Synthesis of 4-Diazocyclohexane Sulfonamide Drug Scaffolds: Investigating Enzyme Inhibition, Antioxidant, and Admet Properties

Abstract

The inhibitory effects of several sulfonamide derivatives with a 4-diazocyclohexane backbone on alpha-glucosidase and alpha-amylase enzymes were explored. IC50 values for five sulfonamide derivatives were determined, ranging from 2.10 +/- 0.115 to 3.22 +/- 0.227 mu M for alpha-glucosidase and from 1.90 +/- 0.379 to 3.19 +/- 0.604 mu M for alpha-amylase. The results indicated that the inhibitory activity of these derivatives was comparable to the standard inhibitor acarbose. Additionally, the antioxidant potential of the sulfonamide derivatives was assessed using in vitro assays, including cupric ion (Cu2+) reduction, ferric ion (Fe3+) reduction (FRAP assay), DPPH radical scavenging, and ABTS+ radical scavenging methods. While no significant radical scavenging activity was observed in the ABTS assay, minimal antioxidant activity was detected in other methods compared to standard antioxidants. These findings suggest the potential of sulfonamide derivatives as dual enzyme inhibitors with limited antioxidant properties. Additionally, molecular docking and molecular dynamics (MD) simulations demonstrated the stability of 4-diazocyclohexane-based sulfonamide compounds-selected proteins complexes and provided detailed insights into 4a-e compounds-protein interactions at the molecular level. These findings formed the foundation for biologic activity these compounds with optimized binding properties and anticipated inhibitory activities. Moreover, an analysis of physicochemical descriptors and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles was conducted to obtain deeper insights into ADMET properties in alpha-glucosidase and alpha-amylase candidate inhibitors.