M. Falsini, D. Catarzi, F. Varano
Aug 27, 2019
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0
Influential Citations
12
Citations
Quality indicators
Journal
Journal of medicinal chemistry
Abstract
New 8-amino-6-aryl-2-phenyl-1,2,4-triazolo[4,3-a]pyrazine-3-ones were designed to obtain dual antioxidant-human A2A adenosine receptor (hA2A 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-terbut-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines (1-21) were potent and selective hA2A AR antagonists (Ki= 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-tert-butyl)phenyl- 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 mouse. In vivo efficacy of 15 makes it a promising neuroprotective agent in oxidative stress-related diseases.