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.
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BibTeX
@article{bakr2026nitrogenfunctionalized,
title = {{Nitrogen-functionalized rigid 3D-spirochroman–cycloalkane hybrids as dual α-amylase and α-glucosidase inhibitors: synthesis, biological evaluation, and computational insights}},
author = {Y. E. Bakr and M. A. Abozeid and M. M. Abou-Elzahab and S. U. Khan and F. H. Elghareeb},
journal = {Scientific Reports},
year = {2026},
month = nov,
doi = {10.1038/s41598-026-74462-y},
url = {https://www.nature.com/articles/s41598-026-74462-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Nitrogen-functionalized rigid 3D-spirochroman–cycloalkane hybrids as dual α-amylase and α-glucosidase inhibitors: synthesis, biological evaluation, and computational insights
AU - Y. E. Bakr
AU - M. A. Abozeid
AU - M. M. Abou-Elzahab
AU - S. U. Khan
AU - F. H. Elghareeb
PY - 2026
DA - 2026/11/05
JO - Scientific Reports
DO - 10.1038/s41598-026-74462-y
UR - https://www.nature.com/articles/s41598-026-74462-y
AB - 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.
SN - 2045-2322
ER -