Novel imidazo[1,2-a][1,8]naphthyridine derivatives and their preliminary in vitro assays for the evaluation as positive inotropes

N Heterocycles present in over 50 % of the US Food and Drug Administration (FDA) approved small-molecule drugs, are of great interest to medicinal chemists to date. Six novel compounds ( S5 - S10 ) with such fused N -heterocyclic system namely imidazo[1,2- a ][1,8]naphthyridine, derived from imidazole and 1,8-naphthyridine scaffolds, have been synthesized in this study. Following the three-step reaction scheme, these six compounds were further characterized using spectroscopic techniques including 1 H NMR, 13 C NMR, and LCMS; prior to evaluation of their aqueous kinetic solubilities. Molecular docking studies were performed using Na + /K + -ATPase and PDE3B enzymes to evaluate their potential for positive inotropy. It was found that compounds S5 - S10 had more potential to bind with the PDE3B enzyme than Na + /K + -ATPase, among which S6 and S8 had the best binding affinities and interactions with the former. This trend was correlated to in vitro activity in H9c2(2–1) cardiomyoblasts as the compounds failed to inhibit Na + /K + -ATPase significantly, while S5, S9 , and S10 preliminarily indicated PDE3 inhibition via increasing intracellular cAMP concentrations. Among these three compounds, compound S9 further demonstrated cell viability (IC 50 >100 µM) that was comparable to the marketed positive inotrope digoxin , and was predicted as a weak/moderate hERG channel blocker .