Novel imidazo[1,2-a][1,8]naphthyridine derivatives and their preliminary in vitro assays for the evaluation as positive inotropes
Document Type
Article
Publication Date
4-1-2025
Abstract
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 Nheterocyclic system namely imidazo1,2-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 H-1 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 (IC50>100 mu M) that was comparable to the marketed positive inotrope digoxin, and was predicted as a weak/moderate hERG channel blocker.
Keywords
N -heterocycle, Heart failure, Positive inotropes, H9c2(2-1) cardiomyoblasts, Imidazo1, 2-alpha]1, 8]naphthyridine
Divisions
CHEMISTRY
Funders
Monash University (2023 (I-M010-STG-000003)),Graduate Research Excellence Scholarship
Publication Title
Journal of Molecular Structure
Volume
1327
Publisher
Elsevier
Publisher Location
RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS