Xanthine–Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases

Multitarget drugs based on a hybrid dopamine–xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A2A adenosine receptor (A2AAR) antagonistic properties further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D2 (D2R) agonistic activity. While all compounds showed MAO-B in nanomolar range mostly combined submicromolar A2AAR affinity, enhancement PDE-inhibitory D2R-agonistic activity was additionally reached some through various structural modifications. The final multitarget also promising antioxidant vitro. In order evaluate their neuroprotective effect, representative ligands tested cellular model toxin-induced neurotoxicity. As result, protective effects against oxidative stress neuroblastoma cells observed, confirming utility applied strategy. Further evaluation newly preclinical models Alzheimer’s Parkinson’s diseases is warranted.