The Synthesis of Schiff bases and new secondary amine derivatives of p-vanillin and evaluation of their neuroprotective, antidiabetic, antidepressant and antioxidant potentials

Abstract

In the current study, five Schiff base derivatives coded as VDOPL (1), VHISL (2), V2-AFL (3), V4-AFL (4) and VAML (5) from p-vanillin were synthesized with dopamine, histamine, 2-aminophenol, 4-aminophenol and 4-aminomorpholine. Afterwards, these Schiff bases were reduced with NaBH4 to produce secondary amines coded as VDOPA (6), V2-AFA (7), V4-AFA (8) and VAMA (9). The chemical structures of the synthesized molecules were characterized by UV-Visible, FTIR, 1H-NMR, 13C-NMR, DEPT, APT, 1H, 1H-COSY, HMQC and HMBC methods. The enzyme inhibitory properties of p-vanillin, the primary amines, the Schiff bases and novel secondary amine derivatives on cholinesterase's (AChE and BChE) and on α-glycosidase and α-amylase enzyme activities were evaluated for the first time to determine their neuroprotective and antidiabetic effects, respectively. The antioxidant potentials of all molecules were also investigated by testing the ABTS and DPPH radical scavenging activities and reducing power. The neuroprotective, antidiabetic and antioxidant potentials of the molecules were also compared with the commercial drugs, neostigmine and galantamine (anticholinesterases), acarbose (antidiabetic), BHA and Trolox (antioxidants), respectively. The results of the molecules’ inhibitory effects on the AChE indicated that the neuroprotective effects of all molecules, except for VDOPL (1) are much weaker than the anticholinesterases, neostigmine and galantamine. VDOPL (1) demonstrated a potent inhibitory effect on the AChE with IC50=1.53 mg/mL. Whereas, it was proved that all of the tested molecules showed the stronger inhibitory effects against BChE enzyme than AChE enzyme, and VDOPL (1) and V2-AFL (3) were found to be the most effective inhibitors against both AChE and BChE enzymes among the tested molecules. The results on the antidiabetic potentials of the molecules showed that all synthesized molecules except V2-AFL (3) and VAML (5) inhibited α-glucosidase enzyme more potently than the antidiabetic agent, acarbose. Among the tested molecules, 4-aminophenol (IC50=0.44 mg/mL) and VDOPL (1) (IC50=0.45 mg/mL) were found to be the strongest inhibitors on α-glycosidase activity. However, all the tested molecules demonstrated the weaker inhibition effects as compared with the inhibition effect of the acarbose against α-amylase. Moreover, all of the tested molecules exhibited strong antioxidant potentials. Based on the current results, VDOPL (1) stands out as a target molecule for in vivo as well as clinical studies due to its potent neuroprotective, antidiabetic and antioxidant potentials. In addition, the antidepressant properties of p-vanillin, the Schiff bases and the secondary amines were tested for the first time against the MAO-A enzyme and their antidepressant properties were compared with the MAO inhibitor, clorgiline. The current results showed that p-vanillin (IC50=0.72 mg/mL), V2-AFL (3) (IC50=0.71 mg/mL), V2-AFA (7) (IC50=1.22 mg/mL) and V4-AFA (8) (IC50=2.36 mg/mL) are the potential antidepressant agents, despite the fact that the antidepressant effects were lower than that of clorgiline (IC50=0.34 mg/mL). However, the in vivo antidepressant properties, safeties and toxicities of the molecules should be investigated with further studies.