Discovery of Novel 6-(Piperidin-1-ylsulfonyl)-2h-chromenes Targeting Α-Glucosidase, Α-Amylase, and PPAR-γ: Design, Synthesis, Virtual Screening, and Anti-Diabetic Activity for Type 2 Diabetes Mellitus.

A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100µg/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6 to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC50 values were determined, and the designed derivatives exhibited inhibitory potency less than 11µg/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC50 values of 0.975 ± 0.04 and 0.584 ± 0.02µg/mL, respectively, compared to Acarbose (IC50 = 0.805 ± 0.03µg/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC50 values of 3.453 ± 0.14 and 4.653 ± 0.04µg/mL compared to Pioglitazone (IC50 = 4.884±0.29µg/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity.