Exploring density functional theory to gain insight into the enolimine-ketoenamine tautomerism of dihydroxyl Schiff bases derived from 4-(diethylamino)salicylaldehyde and investigating their use as antidiabetes and antioxidant agents

• Three dihydroxyl Schiff bases derived from 4-(diethylamino)salicylaldehyde were synthesized and characterized. • Slow evaporation of a hot solution of (DAC and DAM) crystallized as their ketoenamine form (DAC′ and DAM′). • DFT studies shed light on the enolimine-ketoenamine tautomers of the compounds. • Calculated quantum chemical descriptors revealed that DAN has the lowest energy bandgap of 6.158 eV. • The compounds showed good antioxidant potential with DAN scavenging nitric oxide radical better than quercetin. • All the compounds showed moderate antidiabetes potential. Three dihydroxyl Schiff bases namely, 5-chloro-2-((4-(diethylamino)-2-hydroxybenzylidene)amino)phenol ( DAC ), 2-((4-(diethylamino)-2-hydroxybenzylidene)amino)-4-methylphenol ( DAM ) and 5-(diethylamino)-2-(((2-hydroxy-4-nitrophenyl)imino)methyl)phenol ( DAN ) were prepared by the condensation reaction between 4-(diethylamino)salicylaldehyde and amino-phenol derivatives. The compounds were elucidated using spectroscopic and elemental analysis techniques. Attempts to grow the crystal structure of DAC and DAM (enolimine form) at 60 – 70 ºC in methanol resulted in the formation of their ketoenamine form and are denoted as DAC′ and DAM′ . The molecular conformation of DAC′ and DAM′ revealed that the 4-diethylamino and the aminophenol phenyl rings are coplanar with the azomethine functional group as evident by C13—C8—C7—N1 dihedral angles of -178.78º ( DAC′ ) and -174.99º ( DAM′ ) as well as C1/C3—C6/C4—N1—C7 dihedral angles of 179.16º ( DAC′ ) and 174.08º ( DAM′ ). The longer bond length observed in C7—N1 as well as slightly shorter bond length observed in C9—O1 of DAC′ and DAM′ affirms their tautomeric properties related to DAC and DAM . We used Density functional theory (DFT) to investigate the structural, electronic, and tautomeric properties of DAM, DAC , and DAN . Notably, all the compounds exhibit single intramolecular hydrogen bonding that stabilizes its structure and facilitates proton transfer to yield its ketoenamine tautomer. However, the enamine tautomer is more stabilized due to the presence of dual intermolecular hydrogen bonding, hence supporting the crystallization of DAC′ and DAM′ over DAC and DAM . Compound DAN with the lowest energy bandgap of 6.158 eV is suggested to be the most reactive and polarizable molecule among the three compounds. Ferric reducing ability power (FRAP), 2,2-diphenyl-1-picrylhydrazyl (DPPH) as well as nitric oxide assays were explored to evaluate the antioxidant potential of the compounds. They exhibited good to moderate antioxidant activities i.e., DAN with IC 50 value of 0.51 μΜ scavenge nitric oxide radical better than quercetin with an IC 50 value of 149.96 μΜ. The evaluation of the antidiabetic potential was carried out using α-glucosidase and α-amylase inhibition assays. For the α-amylase assay, DAC with an IC 50 value of 0.13 μΜ exhibited almost equivalent capacity as acarbose with IC 50 value of 0.11 μΜ.