Synthesis, in vitro evaluation and molecular docking studies of hybrid 4-quinolinyl bearing 1,3,4-thiadiazole-2-amine as a new inhibitor of ?-amylase and ?-glucosidase

Synthesized scaffolds (1-19) of 4-quinolinyl based 1,3,4-thiadiazole-2-amine were evaluated in vitro for their alpha-amylase and alpha-glucosidase inhibition. All the newly synthesized scaffolds (1-19) were found to illustrate variable degree of inhibitory profile against alpha-amylase and alpha-glucosidase enzymes ranging from 1.30 +/- 0.05 to 45.60 +/- 0.80 mu M and 2.70 +/- 0.10 mu M to 47.60 +/- 0.90 mu M. Among the series, compounds 2 (IC50 = 2.20 +/- 0.10 mu M), (IC50 = 8.40 +/- 0.20 mu M), 3 (IC50 = 4.10 +/- 0.10 mu M), (IC50 = 5.60 +/- 0.10 mu M), 4 (IC50 = 1.30 +/- 0.05 mu M), (IC50 = 2.90 +/- 0.10 mu M) and 5 (IC50 = 1.90 +/- 0.10 mu M), (IC50 = 2.70 +/- 0.10 mu M) were found to be the most potent inhibitors of alpha-amylase and alpha-glucosidase enzymes. The elevated in-hibitory profile of these scaffolds might be due to presence of flouro and chloro group at different po-sitions of phenyl ring attached to 1,3,4-thiadiazole ring. Various types of spectroscopic techniques such as 1 H-, 13 C-NMR and HREI-MS spectroscopy were used to confirm the structure of all the newly devel-oped scaffolds. To find SAR, molecular docking studies were performed to understand the binding mode of potent inhibitors with active site of enzymes and results supported the experimental data. Molecular dynamics study were performed to further investigate the orientation and binding interaction of the syn-thesized analogues with active site of alpha-amylase and alpha-glucosidase enzyme. ADMET prediction and in silico drug likeness analysis of the synthesized analogues demonstrated that these analogues have satis-factory ADMET profile and drug likeness. (c) 2023 Elsevier B.V. All rights reserved.

Automated summary

In this study, a series of 4-quinolinyl based 1,3,4-thiadiazole-2-amine scaffolds (1-19) were synthesized and evaluated for their in vitro inhibition against alpha-amylase and alpha-glucosidase enzymes. The newly synthesized scaffolds demonstrated varying degrees of inhibitory activity, with compounds 2, 3, and 4 being the most potent inhibitors. The presence of fluorine and chlorine groups at different positions of the phenyl ring attached to the thiadiazole ring may contribute to the enhanced inhibitory profile of these scaffolds. Spectroscopic techniques and molecular docking studies were used to confirm the structures and understand the binding mode of the inhibitors. ADMET prediction and in silico drug likeness analysis showed satisfactory ADMET profile and drug likeness for the synthesized analogues.