Synthesis of Alpha‐Acyloxy‐(1,2,5‐Oxadiazole‐2‐Oxide) Carboxamides via Passerini Multicomponent Reaction. Evaluation of Nitric Oxide‐Releasing and Anti‐Proliferative Properties

ABSTRACT High intracellular levels of nitric oxide (NO) lead to cytotoxic effects against tumor cells. In this context, organic compounds containing the 1,2,5‐oxadiazole‐2‐oxide (furoxan) scaffold play an important role as exogenous NO donors under physiological conditions and, therefore, may act as potential antitumor agents. Multicomponent reactions are considered useful synthetic tools for the rapid and efficient construction of structurally diverse organic compounds, such as furoxan hybrid molecules. Herein, we report the Passerini multicomponent reaction applied to the synthesis of nitric oxide‐releasing furoxan based α‐acyloxy carboxamides as well as their NO release capacity and anti‐proliferative activity. A total of 23 α‐acyloxy‐(1,2,5‐oxadiazole‐2‐oxide) carboxamides were synthesized using the Passerini reaction under microwave heating, in moderate to excellent yields (67%–95%). The quantification of nitric oxide release demonstrated that all compounds were capable of releasing NO within the range of 0.8–7.4 μM. In vitro anti‐proliferative assays were carried out with mama (MCF‐7), melanoma (SK‐MEL‐28), and prostate (LNCaP) cancer cell lines, as well as normal cell line (HUVEC). Compounds 21 and 22 showed moderate anti‐proliferative activity (IC 50 = 95.5 and 66.6 μM, respectively) against LNCaP cells. This study demonstrated the potential of α‐acyloxy‐(1,2,5‐oxadiazole‐2‐oxide) carboxamides as a promising class of compounds to be explored for antitumor activity.