Spiro-benzopyran structure: a new scaffold for cardioprotection

Many evidences underline that the opening of mitochondrial ATP-sensitive potassium channels (mitoKATP) is cardioprotective in ischemia-reperfusion process. Due to different localization of KATP channel in various part of the cell (sarcolemmal and inner mitochondrial membrane) and its distribution in many tissues (smooth muscle, pancreas, miocardiocytes) the possibility to manipulate the KATP channel status has become an important target in the treatment of various diseases, including diabetes, hypertension, heart failure and ischemia. In particular, the selective activation of mitoKATP channels as protective mechanism against ischemia represents a recent and intriguing field of medicinal and pharmacological investigation. Recently, we planned the synthesis of a limited number of 4-spiro-morpholone (A) and 4-spiromorpholine (B) compounds in order to evaluate their cardioprotective activity. These preliminary works led us to identify new compounds endowed of a good cardioselectivity1,2 and lacking of some systemic and deleterious effects such as hypotension and vasodilation. With the aim to investigate more deeply this kind of spiro-like structure and the influence of some molecular modifications on their cardioprotective properties, we synthesized new derivatives in which the spiro-nucleus in C4 position is a five-membered heterocycle such as the oxazolidine (C) or the 5-imino-oxazolidine (D) or a morpholone isoster (i.e.: thiomorpholone (E)). The pharmacological evaluation of the cardioprotective effects on cultured cardiomyoblastic cells allow us to select the most interesting compounds to submit to further pharmacological investigations on different experimental models of ischemia/reperfusion.