Molecules. 2026 Aug 13;31(16):2830. doi: 10.3390/molecules31162830.
ABSTRACT
A light-promoted C-H/C-H coupling of imidazo[1,2-a]pyridines with 5-(hetero)aryl-1,2,5-oxadiazolo[3,4-b]pyrazines was developed using a heterogeneous oxidative photocatalytic system based on molecular oxygen, nanosized TiO2, and light irradiation. The method provides direct access to C3-heteroarylated imidazo[1,2-a]pyridines under metal-free conditions and expands the synthetic utility of electron-deficient oxadiazolopyrazine partners in the construction of biheteroaryl scaffolds. The synthesized compounds were evaluated computationally using a fully connected convolutional correlation neural network based on multiple-docking energy spectra, which prioritized the series as potential COX-1 and COX-2 ligands. To test this prioritization experimentally, all 18 compounds were screened in fluorometric COX-1 and COX-2 inhibitor assays at 1 µM. Compound 3f emerged as a strong preliminary COX-1 hit at 1 µM (86.64 ± 5.18% inhibition), whereas 3h and 3l showed weaker COX-1 inhibition. No compound showed high or moderate COX-2 inhibition at the screening concentration; only weak COX-2 inhibitory signals were observed for several derivatives. Thus, the combined synthetic, computational, and enzymatic data identify compound 3f as the main COX-1-skewed hit in this series and provide a basis for further dose-response, selectivity, and cell-based anti-inflammatory studies. It should also be noted that the COX-1 inhibition assay used ovine COX-1, whereas the computational models were built on human COX-1 and COX-2 structures; this species difference is an additional reason to treat the in silico-experimental comparison as approximate.
PMID:42653912 | DOI:10.3390/molecules31162830