Antioxidant-Conjugated 1,2,4-Triazolo[4,3- a ]pyrazin-3-one Derivatives: Highly Potent and Selective Human A 2A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain

New 8-amino-6-aryl-1,2,4-triazolo[4,3- ]pyrazin-3-ones were designed to obtain dual antioxidant-human A adenosine receptor (hA AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di- but-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines ( ) were potent and selective hA AR antagonists ( = 0.17-54.5 nM). Compounds , , and , featuring antioxidant moieties, and compound , lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative and the (4-hydroxy-3,5-di- -butyl)benzoyl-analogue which were effective in reducing the oxygen free radical level. The lipoyl-derivative was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of makes it a promising neuroprotective agent in oxidative stress-related diseases.