• Bulletin of the Korean Chemical Society
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• 제18권6호
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• pp.644-648
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• 1997

Introduction of an alkyl substituent at the $C_{4\beta}$ position of antimalarial trioxanes has caused them to become more active in their antimalarial activity. We have designed a structurally simple 4β-phenyl substituted trioxane (3) as an active antimalarial since it can form a more stable carbon radical when reacting with ferrous bromide. The trioxane 3 has been prepared along with the corresponding isomer 4 according to the previously reported procedure. The synthesized trioxanes 3 and 4 were finally separated by using HPLC and assigned their stereochemistry by spectroscopy and X-ray crystallography. Their antimalarial activities were surprisingly low. The low activity was then rationalized based on the product distribution of the ferrous ion induced reaction of these trioxanes. These trioxanes with ferrous bromide did not produce any detectable amount of the corresponding $C_4$-hydroxylated product, consistent with the fact that neither $C_{4\beta}$-phenyl substituted nor $C_{4\alpha}$-phenyl substituted trioxane has any antimalarial activity. It implies that a $C_4$ substituent of antimalarial trioxanes has to stabilize an adjacent carbon-centered radical in a specific stability range in order to show a good antimalarial activity. This study, combined with related studies, could help develop more potent antimalarial trioxanes.

• Parasites, Hosts and Diseases
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• 제55권6호
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• pp.661-665
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• 2017

We synthesized C-10 substituted triazolyl artemisinins by the Huisgen cycloaddition reaction between dihydroartemisinins (2) and variously substituted 1, 2, 3-triazoles (8a-8h). The antimalarial activities of 32 novel artemisinin derivatives were screened against a chloroquine-resistant parasite. Among them, triazolyl artemisinins with electron-withdrawing groups showed stronger antimalarial activities than those shown by the derivatives having electron-donating groups. In particularly, m-chlorotriazolyl artemisinin (9d-12d) showed antimalarial activity equivalent to that of artemisinin and could be a strong drug candidate.

• Bulletin of the Korean Chemical Society
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• 제28권12호
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• pp.2495-2497
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• 2007

• Journal of Physiology & Pathology in Korean Medicine
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• 제19권1호
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• pp.102-105
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• 2005

Eighteen methanol extracts of herb-medicine used for malarial and antipyretic therapies in Korea were assessed for their antimalarial activities. Eighteen extracts showed evident antimalarial activity with $EC_50$ values ranged from $2.8\;to\;110mg/m{\ell}$. Evodia fructus showed the antimalarial activity of $EC_50\;=\;4.1\;mg/m{\ell}$ and higher selective toxicity(>8) with no cytotocixity for mammalian cells. This indicated that Evodia fructus is potent for a new effective and safe antimalarial agent. The methanol extract of Physalli radix had also strongest antiplasmodial activity with $EC_50$ value of $2.8{\mu}g/m{\ell}$.

• Journal of Physiology & Pathology in Korean Medicine
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• 제23권2호
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• pp.494-498
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• 2009

The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Useful antimalarial drugs such as chloroquine have resistance in the world now. Moreover, other antimalarialdrugs such as mefloquine, halofantrine, atovaquone, proguanil, artemether and lumefantrine retain efficacy but have limitations, one of which is their high cost. New antimalarial drugs are clearly needed now. Cytotoxicity assay and susceptibility assay were performed for the selectivity of herb extracts in vitro. On the basis of high selectivity, 4-day suppressive test and survival test were progressed in Plasmodium berghei-infected mice. The selectivity of Areca catechu L. (ACL) and butanol extract of ACL (ACL-BuOH extract) were 3.4 and 3.0 in vitro, respectively. Moreover in vivo, 4-day suppressive test showed 39.1 % inhibition effect after treated with 150 mg/kg/day ACL-BuOH to P. berghei-infected mice. Survival test also showed 60% survival rate with ACL-BuOH-treated group while all other group mice died. In this study, ACL and ACL-BuOH were investigated for antimalarial activity in vitro and in vivo and they showed a potent antimalarial activity. In particular,ACL-BuOH could specifically lead higher survival rate of mice in vivo. Therefore ACL-BuOH would be a candidate of antimalarial drugs.

