Sequential Multicomponent Reactions Applied to the Synthesis of Furoxan Nitrogen-Heterocycles as Nitric Oxide Donors with Potential Antitumor Activity

High levels of nitric oxide (NO) in the tumor microenvironment lead to cytotoxic effects against tumor cells (antitumor activity). In this context, exogenous NO donors such as the 1,2,5-oxadiazole-2-oxide scaffold (furoxan), can act as potential antitumor compounds. Sequential multicomponent reactions are useful synthetic tools for the construction of structurally diverse nitrogen-fused heterocycles containing the furoxan scaffold. This study applies sequential Groebke-Blackburn-Bienaymé (GBB) and Passerini multicomponent reactions to synthesize novel furoxan-imidazo[1,2-a]pyridines with potential antitumor activity. First, a microwave-assisted GBB reaction followed by alkaline hydrolysis led to carboxylic acid-functionalized imidazopyridines in 85% yield. Subsequent Passerini reactions with furoxan aldehydes and isocyanides afforded ten furoxan-imidazo[1,2-a]pyridines (29–75% yield), with NO release capacities ranging from 1.0 to 9.7 μM. In vitro antiproliferative screening against colorectal cancer lines identified three highly active compounds: HCT-116 (IC₅₀ = 1.9–6.4 μM), SW837 (IC₅₀ = 1.2–1.4 μM), and SW1116 (IC₅₀ = 3.1–7.3 μM).