Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France.
Molecules. 2024 Aug 14;29(16):3847. doi: 10.3390/molecules29163847.
The adenosine A receptor (AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine ( (AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound showed a high affinity for AR with a value of 5 nM and demonstrated antagonist activity with an IC of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (, = 21 nM; , = 15 nM) and functional antagonist activities (, IC = 9 µM; , IC = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of AR antagonists for therapeutic applications.
腺嘌呤核苷 A 受体 (AR) 已被确定为治疗神经退行性疾病和癌症的治疗靶点。近年来，我们强调了 2-氨基喹唑啉杂环作为设计新型 AR 拮抗剂的有前途的支架，以 6-溴-4-(呋喃-2-基)喹唑啉-2-胺 (AR = 20 nM) 为例。在这里，我们报告了具有 C6-和 C7-取代基的新型 2-氨基喹唑啉衍生物的合成，以及在 C2-位引入含有叔胺的氨基烷基链，以增强拮抗剂活性和溶解度性质。化合物 对 AR 具有高亲和力， 值为 5 nM，并在环 AMP 测定中表现出 6 µM 的 IC 拮抗剂活性。引入氨基戊基哌啶和 4-[(哌啶-1-基)甲基]苯胺取代基，在保持结合亲和力 (, = 21 nM;, = 15 nM) 和合成化合物的功能拮抗剂活性 (, IC = 9 µM;, IC = 5 µM) 的同时，提高了溶解度。本研究为 AR 拮抗剂的治疗应用提供了未来发展的思路。
