Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica , Università degli Studi di Firenze , Via Ugo Schiff, 6 , 50019 Sesto Fiorentino , Italy.
Scuola di Scienze del Farmaco e dei Prodotti della Salute , Università degli Studi di Camerino , Via S. Agostino 1 , 62032 Camerino , Macerata , Italy.
J Med Chem. 2019 Sep 26;62(18):8511-8531. doi: 10.1021/acs.jmedchem.9b00778. Epub 2019 Sep 10.
New 8-amino-6-aryl-1,2,4-triazolo[4,3-]pyrazin-3-ones were designed to obtain dual antioxidant-human A adenosine receptor (hA 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-but-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines () were potent and selective hA AR antagonists ( = 0.17-54.5 nM). Compounds , , and , featuring antioxidant moieties, and compound , lacking the antioxidant functionality, reduced oxaliplatin-induced toxicity in microglia cells, the most active being the lipoyl-derivative and the (4-hydroxy-3,5-di--butyl)benzoyl-analogue which were effective in reducing the oxygen free radical level. The lipoyl-derivative was also able to revert oxaliplatin-induced neuropathy in the mouse. In vivo efficacy of makes it a promising neuroprotective agent in oxidative stress-related diseases.
新型 8-氨基-6-芳基-1,2,4-三唑并[4,3-a]吡嗪-3-酮被设计用来获得双重抗氧化剂-人类 A 腺苷受体（hAAR）拮抗剂。合成了两组化合物，第一组在 6-位具有酚环，第二组在 6-苯基环上带有不同连接子的 lipoyl 和 4-羟基-3,5-二丁基苯甲酰基残基。几种新型三唑并吡嗪（）是强效和选择性的 hAAR 拮抗剂（=0.17-54.5 nM）。具有抗氧化功能的化合物、和，以及缺乏抗氧化功能的化合物，可以减轻微胶质细胞中奥沙利铂诱导的毒性，其中最活跃的是 lipoyl 衍生物和（4-羟基-3,5-二--丁基）苯甲酰类似物，它们可以有效降低氧自由基水平。lipoyl 衍生物还能够逆转奥沙利铂诱导的小鼠神经病变。在体内，使它成为氧化应激相关疾病中一种有前途的神经保护剂。
