Integrated insights into the synthesis and biological significances of novel benzofuran based oxadiazole/thiadiazole derivatives: A comprehensive computational and experimental study

We have synthesized a novel library of benzofuran-derived thiadiazole/oxadiazole-based thiourea derivatives (128) targeting one of the rising health issues all over the world, Diabetes Mellitus. In this approach, all the synthesized analogs were evaluated against alpha-glucosidase in biological efficiency investigation. These analogs were found biologically active and recorded with moderate to good inhibitory profile, termed as potent antidiabetic agents. These derivatives potentially inhibit alpha-glucosidase via developing interactions with amino acids of active site. For the biological comparative analysis, widely used standard drug acarbose (IC50 = 4.80 +/- 0.10 mu M) was chosen. Among benzofuran-derived thiadiazole-based thiourea derivatives (1-14), analog 3 (IC50 = 3.90 +/- 0.40 mu M) having two -OH groups at 2,4-position of the ring displayed the top ranking biological potential to inhibit the target enzyme while, among benzofuran-derived oxadiazole-based thiourea derivatives (15-28), analog 15 (IC50 = 2.40 +/- 0.10 mu M) having three -OH groups at 2,4,6-position of the ring showed excellent inhibition of alpha-glucosidase. The stronger inhibition of these analogs might be assigned to electron donating -OH groups at varied positions, interacting with the target enzyme via hydrogen bond. All the biologically potent compounds and their interactions with enzyme were computationally visualized in molecular docking study which provided insight into inhibiting mode of potent compounds with alpha-glucosidase through a number of interactions. Among all these compounds, analog 15 was found with excellent biological profile as promising anti-diabetic. Their drug likeness characteristics were also assessed in ADME analysis. The synthesized novel derivatives were structurally validated through 13C-NMR, 1H-NMR and HREI-MS.