Synthesis of caffeine derivatives and evaluation of their anticholinesterase activities

Abstract

Owing to the broad medicinal and agrochemical applications of cholinesterase inhibitors, the search for new molecules exhibiting this activity, particularly those with novel structural frameworks, is of great interest. Caffeine was selected as the base scaffold for the synthesis of new anticholinesterase compounds due to its neuroprotective effects and its favorable blood brain barrier permeability constant, which facilitates action in the central nervous system. In this study, six caffeine derivatives were synthesized (yields ranging from 51-95%), incorporating functional groups inspired by commercially available acetylcholinesterase (AChE) inhibitors. Among the compounds obtained, the brominated analog (CAF-Br (2)) stood out by exhibiting the highest inhibitory activity against AChE (55% inhibition at 50 μmol L-1). Computational studies conducted herein suggest that the formation mechanism of this derivative most likely proceeds via an electrophilic aromatic substitution (SEAr) pathway, rather than through a radical mechanism. In addition, molecular docking analyses, together with physicochemical parameter evaluations, indicate a possible association between smaller structural volumes and increased AChE inhibitory effects.