Ge, Siyuan, Jian, Rongchao, Xuan, Qiwei, Zhu, Yingxiang, Ren, Xiaofei, Li, Wenjiao, Chen, Xiaole, Huang, Rui-Kang, Lee, Chi-Sing, Leung, Suet C et al (show 8 more authors)
(2025)
Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties.
European journal of medicinal chemistry, 284.
117228-.
ISSN 0223-5234, 1768-3254
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Manuscript_Quinonlone bioisosteres_EJMC_final.pdf - Author Accepted Manuscript Available under License Creative Commons Attribution. Download (909kB) | Preview |
Abstract
Aryl quinolone derivatives can target the cytochrome bc<sub>1</sub> complex of Plasmodium falciparum, exhibiting excellent in vitro and in vivo antimalarial activity. However, their clinical development has been hindered due to their poor aqueous solubility profiles. In this study, a series of bioisosteres containing saturated heterocycles fused to a 4-pyridone ring were designed to replace the inherently poorly soluble quinolone core in antimalarial quinolones with the aim to reduce π-π stacking interactions in the crystal packing solid state, and a synthetic route was developed to prepare these alternative core derivatives. One such novel derivate, F14, exhibited significant enhancements in both aqueous solubility (20 μM) and lipophilicity (LogD 2.7), whilst retaining nanomolar antimalarial activity against the W2 strain of P. falciparum (IC<sub>50</sub> = 235 nM). The pharmacokinetic studies reported, provide preliminary insights into the in vivo distribution and elimination of F14, while findings from single crystal X-ray diffraction experiment rationalized the enhanced solubility. Protein X-ray crystallography and in silico docking simulations provide insight into the potential mode of action within the cytochrome bc<sub>1</sub> complex. These findings demonstrated the viability of this bioisostere replacement strategy and provided support for further exploration of in vivo efficacy in preclinical animal models and valuable insights for new drug design strategies in the fight against malaria.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Animals, Humans, Plasmodium falciparum, Quinolones, Cytochromes, Antimalarials, Crystallography, X-Ray, Parasitic Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Solubility, Molecular Docking Simulation |
| Divisions: | Faculty of Science and Engineering Faculty of Science and Engineering > School of Physical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Jan 2025 16:01 |
| Last Modified: | 15 Apr 2025 10:02 |
| DOI: | 10.1016/j.ejmech.2024.117228 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3189549 |
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