragment and Alkyl Extension for Potential PL Inhibition

Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary fat. Hence the inhibition of PL is an effective strategy for mitigating obesity. In this study, a novel series of 18 indolyl oxoacetamide–quinazolinone hybrid analogues (9a-h, 13aa-13fd) were designed, synthesized, and evaluated for PL inhibition activity. An approach of molecular hybridization was utilized by considering the PL inhibitory potential of indole, α-ketoamide, and quinazolinone scaffolds. A Propyl linker was attached for better binding at the PL active site, leading to enhanced PL inhibitory potential. Among all the synthesized analogues, 13be exhibited the highest PL inhibitory activity (IC50= 4.71 ± 0.851 μM) with a docking score of -147.06 kcal/mol. The activities of all the synthesized analogues were compared with the orlistat (IC50 = 0.86 ± 0.090 µM). The most potent analogue, 13be revealed the competitive mode of enzyme inhibition with the Ki value of 1.826 µM. The molecular docking and dynamics simulation analysis also revealed the strong binding of 13be at the active site of PL. Interestingly, the potent analogue 13be when tested on RAW 264.7 cell line using MTT assay, was found to be non-toxic at a concentration range of 1-20 µM. Therefore, the current work validates the effectiveness of the molecular hybridization approach for designing indolyl oxoacetamide–quinazolinone hybrids for inhibiting PL.