Design, synthesis, biological evaluation and molecular modelling studies of oxoacetamide warhead containing indole-quinazolinone based novel hybrid analogues as potential pancreatic lipase inhibitors†
A novel series of indolyl oxoacetamide-quinazolinone hybrid analogues (9aa–9df) were designed, synthesized, and evaluated for their in vitro pancreatic lipase (PL) inhibitory potential which may lead to efficient anti-obesity agents. All the synthesized hybrid analogues exhibited moderate to potent PL inhibitory activity (IC50 = 32.51 to 4.86 μM). Among all the analogues, 9ak, 9af, 9aj, and 9ah were found to have the most potent PL inhibitory activity (IC50 = 4.86, 5.73, 5.83, and 5.94 μM respectively), as compared to orlistat (IC50 = 0.86 μM). The most potent analogues 9af and 9ak were found to inhibit PL competitively with an inhibition constant (Ki) of 2.136, 1.648 μM. Furthermore, the docking study confirmed the binding of analogues 9ak and 9af (MolDock score of −161.25, −133.67 kcal mol−1) that exhibited docking interactions with important active site amino acids, namely Phe 77, Tyr 114, Ser 152, Arg 256, His 263, etc. Also, the analysis of analogue 9ak and 9af in SeeSAR revealed the covalent inhibition of PL. In molecular dynamics simulations of 100 ns, the complex between each analogue (9ak & 9af) and PL was found to be stable (RMSD < 1.5 Å). The present work highlights the importance of a hybrid drug design approach for the development of indole and quinazolinone containing hybrids as potential PL inhibitors.