Schiff bases derived from 2,3-dimethoxylbenzaldehydes as antioxidant and antidiabetes agents: Synthesis, structural analysis, DFT computational, molecular docking and in vitro studies

Abstract

Five Schiff base compounds were prepared by the condensation reaction between 2,3-dimethoxylbenzaldehyde and a series of amino-compounds. These were (E)-5-chloro-2-((2,3-dimethoxybenzylidene)amino)phenol (DMC), (E)-N-(3-chloro-4-fluorophenyl)-1-(2,3-dimethoxyphenyl)methanimine (DMCF), (E)-1-(2,3-dimethoxyphenyl)-N-(4-fluorophenyl)methanimine (DMF), (E)-2-((2,3-dimethoxybenzylidene)amino)-4-methylphenol (DMM), and (E)-2-((2,3-dimethoxybenzylidene)amino)-5-nitrophenol (DMN). These compounds were elucidated using spectroscopic techniques such as UV–visible, FT-IR, NMR (¹H & ¹³C) and mass spectrometry while elemental/combustion analysis was explored to confirm the purity of the compounds. Furthermore, the structures of DMM and DMCF were confirmed using the single crystal-Xray crystallography technique. In these structures, the central C9—C8—N7—C5(C6) plane is inclined to 2,3-dimethoxyphenyl ring at 8.59° and 2.01° for DMM and DMCF while it inclined to the phenol ring at 23.14° and 23.64° for DMM and DMCF respectively. Calculations using quantum chemistry showed that molecules with a hydroxyl group have a lower energy bandgap (∆E) than those without one. The α-amylase and α-glucosidase assays were employed to assess the ability of the compounds to treat diabetes. In both assays, all the compounds showed good antidiabetes activities except DMN. However, none of the compounds outperformed acarbose. Compound DMF displayed the highest α-amylase inhibitory potential with IC₅₀ value of 122.55 μΜ while DMC with IC₅₀ value of 88.50 μΜ exhibited the highest α-glucosidase inhibitory potential when compared to other compounds evaluated for both assays. Nitric oxide (NO), ferric reducing ability power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays were used to measure the compounds' antioxidant capability. All the compounds showed excellent antioxidant potential and outshined vanillin (standard drug) in all the assays. Hydroxyl-containing compounds performed better than those without the hydroxyl group. For example, in DPPH assay, DMC has the highest DPPH free radical scavenging activity, with IC₅₀ value of 50.30 μM, followed by DMM and DMN having IC₅₀ values of 58.42 μM and 63.43 μM respectively. All the compounds complied with Lipinski's Ro5, suggesting that, they are less toxic and orally bioavailable.