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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 (CC<sub>50<\/sub>) > 100 \u00b5M, 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) (CC<sub>50<\/sub>\/IC<sub>50<\/sub>) than SKM13-2HCl in vitro against both chloroquine-sensitive (3D7) and chloroquine -resistant (K1) <i>Plasmodium falciparum<\/i> strains, respectively. Thus, the presence of morpholine amide may help to effectively suppress human-infectious <i>P. falciparum<\/i> parasites. However, the antimalarial activity of SAM13-2HCl was inferior to that of the SKM13-2HCl template compound in the <i>P. berghei<\/i> 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 <i>P. falciparum<\/i> but was less efficient in vivo in a <i>P. berghei<\/i>-infected animal model when compared with SKM13-2HCl. Therefore, SAM13-2HCl containing morpholine could be considered a promising compound to treat chloroquine-resistant <i>P. falciparum<\/i> infections, although further optimization is crucial to maintain antimalarial activity while reducing toxicity in animals.<\/jats:p>","DOI":"10.3347\/phd.23093","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T05:37:27Z","timestamp":1709185047000},"page":"42-52","update-policy":"https:\/\/doi.org\/10.3347\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Evaluation of the antimalarial activity of SAM13-2HCl with morpholine amide (SKM13 derivative) against antimalarial drug-resistant Plasmodium falciparum and Plasmodium berghei infected ICR 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Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/parahostdis.org\/upload\/pdf\/PHD-23093.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T05:38:18Z","timestamp":1709185098000},"score":1,"resource":{"primary":{"URL":"https:\/\/parahostdis.org\/journal\/view.php?doi=10.3347\/PHD.23093"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,23]]},"references-count":20,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,2]]}},"URL":"https:\/\/doi.org\/10.3347\/phd.23093","relation":{},"ISSN":["2982-5164","2982-6799"],"issn-type":[{"value":"2982-5164","type":"print"},{"value":"2982-6799","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,23]]},"assertion":[{"value":"2023-08-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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