DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW MULTI-TARGET 4-METHYLTHIAZOLE DERIVATIVES FOR TREATMENT OF ALZHEIMER’S DISEASE

Objective: In this study, eight new 4-methylthiazole derivatives were designed and synthesized with the aim of exhibiting multi-target effects in the treatment of Alzheimer's disease. Their cholinesterase inhibitor activities, antioxidant properties, and metal chelator effects were tested in vitro.Material and Method: The title compounds were obtained using 4-methylthiazole-2-amine as the starting material. According to method A, intermediate 1 was synthesized by reacting the starting material with 3-chloropropionyl chloride. Subsequently, the title compounds (2a-f) were obtained via substitution reactions with suitable amine derivatives. The title compounds that could not be obtained by method A were prepared from the reaction of starting material with appropriate propanoic acid derivatives using method B. Structural analysis of the synthesized and purified final compounds were elucidated using 1H-NMR, 13C-NMR, and HRMS methods. The cholinesterase inhibitor effects of all synthesized compounds were determined using the modified Ellman method. Additionally, the antioxidant properties of all the compounds were measured using the DPPH and ORAC methods, and their metal-chelator effects were analysed using UV spectroscopy.Result and Discussion: The cholinesterase inhibitory effects of all title compounds were evaluated, and compounds 2c, 2f, and 3b were determined to be selective butyrylcholinesterase (BChE) inhibitors. Specifically, the 4-fluorobenzylpiperazine derivative compound 2c (IC50=8.96 μM) is the most potent selective BChE inhibitor in the series. In addition, all final compounds exhibit antioxidant properties according to the ORAC test. Also, all compounds chelate with different amounts of Cu(II), Fe(II), and Zn(II) ions.