Synthesis, in vitro inhibitor screening, structure–activity relationship, and molecular dynamic simulation studies of novel thioquinoline derivatives as potent α-glucosidase inhibitors

Abstract

New series of thioquinoline structures bearing phenylacetamide 9a–p were designed, synthesized and the structure of all derivatives was confirmed using different spectroscopic techniques including FTIR, ¹H-NMR, ¹³C-NMR, ESI–MS and elemental analysis. Next, the α-glucosidase inhibitory activities of derivatives were also determined and all the synthesized compounds (IC₅₀ = 14.0 ± 0.6–373.85 ± 0.8 μM) were more potent than standard inhibitors acarbose (IC₅₀ = 752.0 ± 2.0 μM) against α-glucosidase. Structure–activity relationships (SARs) were rationalized by analyzing the substituents effects and it was shown that mostly, electron-donating groups at the R position are more favorable compared to the electron-withdrawing group. Kinetic studies of the most potent derivative, 9m, carrying 2,6-dimethylphenyl exhibited a competitive mode of inhibition with K_i value of 18.0 µM. Furthermore, based on the molecular dynamic studies, compound 9m depicted noticeable interactions with the α-glucosidase active site via several H-bound, hydrophobic and hydrophilic interactions. These interactions cause interfering catalytic potential which significantly decreased the α-glucosidase activity.