Antioxidant-Conjugated 1,2,4-Triazolo4,3-apyrazin-3-one Derivatives: Highly Potent and Selective Human A(2A) Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain

摘要

New 8-amino-6-aryl-1,2,4-triazolo4,3-apyrazin-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-tertbut-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines (1-21) were potent and selective hA(2A) AR antagonists (K-i = 0.17-54.5 nM). Compounds 11, 15, and 21, featuring antioxidant moieties, and compound 12, lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative 15 and the (4-hydroxy-3,5-di-tertbutyl)benzoyl-analogue 21 which were effective in reducing the oxygen free radical level. The lipoyl-derivative 15 was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of 15 makes it a promising neuroprotective agent in oxidative stress-related diseases.