Design and synthesis of new derivatives of the 1,3,5-triazine-isatin Schiff base as anti-Alzheimer compounds

Abstract

Introduction: Alzheimer's disease is known as an irreversible neurodegenerative disease that mostly affects elderly people. Since several factors are involved in the process of this disease, the compounds directed to several targets are considered as beneficial compounds for its control. Isatin and 1,3,5-triazine are compounds with different biological effects and their different derivatives had anti-Alzheimer effects.Aims: The aim of this research was to design, synthesize and biological evaluations of the isatin-1,3,5-triazine-aniline/benzylamine hybrids as multi-target directed ligand against Alzheimer's disease. Methods: In this thesis the two groups of isatin-1,3,5-triazine-aniline 8(a-o) and isatin-1,3,5-triazine-benzylamine 8(p-z) derivatives were designed and synthesized. These molecules were evaluated as multi-target directed ligand that inhibit the cholinesterase enzymes, have antioxidant effects and could chelate to biometal ions, which Ellman’s colorimetric assay, the DPPH method, and the UV-Vis method was used in order to check these properties, respectively. Auto dock 4.2 software was used to investigate the mode of interaction between the compounds and the active site of cholinesterase enzymes.Results: The designed compounds were synthesized by different methods and their final structure confirmed by 1H, 13CNMR, IR and mass spectrometry methods. The range of molecules IC50 for acetylcholinesterase and butyrylcholinesterase enzymes were 0.2-734.5nM and 0.02-3.88μM, respectively. The compounds with hydroxy group had acceptable antioxidant effects. Changes in the compounds and biometal ions mixture UV-Vis spectrum confirmed these compounds have a good ability to form complexes with the studied ions. Molecular docking studies confirmed these compounds have effective interactions with the active site residues of the acetyl/butyrylcholinesterase enzymes.Conclusion: The results showed this study molecules are good scaffolds as multi-target directed ligands for Alzheimer's disease, and have good potential for optimization and further investigations as lead compounds.