Synthesis and Structural Characterization of the Trimeric Furoxan (= Furazan 2-Oxide) System,a New Potent Vasodilating Moiety

The synthesis, structural characterization, and NO donor properties of a series of terfuroxan (= terfurazan trioxide) derivatives 1a–h and 2a–j are reported (Schemes 1 and 2). Structural assignments were confirmed principally by mass and ¹³C- and ¹H-NMR spectroscopy. The extent and the initial rate of NO release in the presence of thiol cofactor was evaluated for each derivative. Vasodilator effects of all the terfuroxan derivatives were evaluated on endothelium-denuded strips of rat aorta precontracted with noradrenaline. Concentration-response curves were also evaluated in the presence of 10 m?M oxyhemoglobin (HbO₂), a well known NO scavenger. The whole series displays high vasodilating potency; the most active terfuroxans ( 1a, b, g and 2i ) are 5–10 times as potent as glyceryl trinitrate taken as reference (see Table 3). The potency decrease observed in the presence of HbO₂ agrees with the involvement of NO in the vasorelaxing action. The 4,3′:4′,4″ connection (series 1 ; furoxan numbering) gives rise to the most potent compounds. The conformational factors seem to play important roles in the activity. No clear relationship between physico-chemical properties of the substituents and potencies of derivative emerges.