3-acetyl-5-acylpyridin-2(1H)-ones and 3-acetyl-7,8-dihydro-2,5(1H,6H)-quinolinediones: synthesis, cardiotonic activity and computational studies

A series of milrinone analogues, namely 6-substituted 3-acetyl-5-acylpyridi n-2(1H)-ones 4a-c, e, f and 7-substituted or unsubstituted 3-acetyl-7,8-dih ydro-2,5(1H,6H)-quinolinediones 4g-j, in which the cyano group was replaced by the acetyl function, was prepared. In a preliminary pharmacological inv estigation on spontaneously beating atria from reserpine-treated guinea-pig s, all new compounds did not induce any inotropic effect equivalent or high er than that of the milrinone chosen as the reference compound. In order to rationalise how the structure modifications influence the activity and the selectivity of the title compounds, a computational study has been perform ed. The important role of the substituents in position-3 and -6 on the pyri done nucleus has been highlighted. (C) 1999 Elsevier Science S.A. All right s reserved.