New quinoline-based triazole hybrid analogs as effective inhibitors of α-amylase and α-glucosidase: Preparation, in vitro evaluation, and molecular docking along with in silico studies

Abstract

The 7-quinolinyl-bearing triazole analogs were synthesized <b>(1d-19d)</b> and further assessed <i>in vitro</i> for their inhibitory profile against α-amylase andα-glucosidase. The entire analogs showed a diverse range of activities having IC₅₀ values between 0.80 ± 0.05 µM to 40.20 ± 0.70 µM (α-amylase) and 1.20 ± 0.10 µM to 43.30 ± 0.80 µM (α-glucosidase) under the positive control of acarbose (IC₅₀ = 10.30 ± 0.20 µM) (IC₅₀ = 9.80 ± 0.20 µM<b>)</b> as the standard drug. Among the synthesized scaffolds, seven scaffolds <b>12d</b>, <b>10d</b>, <b>8d</b>, <b>9d</b>, <b>11d</b>, <b>5d</b>, and <b>14d</b> showed excellent α-amylase and α-glucosidase inhibitory potentials with IC₅₀ values of 4.30 ± 0.10, 2.10 ± 0.10, 1.80 ± 0.10, 1.50 ± 0.10, 0.80 ± 0.05, 5.30 ± 0.20, and 6.40 ± 0.30 µM (against α-amylase) and 3.30 ± 0.10, 2.40 ± 0.10, 1.20 ± 0.10, 1.90 ± 0.10, 8.80 ± 0.20, 7.30 ± 0.40, and 5.50 ± 0.10 µM (against α-glucosidase), respectively, while the remaining 12 scaffolds <b>19d</b>, <b>8d</b>, <b>17d</b>, <b>16d</b>, <b>15d</b>, <b>7d</b>, <b>4d</b>, <b>3d</b>, <b>1d</b>, <b>2d</b>, <b>13d</b> and <b>6</b> <b>d</b> showed less α-amylase and α-glucosidase inhibitory potentials than standard acarbose but still found to be active. Structure-activity connection studies also showed that scaffolds with electron-withdrawing groups like -Cl, -NO₂, and -F linked to the phenyl ring had higher inhibitory potentials for -amylase and -glucosidase than scaffolds with -OCH₃, -Br, and -CH₃ moieties. In order to better understand their binding sites, the powerful scaffolds <b>11d</b> and <b>9d</b> were also subjected to molecular docking studies. The results showed that these powerful analogs provide a number of important interactions with the active sites of both of these targeted enzymes, including conventional hydrogen bonding, pi-pi stacking, pi-sulfur, pi-anion, pi-pi, pi-sigma, T-shaped, and halogen (fluorine). Furthermore, various techniques (spectroscopic), including 1H, ¹³C-NMR, and HREI-MS mass, were used to explore the correct structure of newly afforded hybrid scaffolds based on quinoline-bearing triazole ring.