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

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, H-1-NMR, C-13-NMR, ESI-MS and elemental analysis. Next, the alpha-glucosidase inhibitory activities of derivatives were also determined and all the synthesized compounds (IC50 = 14.0 +/- 0.6-373.85 +/- 0.8 mu M) were more potent than standard inhibitors acarbose (IC50 = 752.0 +/- 2.0 mu M) against alpha-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 mu M. Furthermore, based on the molecular dynamic studies, compound 9m depicted noticeable interactions with the alpha-glucosidase active site via several H-bound, hydrophobic and hydrophilic interactions. These interactions cause interfering catalytic potential which significantly decreased the alpha-glucosidase activity.

Automated summary

A new series of thioquinoline compounds with phenylacetamide were synthesized and their structures were confirmed. The synthesized compounds showed potent inhibitory activities against α-glucosidase, surpassing the standard inhibitor acarbose. The most effective compound, 9m, exhibited competitive inhibition with α-glucosidase through various interactions.