{"_":"Design, synthesis, and pharmacological evaluation of thiazolo[5,4-d]pyrimidines hybridized with lipoic acid or catechol. Novel A adenosine receptor antagonists in neuroinflammatory diseases.","sub":["2A"]}
氧化应激与炎症是神经退行性疾病发病机制中密切相关的两个过程。腺苷通过A受体亚型在炎症过程中发挥关键作用，使A腺苷受体（AR）拮抗剂成为有前景的治疗候选物。本研究设计并合成了三种噻唑并[5,4-d]嘧啶衍生物，分别引入抗氧化部分，即儿茶酚（化合物1）和硫辛酸（化合物2和3），以获得兼具A AR拮抗作用与抗氧化活性的配体。所有化合物均对A AR表现出纳摩尔级亲和力和拮抗活性，而化合物1还对A AR具有活性。在无细胞实验（DPPH）中，化合物1表现出显著的自由基清除活性。在LPS刺激的BV2小胶质细胞中，这些衍生物显著减少了一氧化氮的产生并改善了小胶质细胞形态。此外，这些化合物增强了抗炎细胞因子的释放。值得注意的是，化合物1显著降低了ERK磷酸化水平，表明其调节了细胞内炎症信号通路。总体而言，这些结果凸显了基于噻唑并[5,4-d]嘧啶的杂合体作为抗炎A AR拮抗剂的潜力，支持对该系列化合物进行进一步研究，以开发治疗神经炎症性疾病的新策略。
Oxidative stress and inflammation are closely interconnected processes involved in the pathogenesis of neurodegenerative diseases. Adenosine, acting through the A receptor subtype, plays a crucial role in inflammatory processes, making A adenosine receptor (AR) antagonists promising therapeutic candidates. In this study, we designed and synthesized three thiazolo[5,4-d]pyrimidine derivatives incorporating antioxidant moieties, namely catechol (compound 1) and lipoic acid (compounds 2 and 3), to obtain ligands combining A AR antagonism with antioxidant activity. All compounds displayed nanomolar affinity and antagonist activity at the A AR, while compound 1 also exhibited activity at the A AR. In cell-free assays (DPPH), compound 1 showed pronounced radical-scavenging activity. In LPS-stimulated BV2 microglial cells, the derivatives significantly reduced nitric oxide production and improved microglial morphology. Furthermore, the compounds enhanced the release of anti-inflammatory cytokines. Notably, compound 1 markedly decreased ERK phosphorylation levels, indicating modulation of intracellular inflammatory signaling pathways. Overall, these results highlight the potential of thiazolo[5,4-d]pyrimidine-based hybrids as anti-inflammatory A AR antagonists, supporting further investigation of this series for the development of new strategies for the treatment of neuroinflammatory diseases.
Sara Calenda, Katarina Mihajlovic, Flavia Varano, Daniela Catarzi, Costanza Ceni, Elisa Marinari, et al. {"_":"Design, synthesis, and pharmacological evaluation of thiazolo[5,4-d]pyrimidines hybridized with lipoic acid or catechol. Novel A adenosine receptor antagonists in neuroinflammatory diseases.","sub":["2A"]}. Bioorganic chemistry. 2026; doi:10.1016/j.bioorg.2026.110166.
Sara Calenda, Katarina Mihajlovic, Flavia Varano, Daniela Catarzi, Costanza Ceni, Elisa Marinari, et al (2026). {"_":"Design, synthesis, and pharmacological evaluation of thiazolo[5,4-d]pyrimidines hybridized with lipoic acid or catechol. Novel A adenosine receptor antagonists in neuroinflammatory diseases.","sub":["2A"]}. Bioorganic chemistry. https://doi.org/10.1016/j.bioorg.2026.110166
Sara Calenda, Katarina Mihajlovic, Flavia Varano, Daniela Catarzi, Costanza Ceni, Elisa Marinari, et al. {"_":"Design, synthesis, and pharmacological evaluation of thiazolo[5,4-d]pyrimidines hybridized with lipoic acid or catechol. Novel A adenosine receptor antagonists in neuroinflammatory diseases.","sub":["2A"]}[J]. Bioorganic chemistry, 2026 doi:10.1016/j.bioorg.2026.110166.
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