• Journal of the Korean Wood Science and Technology
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• 제47권5호
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• pp.587-596
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• 2019

This study aimed to determine the antimalarial effect of the Strychnos ligustrina (SLW) wood extracts and to analyze its phytochemicals. The SLW powder samples were macerated with 100% ethanol (E100), 75% ethanol (E75), 50% ethanol (E50), 25% ethanol (E25), and aqueous (A100). The extracts were analyzed by LCMS/MS, and its in-vitro antimalarial activity was tested with Plasmodium falciparum. The results showed that the extract yields of E100, E75, E50, E25, and A100 were 4.3, 5.2, 5.3, 4.7, and 3.6%, respectively. The antimalarial activities of the A100, E25, E50, and E75 extracts were classified as active with $IC_{50}$ values of 38.6, 42.6, 42.9, and $43.7{\mu}g/mL$, respectively. But, the antimalarial activity of the E100 extract was classified as slightly active with $IC_{50}$ values of $87.4{\mu}g/mL$. The dominant compounds contained in the extracts of A100, E25, E50, E75, and E100 was the alkaloid compound, namely brucine with relative concentrations of 24.96, 24.55, 21.33, 11.79, and 11.62%, respectively.

• Parasites, Hosts and Diseases
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• 제60권6호
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• pp.401-407
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• 2022

Antimalarial drugs play an important role in the control and treatment of malaria, a deadly disease caused by the protozoan parasite Plasmodium spp. The development of novel antimalarial agents effective against drug-resistant malarial parasites is urgently needed. The novel derivatives, SKM13-MeO and SKM13-F, were designed based on an SKM13 template by replacing the phenyl group with electron-donating (-OMe) or electron-withdrawing groups (-F), respectively, to reverse the electron density. A colorimetric assay was used to quantify cytotoxicity, and in vitro inhibition assays were performed on 3 different blood stages (ring, trophozoite, and schizonts) of P. falciparum 3D7 and the ring/mixed stage of D6 strain after synchronization. The in vitro cytotoxicity analysis showed that 2 new SKM13 derivatives reduced the cytotoxicity of the SKM13 template. SKM13 maintained the IC₅₀ at the ring and trophozoite stages but not at the schizont stage. The IC₅₀ values for both the trophozoite stage of P. falciparum 3D7 and ring/mixed stages of D6 demonstrated that 2 SKM13 derivatives had decreased antimalarial efficacy, particularly for the SKM13-F derivative. SKM13 may be comparably effective in ring and trophozoite, and electron-donating groups (-OMe) may be better maintain the antimalarial activity than electron-withdrawing groups (-F) in SKM13 modification.

• Parasites, Hosts and Diseases
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• 제62권1호
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• pp.42-52
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• 2024

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.

• Parasites, Hosts and Diseases
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• 제61권1호
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• pp.33-41
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• 2023

The discovery of new antimalarial drugs can be developed using asynchronized Plasmodium berghei malaria parasites in vivo in mice. Studies on a particular stage are also required to assess the effectiveness and mode of action of drugs. In this report, we used endoperoxide 6-(1,2,6,7-tetraoxaspiro [7.11] nonadec-4-yl) hexan-1-ol (N-251) as a model antimalarial compound on P. chabaudi parasites. We examined the antimalarial effect of N-251 against ring-stage- and trophozoite-stage-rich P. chabaudi parasites and asynchronized P. berghei parasites using the 4-day suppressive test. The ED₅₀ values were 27, 22, and 22 mg/kg, respectively, and the antimalarial activity of N-251 was verified in both rodent malaria parasites. To assess the stage-specific effect of N-251 in vivo, we evaluated the change of parasitemia and distribution of parasite stages using ring-stage- and trophozoite-stage-rich P. chabaudi parasites with one-day drug administration for one life cycle. We discovered that the parasitemias decreased after 13 and 9 hours post-treatment in the ring-stage- and trophozoite-stage-rich groups, respectively. Additionally, in the ring-stage-rich N-251 treated group, the ring-stage parasites hindered trophozoite parasite development. For the trophozoite-stage-rich N-251 treated group, the distribution of the trophozoite stage was maintained without a change in parasitemia until 9 hours. Because of these findings, it can be concluded that N-251 suppressed the trophozoite stage but not the ring stage. We report for the first time that N-251 specifically suppresses the trophozoite stage using P. chabaudi in mice. The results show that P. chabaudi is a reliable model for the characterization of stage-specific antimalarial effects.

• Bulletin of the Korean Chemical Society
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• 제34권6호
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• pp.1823-1828
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• 2013

Tetraoxanes (1,2,4,5-tetraoxanes) have been reported to exhibit potent antimalarial activity. In the present study, the three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on a series of tetraoxanes derivatives using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The best predictive CoMFA model with atom fit alignment resulted in cross-validated coefficient ($q^2$) value of 0.719, non-cross-validated coefficient ($r^2$) value of 0.855 with standard error of estimate (SEE) 0.335. Similarly, the best predictive CoMSIA model was derived with $q^2$ of 0.739, $r^2$ of 0.847 and SEE of 0.344. The generated models were externally validated using test sets. The final QSAR models as well as the information gathered from 3D contour maps should be useful for the design of novel tetraoxanes having improved antimalarial activity.