Design and synthesis of new [4,5-b] and [4,5-c] imidazopyridines as potential fluorophores/inhibitors for Human Cyclooxygenase-1.

In recent years, a great deal of research effort has been devoted to identifying targeted fluorophores, for intraoperative detection of neoplastic bodies and real-time assessment of tumor borders to achieve complete tumor removal [1]. The aim of this work is to design, synthesize new aryl derivatives of [4,5-b] and [4,5-c] imidazopyridines as potential ligand/inhibitors of Cyclooxygenase-1, isoform definitively ascertained as a tumor-associated target in ovarian cancer. In this regard, it was possible to carry out a Structure-based virtual screening (SBVS) performed with the Fingerprints for Ligands and Proteins (FLAP) software, by taking advantage of the recently published crystallographic structure of human Cyclooxygenase-1 (hCOX1) [2]. In this preliminary step, we designed different imidazopyridine derivates, substituted on both the imidazole ring and the aromatic ring, as can be seen from Figure 1. Then, identified the pocket of hCOX1, it was possible to calculate binding poses of our compounds and differentiate highly active structures from less active or inactive structures. Based on the results of the SBVS, we select the most promising candidates for the synthetic phase: the strategy adopted involves the direct condensation between different benzaldehydes, previously treated with Na2S2O5, and the appropriate diaminopyridine. The products obtained were isolated, purified and characterized by NMR Spectroscopy and Mass Spectrometry. The synthesized compounds were finally tested to evaluate their binding/inhibitory activity and selectivity towards COX-1 enzyme.