Fairuz, Shadreen and Ang, Chee Wei and Tan, Kong Wai and Mraiche, Fatima and Chow, Sek Chuen and Goh, Joo Kheng (2025) Novel imidazo[1,2-a][1,8]naphthyridine derivatives and their preliminary in vitro assays for the evaluation as positive inotropes. Journal of Molecular Structure, 1327. p. 141202. ISSN 0022-2860, DOI https://doi.org/10.1016/j.molstruc.2024.141202.
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Funders: | Monash University (2023 (I-M010-STG-000003)), Graduate Research Excellence Scholarship |
| Uncontrolled Keywords: | N -heterocycle; Heart failure; Positive inotropes; H9c2(2-1) cardiomyoblasts; Imidazo1,2-alpha]1,8]naphthyridine |
| Subjects: | Q Science > Q Science (General) Q Science > QD Chemistry |
| Divisions: | Faculty of Science > Department of Chemistry |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 13 Mar 2025 04:32 |
| Last Modified: | 14 Mar 2025 01:05 |
| URI: | http://eprints.um.edu.my/id/eprint/47743 |
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