Facile one-pot multicomponent synthesis of polyhydroquinolines: a new class of α-glucosidase inhibitors

A series of 20 novel polyhydroquinolines ( 1–20 ) were synthesized via a simple, efficient and straightforward way of four-component reaction using a one-pot synthetic method in good-to-excellent/high yields. All synthesized compounds were characterized using spectroscopic techniques such ¹H NMR, ¹³C NMR, and High-Resolution Mass Spectrometry (HRMS-ESI + ) to confirm their structures. These compounds were evaluated against α-glucosidase enzymes and as results most compounds showed better inhibitory potential than the standard drug, acarbose (IC 50 = 873±1.20 µM) with IC 50 values in the range of 28.60 ± 0.51 µM to 268.34 ± 1.24 µM, except compounds 1 , 3 , 4 , and 6. Among all, compounds 16 , 20 , 12 , 8 , 19 , 9 , 15 and 13 exhibited excellent inhibitory profile with IC 50 values of 28.60 ± 0.51 µM, 35.62 ± 0.37 µM, 38.89 ± 0.46 µM, 50.17 ± 0.84 µM, 53.15 ± 0.74 µM, 56.53 ± 0.41 µM, 80.74 ± 0.52 µM, and 99.94 ± 0.60 µM, respectively. Furthermore, the binding modes of the active molecules were predicted through in-silico molecular docking and molecular dynamics simulation. Docking study reflects a good role of the quinoline moiety in the binding of molecules with Glu277 of α-glucosidase. The R group of all these compounds is located near the entrance of the active site, where the addition of bulky groups with polar substituents may favor high binding of compounds with the entrance residues. Compound- 16 with standard and APO were studied by MD simulation, dynamical behaviour and the interaction of drug-protein was evaluated by different dynamical parameters. Interaction energy was computed by MM-PBSA method and binding of compuond- 16 and standard are − 17.634 ± 2.98 Kcal mol − 1 and − 13.239 ± 3.96 Kcal mol − 1 , respectively. The combined in vitro and in-silico results show a great potential of these molecules as drug-like candidates for diabetes mellitus.