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.
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| Abstract |
New 8-amino-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-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-tertbut-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)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.
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| Authors | Matteo Falsini, Daniela Catarzi, Flavia Varano, Costanza Ceni, Diego Dal Ben, Gabriella Marucci, Michela Buccioni, Rosaria Volpini, Lorenzo Di Cesare Mannelli, Elena Lucarini, Carla Ghelardini, Gianluca Bartolucci, Marta Menicatti, Vittoria Colotta |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 18 Pg. 8511-8531 (09 26 2019) ISSN: 1520-4804 [Electronic] United States |
| PMID | 31453698 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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