Synthesis and molecular docking analysis of novel hydrazone and thiosemicarbazide derivatives incorporating a pyrimidine ring: exploring neuroprotective activity

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The increasing global prevalence of Alzheimer’s disease necessitates the development of novel therapeutic approaches. Neurodegenerative diseases are associated with increased oxidative stress and levels of cholinesterase enzymes. Hence, the development of cholinesterase inhibitors and antioxidants may provide neuroprotective effects. Our study focused on the synthesis of a new series of hydrazone and thiosemicarbazide derivatives bearing a pyrimidine ring. The compounds of structures were characterized by FT-IR, 1H NMR, 13C NMR, and HR-MS spectroscopic methods. Compounds 3a and 4f were determined using COSY and HSQC spectra. Compared to the standard drug galantamine (IC50 = 4.82 ± 0.75 µM), compound 3d exhibited remarkable inhibitory activity against AChE (IC50 values of 20.15 ± 0.44 µM). This compound was more effective against BChE (IC50 = 36.42 ± 0.73 µM) than galantamine (IC50 = 45.54 ± 0.18 µM). Antioxidant assays revealed the robust antioxidant activity of compound 3d. Furthermore, docking studies have shown that the active site of enzymes interacts strongly with electron donors through hydrogen bonds, while the aromatic ring structure plays an active role in π interactions.