Parasites, Hosts and Diseases

The Korea Society for Parasitology and Tropical Medicine (대한기생충학·열대의학회)
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Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR mice

  • Hyelee Hong (Department of Tropical Medicine and Parasitology, Department of Biomedical Sciences, College of Medicine, Seoul National University) ;
  • Kwonmo Moon (College of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University) ;
  • Thuy-Tien Thi Trinh (Department of Tropical Medicine and Parasitology, Medical Research Center, Institute of Endemic Diseases, Seoul National University) ;
  • Tae-Hui Eom (Department of Tropical Medicine and Parasitology, Department of Biomedical Sciences, College of Medicine, Seoul National University) ;
  • Hyun Park (Zoonosis Research Center, Department of Infection Biology, School of Medicine, Wonkwang University) ;
  • Hak Sung Kim (College of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University) ;
  • Seon-Ju Yeo (Department of Tropical Medicine and Parasitology, Department of Biomedical Sciences, College of Medicine, Seoul National University)
  • Received : 2023.08.29
  • Accepted : 2023.12.20
  • Published : 2024.02.29
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Abstract

Antimalarial drugs are an urgently need and crucial tool in the campaign against malaria, which can threaten public health. In this study, we examined the cytotoxicity of the 9 antimalarial compounds chemically synthesized using SKM13-2HCl. Except for SKM13-2HCl, the 5 newly synthesized compounds had a 50% cytotoxic concentration (CC50) >100 μM, indicating that they would be less cytotoxic than SKM13-2HCl. Among the 5 compounds, only SAM13-2HCl outperformed SKM13-2HCl for antimalarial activity, showing a 3- and 1.3-fold greater selective index (SI) (CC50/IC50) than SKM13-2HCl in vitro against both chloroquine-sensitive (3D7) and chloroquine -resistant (K1) Plasmodium falciparum strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious P. falciparum parasites. However, the antimalarial activity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound in the P. berghei NK65-infected mouse model, possibly because SAM13-2HCl had a lower polarity and less efficient pharmacokinetics than SKM13-2HCl. SAM13-2HCl was more toxic in the rodent model. Consequently, SAM13-2HCl containing morpholine was selected from screening a combination of pharmacologically significant structures as being the most effective in vitro against human-infectious P. falciparum but was less efficient in vivo in a P. berghei-infected animal model when compared with SKM13-2HCl. Therefore, SAM13-2HCl containing morpholine could be considered a promising compound to treat chloroquine-resistant P. falciparum infections, although further optimization is crucial to maintain antimalarial activity while reducing toxicity in animals.

Keywords

Acknowledgement

The following reagent was obtained through BEI Resources, NIAID, NIH: Plasmodium falciparum, Strain K1, MRA-159, contributed by Dennis E. Kyle. The following reagent was obtained through BEI Resources, NIAID, NIH: Plasmodium berghei, Strain NK65, MRA-268, contributed by Victor Nussenzweig. This research was supported by the Priority Research Centers Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (NRF-2015R1A6A1A03032236) and (NRF-2021R1A2C2007346).

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