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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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.
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 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.
참고문헌 (20)
- "Malaria 2022" (2022)[URL]
- "Tackling emerging antimalarial drug resistance in Africa 2022"[URL]
- Balikagala B, "Evidence of artemisinin-resistant malaria in Africa", N Engl J Med, 385(13), pp.1163~1171 (2021)[DOI]
- Imwong M, "Spread of a single multidrug resistant malaria parasite lineage(PfPailin)to Vietnam", Lancet Infect Dis, 17(10), pp.1022~1023 (2017)[DOI]
- Zhu L, "Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response", Commun Biol, 5(1), pp.274~ (2022)[DOI]
- Yeo SJ, "Anti-malarial effect of novel chloroquine derivatives as agents for the treatment of malaria", Malar J, 16(1), pp.80~ (2017)[DOI]
- Trinh TT, "Anti-malarial activity of HCl salt of SKM13(SKM13-2HCl)", Int J Parasitol Drugs Drug Resist, 20, pp.113~120 (2022)[DOI]
- Trinh TT, "In vitro evaluation of two novel antimalarial derivatives of SKM13 : SKM13-MeO and SKM13-F", Parasites Hosts Dis, 60(6), pp.401~407 (2022)[DOI]
- Korn C, "Compound selection for development-is salt formation the ultimate answer? Experiences with an extended concept of the"100mg approach"", Eur J Pharm Sci, 57, pp.257~263 (2014)[DOI]
- Kalepu S, "Insoluble drug delivery strategies : review of recent advances and business prospects", Acta Pharm Sin B, 5(5), pp.442~453 (2015)[DOI]
- Ando K, "A Mechanistic Study of the Horner-Wadsworth-Emmons reaction : computational investigation on the reaction pass and the stereochemistry in the reaction of lithium enolate derived from trimethyl phosphonoacetate with acetaldehyde", J Org Chem, 64(18), pp.6815~6821 (1999)[DOI]
- Zhang Y, "PKSolver : an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel", Comput Methods Programs Biomed, 99(3), pp.306~314 (2010)[DOI]
- Franco A, "Plasmodium berghei purified hemozoin associated with DNA strongly inhibits P. berghei liver-stage development in BALB", c mice after intravenous inoculation, 2023, pp.91(1), e0030422~
- Erkent U, "The use of truncated area under the curves in the bioequivalence evaluation of long half-life drugs. Studies with donepezil and memantine", Arzneimittelforschung, 58(5), pp.255~258 (2008)[DOI]
- Endrenyi L, "Cmax", AUC is a clearer measure than Cmax for absorption rates in investigations of bioequivalence, 1991, pp.29(10), 394~399
- Nqoro X, "Quinoline-based hybrid compounds with antimalarial activity", Molecules, 22(12), pp.2268~ (2017)[DOI]
- Choi S, "Four times of relapse of Plasmodium vivax Malaria despite primaquine treatment in a patient with impaired cytochrome P450 2D6Function", Parasites Hosts Dis, 60(1), pp.39~43 (2022)[DOI]
- Sevene E, "Current knowledge and challenges of antimalarial drugs for treatment and prevention in pregnancy", Expert Opin Pharmacother, 11(8), pp.1277~1293 (2010)[DOI]
- Peng M, "Endoplasmic reticulum stress, a target for drug design and drug resistance in parasitosis", Front Microbiol, 12, pp.670874~ (2021)[DOI]
- Mamedov VA, "Synthesis of morpholine-, piperidine-, and N-substituted piperazine-coupled 2-(benzimidazol-2-yl)-3-arylquinoxalines as novel potent antitumor agents", ACS Pharmacol Transl Sci, 5(10), pp.945~962 (2022)[DOI]