Discovery of novel chromone and acrylate-based pancreatic lipase inhibitors: Molecular modelling, synthesis, and in vitro evaluation for the treatment of obesity

By the optimization of previously established pancreatic lipase (PL) inhibitory lead, we have developed novel chromone-containing analogues with embedded acrylate fragment as potential PL inhibitors. The analogues were designed by considering the structural features required for binding at the active site of PL enzyme with the utilization of molecular docking study. An optimized synthetic scheme was utilized for the synthesis of designed analogues of prototypes 1&2. Through in vitro PL inhibitory screening, three analogues namely, 5fj, 5gj and 9a were identified as potent PL inhibitory leads with IC50 values of 4.92, 4.23 and 3.32 mu M, respectively. The protein binding of analogue 9a was analysed by fluorescence quenching study and it was found to bind at one binding site with a binding constant of 1.93 x 105 L mol-1. Analogue 9a also exhibited a competitive inhibitory mechanism with Ki value of 1.601 mu M. In future, the potent lead 9a can be optimized to get a comparable or more potential PL inhibitory activity than marketed drugs. A novel series of chromone and acrylate-based PL inhibitors were designed with the analogue 9a, being potent of the series, exhibiting IC50 of 3.32 +/- 0.224 mu M. Also, the fluorescence quenching and enzyme kinetics study proved the competitive nature of inhibition.image