ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

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

Madiha Kanwal, Sadia Sarwar, Humaira Nadeem, Rehman Zafar, and Khondaker Miraz Rahman

Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan

E-mail: madiha.kanwal@riphah.edu.pk

Received: 28 August 2023  Accepted: 14 November 2023

Abstract:

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.

Graphical abstract

Keywords: Alzheimer; Pyrazoline derivatives; Molecular docking; Acetylcholine esterase (AChE); Butyrylcholine esterase (BChE); Anti-oxidant

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-03224-1

Chemical Papers 78 (3) 2033–2042 (2024)