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

• Published in: Parasites, hosts and diseases Vol. 62; no. 1; pp. 42 - 52
• Main Authors: Hong, Hyelee, Moon, Kwonmo, Trinh, Thuy-Tien Thi, Eom, Tae-Hui, Park, Hyun, Kim, Hak Sung, Yeo, Seon-Ju
• Format: Journal Article
• Language: English
• Published: Korea (South) The Korean Society for Parasitology and Tropical Medicine 01.02.2024; 대한기생충학ㆍ열대의학회
• Subjects: Amides - pharmacology; Animals; Antimalarials - pharmacology; Chloroquine - pharmacology; Disease Models, Animal; Folic Acid Antagonists; Humans; Mice; Mice, Inbred ICR; Morpholines; Original; Plasmodium berghei; Plasmodium falciparum; 예방의학; antimalarial chemical compound; Plasmodium falciparum; Plasmodium berghei; Morpholine-containing SAM13-2HCl
• ISSN: 2982-5164; 2982-6799; 2982-6799
• DOI: 10.3347/PHD.23093

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.