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.

Antioxidant-conjugated 1,2,4-Triazolo[4,3-a]pyrazin-3-one Derivatives: Highly Potent and Selective Human A2A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain

Dal Ben, Diego;Marucci, Gabriella;Buccioni, Michela;Volpini, Rosaria;
2019-01-01

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.
2019
262
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J. Med. Chem. 2019, 62, pp. 8511−8531.pdf

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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/429474
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