Download MendeleyNovel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties.
Ge, S., Jian, R., Xuan, Q., Zhu, Y., Ren, X., Li, W., Chen, X., Huang, R.K., Lee, C.S., Leung, S.C., Basilico, N., Parapini, S., Taramelli, D., Pinthong, N., Antonyuk, S.V., O'Neill, P.M., Sheng, Z., Hong, W.D.(2024) Eur J Med Chem 284: 117228-117228
- PubMed: 39752821
- DOI: https://doi.org/10.1016/j.ejmech.2024.117228
- Primary Citation of Related Structures:
9GCX - PubMed Abstract:
Aryl quinolone derivatives can target the cytochrome bc 1 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 50 = 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 1 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.
Organizational Affiliation:
School of Pharmacy and Food Engineering, Wuyi University, 529020, Jiangmen, China; Department of Chemistry, University of Liverpool, L69 7ZD, Liverpool, UK; Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region of China.
