LAUSR

Natural products have significantly contributed to drug discovery for neurodegenerative diseases. Caffeine is one of the well‐known central nervous system(CNS)‐active natural products. Besides its CNS stimulant properties, it is a mild inhibitor of acetylcholinesterase (AChE) and possesses memory‐enhancing properties. The present work aimed to improve the AChE inhibition activity of the caffeine. The rationally designed caffeine‐based triazoles were synthesized and evaluated in vitro for cholinesterase and β‐site amyloid precursor protein cleaving enzyme‐1 (BACE‐1) inhibitory activities. The attachment of triazole to the caffeine enhances its AChE inhibition activity from half‐maximal inhibitory concentration (IC50) of 129 µM to 0.49 µM (derivative, 6l). The caffeine core interacts with the peripheral anionic site, whereas the benzyl triazole occupies the catalytic anionic site located at the bottom of the active site gorge. The structure–activity relationship revealed that the four‐atom ester linker is superior to shorter linkers for connecting the caffeine core to the triazole. The 2,6‐difluorobenzyl triazole‐linked caffeine derivative, 6d, exhibits dual inhibition of AChE and BACE‐1 with IC50 values of 1.43 and 10.9 µM, respectively. The derivative 6d inhibits AChE via a mixed‐type mode with an inhibition rate constant (Ki) value of 2.35 μM, which was corroborated by docking studies. The triazole 6d has an acceptable stability profile in human liver microsomes (t1/2 = 54 min) and was found to possess CNS permeability when evaluated using the parallel artificial membrane permeability blood–brain barrier assay. The results presented herein warrant investigating caffeine‐based triazoles in preclinical models of Alzheimer's disease.