Design and synthesis of new caffeine derivatives as multitarget agents for the therapy of Alzheimer’s disease

BISCUSSI, BRUNELLA; PÉREZ, CONCEPCIÓN; RODRÍGUEZ-FRANCO, MARÍA ISABEL; ANA PAULA MURRAY

Granada

Conferencia; XIV Spanish Drug Discovery Network Meeting; 2022

Spanish Drug Discovery Network y Universidad de Granada

To address the multifactorial nature and complexity of Alzheimer’s disease (AD), thesearch for new multitarget agents is emphasized. Three molecular targets for the treatment ofthis disease are the enzyme acetylcholinesterase (AChE), the nicotinic acetylcholine receptors(nAChR) and monoamine oxidases (MAO) enzymes. In a previous work, we confirmed thatcaffeine-pyrrolidine hybrids can inhibits AChE activity and activate both muscle and α7 nAChRswith high potency. Based on this background, we have designed and synthesized new caffeineanalogues, with the aim of obtaining more powerful multifunctional derivatives destined tostimulate cholinergic signage.Appling once again a simple and efficient methodology developed in our researchgroup, a series of new derivatives were synthesized from theophylline and theobromine asstarting material. These natural alkaloids reacted with the corresponding dibromoalkane (n= 3,5, 7) and subsequently with a amine (pyrrolidine, 1-(2-aminoethyl)pyrrolidine and different Nbenzylpiperidines:1-benzylpiperidin-4-amine, (1-benzylpiperidin-4-yl)methanamine, and 2-(1-benzylpiperidin-4-yl)ethan-1-amine). These two synthetic steps were carried out in amicrowave reactor (CEM Discover). Five of the new caffeine analogues obtained wereevaluated as AChE inhibitors and all were potent AChE inhibitors. Compounds 2a and 4ashowed the strongest effect inhibited AChE with IC50 values at the nanomolar scale.Complementary studies are being carried out on their activity as MAO inhibitors and as nAChRactivators.