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.