New 2-hydrazinothiazole derivatives as potential MAO-A, MAO-B, AChE, and BChE inhibitors

Abstract

The incidence of neurodegenerative Alzheimer’s and Parkinson’s diseases is increasing worldwide every day, and treatment options are currently very limited. There is no definitive cure for these diseases, and the drugs available in clinical practice only provide symptomatic relief without halting the progression of neurodegeneration. One commonly employed strategy in the treatment of Alzheimer’s and Parkinson’s diseases is to return neurotransmitter levels by inhibiting enzymes like cholinesterase (ChE) and monoamine oxidase (MAO). In this research, we focused on investigating the therapeutic potential of 2-[2-(substituted benzylidene)hydrazinyl]-4-(substituted phenyl)thiazole derivatives (2a–2h) by incorporating hydrazine, known for its inhibitory effects on monoamine oxidases, into the structure of molecules that inhibit acetylcholinesterase. Thiazole ring was included in these derivatives due to its reported inhibitory activity against both cholinesterases and monoamine oxidase enzymes. When the enzyme inhibition activities were evaluated, it was determined that compounds 2c, 2d, and 2h showed the highest inhibitory activity against AChE, while compounds 2f and 2h expressed the highest activity against MAO-B. It was determined that compound 2h had the highest inhibitory activity on both AChE (0.030 ± 0.001 μM) and MAO-B (0.048 ± 0.002 μM) and compound 2h was the only compound with conspicuous dual inhibitory activity. Furthermore, molecular docking calculations and molecular dynamics simulations were found to agree with experimental results.