Synthesis of Pyrazoline derivatives, condensation of β-dicarbonyl compounds with isoniazid (INH), and their biological evaluation as multitarget anti-Alzheimer' disease agents

Alzheimer's disease is a complex and progressive form of dementia. Its treatment relies on the behavioral and cognitive symptoms of an individual. Inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is a primary strategy used for treating Alzheimer's disease. Pyrazoline is a well-recognized nitrogen-containing five-membered heterocyclic skeleton. The unique structure of pyrazoline gives it a spatial configuration that leads to the multiple substitution pattern and advanced pharmacological properties. In an attempt to identify potent acetylcholine (AChE) and butyrylcholinesterase (BChE) inhibitors, new pyrazoline derivatives (IIIa-IIId) were synthesized using conventional method. The synthesised compounds were purified by column chromatography and were analysed using LCMS, 1HNMR, 13CNMR, and Mass Spectroscopic HR-MS techniques. The derivatives underwent initial screening for in-vitro antioxidant potential. The most potent compound, IIIa, showed IC50 values of 22.15 and 25.09 nM against AChE and BChE, respectively. Additionally, in-silico screening with AutoDock tools indicated that IIIa had promising binding affinities to the targets, with a binding energy (- 8.9 kcal/mol) comparable to donepezil (- 10.6 kcal/mol). The binding pattern of IIIa to AChE's active site justified its in-vitro inhibitory activity. These findings suggest that compound IIIa has potential as a new therapeutic agent for Alzheimer's disease and is suitable for pre-clinical evaluation.