Design, synthesis, and pharmacological evaluation of thiazolo[5,4-d]pyrimidines hybridized with lipoic acid or catechol. Novel A2A adenosine receptor antagonists in neuroinflammatory diseases.

Oxidative stress and inflammation are closely interconnected processes involved in the pathogenesis of neurodegenerative diseases. Adenosine, acting through the A2A receptor subtype, plays a crucial role in inflammatory processes, making A2A 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 A2A AR antagonism with antioxidant activity. All compounds displayed nanomolar affinity and antagonist activity at the A2A AR, while compound 1 also exhibited activity at the A2B 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 A2A AR antagonists, supporting further investigation of this series for the development of new strategies for the treatment of neuroinflammatory diseases.