Novel acrylonitrile derived imidazo[4,5-b]pyridines as antioxidants and potent antiproliferative agents for pancreatic adenocarcinoma.

We present the design, synthesis, computational analysis, and biological assessment of several acrylonitrile derived imidazo[4,5-b]pyridines, which were evaluated for their anticancer and antioxidant properties. Our aim was to explore how the number of hydroxy groups and the nature of nitrogen substituents influence their biological activity. The prepared derivatives exhibited robust and selective antiproliferative effects against several pancreatic adenocarcinoma cells, most markedly targeting Capan-1 cells (IC50 1.2-5.3 µM), while their selectivity was probed relative to normal PBMC cells. Notably, compound 55, featuring dihydroxy and bromo substituents, emerged as a promising lead molecule. It displayed the most prominent antiproliferative activity without any adverse impact on the viability of normal cells. Furthermore, the majority of studied derivatives also exhibited significant antioxidative activity within the FRAP assay, even surpassing the reference molecule BHT. Computational analysis rationalized the results by highlighting the dominance of the electron ionization for the antioxidant features with the trend in the computed ionization energies well matching the observed activities. Still, in trihydroxy derivatives, their ability to release hydrogen atoms and form a stable O-H⋯O•⋯H-O fragment upon the H• abstraction prevails, promoting them as excellent antioxidants in DPPH• assays as well.

Synthesis and Antiproliferative Activity of 2,6-Disubstituted Imidazo[4,5-b]pyridines Prepared by Suzuki Cross Coupling.

A series of novel 2,6-diphenyl substituted imidazo[4,5-b]pyridines was designed and synthesized using optimized Suzuki cross coupling to evaluate their biological activity in vitro. The conditions of the Suzuki coupling were evaluated and optimized using a model reaction. To study the influence of the substituents on the biological activity, we prepared N-unsubstituted and N-methyl substituted imidazo[4,5-b]pyridines with different substituents at the para position on the phenyl ring placed at position 6 on the heterocyclic scaffold. Antiproliferative activity was determined on diverse human cancer cell lines, and the selectivity of compounds with promising antiproliferative activity was determined on normal peripheral blood mononuclear cells (PBMC). Pronounced antiproliferative activity was observed for p-hydroxy substituted derivatives 13 and 19, both displaying strong activity against most of the tested cell lines (IC50 1.45-4.25 µM). The unsubstituted N-methyl derivative 19 proved to be the most active derivative. There was a dose-dependent accumulation of G2/M arrested cells in several cancer cell lines after exposure to compound 19, implying a cell cycle-phase-specific mechanism of action. Additionally, the novel series of derivatives was evaluated for antiviral activity against a broad panel of viruses, yet the majority of tested compounds did not show antiviral activity.