To address the multifactorial nature and complexity of Alzheimer’s disease (AD), the search for new multitarget agents is emphasized. Three molecular targets for the treatment of this disease are the enzyme acetylcholinesterase (AChE), the nicotinic acetylcholine receptors (nAChR) and monoamine oxidases (MAO) enzymes. In a previous work, we confirmed that caffeine-pyrrolidine hybrids can inhibits AChE activity and activate both muscle and α7 nAChRs with high potency. Based on this background, we have designed and synthesized new caffeine analogues, with the aim of obtaining more powerful multifunctional derivatives destined to stimulate cholinergic signage.

Appling once again a simple and efficient methodology developed in our research group, a series of new derivatives were synthesized from theophylline as starting material. This natural alkaloid reacted with the corresponding dibromoalkane (n= 6, 8) and subsequently with a secondary amine (pyrrolidine, piperidine, diethylamine and 1-methylpiperazine). These two synthetic steps were carried out in a microwave reactor (CEM Discover). All the new caffeine analogues inhibited AChE. Among them, compound Teof-C6-DEA (7-(6-(diethylamino)hexyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione) showed the strongest effect (IC₅₀ = 0.14 µM) on AChE. Complementary studies are being carried out on their activity as MAO inhibitors and as nAChR activators.