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KMID : 0425120240620010042
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Parasites, Hosts and Diseases
2024 Volume.62 No. 1 p.42 ~ p.52
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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
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Hong Hye-Lee
Moon Kwon-Mo
Thuy-Tien Thi Trinh
Eom Tae-Hui
Park Hyun
Kim Hak-Sung
Yeo Seon-Ju
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Abstract
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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 SKM132HCl, 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 5compounds, 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) Plasmodiumfalciparum strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious P. falciparum parasites. However, the antimalarialactivity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound inthe P. berghei NK65-infected mouse model, possibly because SAM13-2HCl had a lowerpolarity and less efficient pharmacokinetics than SKM13-2HCl. SAM13-2HCl was moretoxic 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.
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KEYWORD
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Plasmodium falciparum, Plasmodium berghei, Morpholine-containing SAM13 2HCl, antimalarial chemical compound
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