Nitrogen-functionalized rigid 3D-spirochroman–cycloalkane hybrids as dual α-amylase and α-glucosidase inhibitors: synthesis, biological evaluation, and computational insights

Abstract Diabetes mellitus is a major global health concern that demands robust therapeutic strategies to control postprandial hyperglycemia. In this study, a new series of 3D-spirochroman–cycloalkane hybrids bearing nitrogen-containing moieties, including azines, hydrazides, hydrazones, pyrazoles, and pyrroles were rationally designed and effectively synthesized in moderate to excellent yields. Upon evaluation as dual inhibitors of α -amylase and α -glucosidase enzymes, several compounds surpassed the benchmark drug acarbose (IC 50 = 78.9 and 43.3 µM, respectively). Nicotinonitrile 6 showed the strongest α -amylase inhibition (IC 50 = 21.3 µM), while hydrazone 15 exhibited the highest α -glucosidase inhibition potency (IC 50 = 18.2 µM). Hydrazone 12a displayed the most balanced dual inhibitory profile (IC 50 = 25.3 and 29.1 µM). Cytotoxicity assessments of compounds 6 , 12a , and 15 on Vero and WI-38 cell lines revealed minimal inhibitory effects on cell viability (IC 50 ≈ 316.15–611.52 µM). Molecular docking studies highlighted a favourable binding within enzyme active sites stabilized by hydrogen-bonding and hydrophobic interactions, and ADMET predictions indicated improved drug-likeness, gastrointestinal absorption, and high bioavailability of compounds 6 , 12a , and 15 compared with acarbose. DFT calculations showed that the nitrogen substitution modulates molecular orbital energies and reduces HOMO–LUMO gaps, serving as descriptors of electronic structure, while complementary multi-wave function analyses (ESP, NCI, and ELF) revealed charge redistribution and enhanced noncovalent interaction patterns consistent with the observed activity and selectivity.