| Autor: |
Hong H; Department of Tropical Medicine and Parasitology, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea., Moon K; College of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan 54538, Korea., Trinh TT; Department of Tropical Medicine and Parasitology, Medical Research Center, Institute of Endemic Diseases, Seoul National University, Seoul 03080, Korea., Eom TH; Department of Tropical Medicine and Parasitology, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea., Park H; Zoonosis Research Center, Department of Infection Biology, School of Medicine, Wonkwang University, Iksan 54538, Korea., Kim HS; College of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan 54538, Korea., Yeo SJ; Department of Tropical Medicine and Parasitology, Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Korea.; Department of Tropical Medicine and Parasitology, Medical Research Center, Institute of Endemic Diseases, Seoul National University, Seoul 03080, Korea. |
| Abstrakt: |
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. |
