Novel, Dual Target‐Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B

Annelated purinedione derivatives have been shown to act as possible multiple‐target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido‐ and diazepino[2,1‐f]purinedione derivatives were designed as dual‐target‐directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO‐B. This allowed 9‐(2‐chloro‐6‐fluorobenzyl)‐3‐ethyl‐1‐methyl‐6,7,8,9‐tetrahydropyrimido[2,1‐f]purine‐2,4(1H,3H)‐dione (13 e; Ki human A2AAR: 264 nM and IC50 human MAO‐B: 243 nM) to be identified as the most potent dual‐acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure‐activity relationships was complemented by molecular‐docking studies based on previously published X‐ray structures of the protein targets. Such dual‐acting ligands, by selectively blocking A2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO‐B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease Two for one: A series of f‐bond annelated xanthine ligands with expected dual A2AAR/MAO‐B inhibitory activity has been obtained. The lead compound that might act as dual ligand has potential for the treatment of Alzheimer's and Parkinsons’ diseases with expected symptomatic and neuroprotective effects. However, further structural modifications to improve its ADMET properties are required.