Synthesis of some new hydrazone derivatives, anti-alzheimer activities and molecular modeling studies

Within the scope of this thesis, the synthesis of 12 compounds is aimed, in which the synthesis and biological evaluation of pyridazinones containing (2-fluorophenyl) piperazine structure, designed for multiple enzyme targets and expected to act as an AChE, MAO-A and MAO-B inhibitor. Synthesis started with the reaction of commercially available 3,6-dichloropyridazine with 2-fluorophenylpiperazine. The obtained 3-chloro-6- [4-(2-fluorophenyl) piperazin-1-yl]pyridazine molecule is hydrolyzed in glacial acetic acid and 6-[4-(2fluorophenyl) piperazin-1-yl]-3(2H)pyridazinone compound was reached. Then, from the treatment with ethyl bromoacetate, the ester derivative was obtained, and in the next step, the last step of the starting materials, 6- [4- (2-fluorophenyl) piperazin-1-yl] -3 (2H) -pyridazinone-2-ylacetohydrazide, was obtained from the reaction with hydrazine hydrate. Result compounds were obtained by the reaction of substituted or nonsubstituted benzaldehydes and acetohydrazide molecule. The melting point of the obtained compounds were determined, their percentage yields were determined, the structures of the compounds were proved by various spectroscopic methods such as 1H-NMR, 13C-NMR and HRMS. AChE enzyme inhibition was determined by the Ellman method, but none of the compounds showed significant enzyme inhibitory activity. The recombinant human MAO-A and MAO-B inhibitory activities of the compounds were tested using kinuramine (0.06 mM) and benzylamine (0.3 mM), respectively. T6 was found to be the strongest MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 compound with an IC50 value of 0.039 µM. The inhibitory power for MAO-B increased more than para bromo substitution (T7) with meta bromo substitution (T6). T6 and T3 effectively inhibited MAO-A with IC50 values of 1.57 and 4.19 µM. Molecular insertion simulations with MAO binding sites gave higher insertion scores for T6 and T3 with MAO-B than for MAO-A. Conclusion: These results show that T3 and T6 are selective, reversible and competitive inhibitors of MAO-B and can be considered as leading candidates for the treatment of neurodegenerative disorders such as Alzheimer's disease.