Development of 2,6,9-trisubstituted purines as neuroprotective agents targeting butyrylcholinesterase and cannabinoid CB2 receptor

Abstract

Neurodegenerative diseases (ND) are a diverse group of disorders characterized by the progressive loss of neurons, leading to severe cognitive and physical impairments. Parkinson's, Alzheimer's, and Huntington's diseases are among the most prominent examples, with their prevalence steadily increasing due to the aging global population. In 2009, approximately 50 million people worldwide were affected by ND, and current projections suggest this number will exceed 115 million by 2050. The development of ND is complex and multifactorial, influenced by genetic predispositions, environmental factors, aging, and cellular dysfunction. A significant challenge in addressing these diseases lies in the absence of curative treatments; existing therapies are limited to symptom management and enhancing quality of life.

We report the synthesis and biological evaluation of a series of 2,6,9-trisubstituted purine derivatives, some of which exhibited strong neuroprotective effects in cellular models of mitochondrial (3-nitropropionic acid-induced) and oxidative (glutamate-induced) stress. Also, several compounds functioned as selective butyrylcholinesterase (BChE) inhibitors and three of which showed CB2 receptor agonist activity, supporting their potential as multifunctional agents for neurodegenerative disorders. In vitro assays confirmed their protective effects across multiple cellular pathways, including reduction of apoptosis, oxidative stress, and mitochondrial permeability transition. Notably, compound 3e emerged as the most effective derivative, combining strong BChE inhibition, CB2 receptor activation, and cytoprotective effects. These findings identify 2,6,9-trisubstituted purines as promising scaffolds for the development of multi-target-directed ligands in neurodegenerative disease therapy.