Antioxidant-Conjugated 1,2,4-Triazolo[4,3-<i>a</i>]pyrazin-3-one Derivatives: Highly Potent and Selective Human A_2A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain

Abstract

New 8-amino-6-aryl-1,2,4-triazolo[4,3-<i>a</i>]pyrazin-3-ones were designed to obtain dual antioxidant-human A_2A adenosine receptor (hA_2A 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-<i>tert</i>but-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines (<b>1-21</b>) were potent and selective hA_2A AR antagonists (<i>K</i>_i = 0.17-54.5 nM). Compounds <b>11</b>, <b>15</b>, and <b>21</b>, featuring antioxidant moieties, and compound <b>12</b>, lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative <b>15</b> and the (4-hydroxy-3,5-di-<i>tert</i>-butyl)benzoyl-analogue <b>21</b> which were effective in reducing the oxygen free radical level. The lipoyl-derivative <b>15</b> was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of <b>15</b> makes it a promising neuroprotective agent in oxidative stress-related diseases.