2. Academic Validation
  3. Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties

Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties

  • Eur J Med Chem. 2025 Feb 15:284:117228. doi: 10.1016/j.ejmech.2024.117228.
Siyuan Ge 1,  Rongchao Jian 2,  Qiwei Xuan 3,  Yingxiang Zhu 3,  Xiaofei Ren 3,  Wenjiao Li 3,  Xiaole Chen 4,  Rui-Kang Huang 5,  Chi-Sing Lee 6,  Suet C Leung 7,  Nicoletta Basilico 8,  Silvia Parapini 9,  Donatella Taramelli 10,  Nattapon Pinthong 11,  Svetlana V Antonyuk 11,  Paul M O'Neill 7,  Zhaojun Sheng 12,  W David Hong 13
Affiliations

Affiliations

  • 1 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.
  • 2 School of Pharmacy and Food Engineering, Wuyi University, 529020, Jiangmen, China.
  • 3 School of Pharmacy and Food Engineering, Wuyi University, 529020, Jiangmen, China; Liverpool-Jiangmen Public Health Research Centre, International Healthcare Innovation Institute (Jiangmen), 529020, Jiangmen, China.
  • 4 School of Pharmacy and Food Engineering, Wuyi University, 529020, Jiangmen, China; Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region of China.
  • 5 Graduate School of Environmental Science, Hokkaido University, N10W5, Kita-ku, 060-0810, Sapporo, Japan; Research Institute for Electronic Science (RIES), Hokkaido University, N20W10, Kita-ku, Sapporo, Japan.
  • 6 Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong Special Administrative Region of China.
  • 7 Department of Chemistry, University of Liverpool, L69 7ZD, Liverpool, UK.
  • 8 Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Via Pascal 36, 20133, Milano, Italy; Affiliated to Centro Interuniversitario di Ricerche sulla Malaria/ Italian Malaria Network (CIRM-IMN), Università degli Studi di Camerino, UK.
  • 9 Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Pascal 36, 20133, Milano, Italy; Affiliated to Centro Interuniversitario di Ricerche sulla Malaria/ Italian Malaria Network (CIRM-IMN), Università degli Studi di Camerino, UK.
  • 10 Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Pascal 36, 20133, Milano, Italy; Affiliated to Centro Interuniversitario di Ricerche sulla Malaria/ Italian Malaria Network (CIRM-IMN), Università degli Studi di Camerino, UK.
  • 11 Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, L69 7ZB, Liverpool, UK.
  • 12 School of Pharmacy and Food Engineering, Wuyi University, 529020, Jiangmen, China; Liverpool-Jiangmen Public Health Research Centre, International Healthcare Innovation Institute (Jiangmen), 529020, Jiangmen, China. Electronic address: wyuchemszj@126.com.
  • 13 School of Pharmacy and Food Engineering, Wuyi University, 529020, Jiangmen, China; Department of Chemistry, University of Liverpool, L69 7ZD, Liverpool, UK. Electronic address: davidhwq@liverpool.ac.uk.
PMID: 39752821 DOI: 10.1016/j.ejmech.2024.117228
Abstract

Aryl Quinolone derivatives can target the cytochrome bc1 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 (IC50 = 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 bc1 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.

Keywords

Antimalarial; Bioisosteres; Plasmodium falciparum; Quinolone; Solubility.

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