Parasites, Hosts and Diseases

"antimalarial"

Original Articles

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: Hyelee Hong, Kwonmo Moon, Thuy-Tien Thi Trinh, Tae-Hui Eom, Hyun Park, Hak Sung Kim, Seon-Ju Yeo; Parasites Hosts Dis 2024;62(1):42-52.
Published online February 23, 2024; DOI: https://doi.org/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.

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The Importance of Murine Models in Determining In Vivo Pharmacokinetics, Safety, and Efficacy in Antimalarial Drug Discovery
Glory Adebayo, Opeyemi I. Ayanda, Matthias Rottmann, Olusola S. Ajibaye, Gbolahan Oduselu, Julius Mulindwa, Olayinka O. Ajani, Oluwagbemiga Aina, Pascal Mäser, Ezekiel Adebiyi
Pharmaceuticals.2025; 18(3): 424. CrossRef
Structural, electrochemical and theoretical studies of some carboxamides
David Izuchukwu Ugwu, Nandisiwe GS Mateyise, Jeanet Conradie
Journal of Molecular Structure.2025; 1348: 143454. CrossRef

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Evaluating the activity of N-89 as an oral antimalarial drug: Nagwa S. M. Aly, Hiroaki Matsumori, Thi Quyen Dinh, Akira Sato, Shin-ichi Miyoshi, Kyung-Soo Chang, Hak Sun Yu, Takaaki Kubota, Yuji Kurosaki, Duc Tuan Cao, Gehan A. Rashed, Hye-Sook Kim; Parasites Hosts Dis 2023;61(3):282-291.
Published online August 21, 2023; DOI: https://doi.org/10.3347/PHD.23044

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Despite the recent progress in public health measures, malaria remains a troublesome disease that needs to be eradicated. It is essential to develop new antimalarial medications that are reliable and secure. This report evaluated the pharmacokinetics and antimalarial activity of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) using the rodent malaria parasite Plasmodium berghei in vivo. After a single oral dose (75 mg /kg) of N-89, its pharmacokinetic parameters were measured, and t_1/2 was 0.97 h, T_max was 0.75 h, and bioavailability was 7.01%. A plasma concentration of 8.1 ng/ml of N-89 was maintained for 8 h but could not be detected at 10 h. The dose inhibiting 50% of parasite growth (ED₅₀) and ED₉₀ values of oral N-89 obtained following a 4-day suppressive test were 20 and 40 mg/kg, respectively. Based on the plasma concentration of N-89, we evaluated the antimalarial activity and cure effects of oral N-89 at a dose of 75 mg/kg 3 times daily for 3 consecutive days in mice harboring more than 0.5% parasitemia. In all the N-89- treated groups, the parasites were eliminated on day 5 post-treatment, and all mice recovered without a parasite recurrence for 30 days. Additionally, administering oral N-89 at a low dose of 50 mg/kg was sufficient to cure mice from day 6 without parasite recurrence. This work was the first to investigate the pharmacokinetic characteristics and antimalarial activity of N-89 as an oral drug. In the future, the following steps should be focused on developing N-89 for malaria treatments; its administration schedule and metabolic pathways should be investigated.

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The antimalarial activity of transdermal N-89 mediated by inhibiting ERC gene expression in P. Berghei-infected mice
Hiroaki Matsumori, Thi Quyen Dinh, Shin-ichi Miyoshi, Masayuki Morita, Hye-Sook Kim
Parasitology International.2025; 106: 103026. CrossRef
Evaluating the effect of new antimalarial N-89 for gametocytes in P. berghei-infected mice
Thi Quyen Dinh, Hiroaki Matsumori, Mamoru Niikura, Shin-ichi Miyoshi, Hye-Sook Kim
Parasitology International.2025; 109: 103093. CrossRef

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Antimalarial effect of synthetic endoperoxide on synchronized Plasmodium chabaudi infected mice: Nagwa S. M. Aly, Hiroaki Matsumori, Thi Quyen Dinh, Akira Sato, Shin-Ichi Miyoshi, Kyung-Soo Chang, Hak Sun Yu, Fumie Kobayashi, Hye-Sook Kim; Parasites Hosts Dis 2023;61(1):33-41.
Published online February 22, 2023; DOI: https://doi.org/10.3347/PHD.22119

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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.

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The Importance of Murine Models in Determining In Vivo Pharmacokinetics, Safety, and Efficacy in Antimalarial Drug Discovery
Glory Adebayo, Opeyemi I. Ayanda, Matthias Rottmann, Olusola S. Ajibaye, Gbolahan Oduselu, Julius Mulindwa, Olayinka O. Ajani, Oluwagbemiga Aina, Pascal Mäser, Ezekiel Adebiyi
Pharmaceuticals.2025; 18(3): 424. CrossRef
Evaluating the activity of N-89 as an oral antimalarial drug
Nagwa S. M. Aly, Hiroaki Matsumori, Thi Quyen Dinh, Akira Sato, Shin-ichi Miyoshi, Kyung-Soo Chang, Hak Sun Yu, Takaaki Kubota, Yuji Kurosaki, Duc Tuan Cao, Gehan A. Rashed, Hye-Sook Kim
Parasites, Hosts and Diseases.2023; 61(3): 282. CrossRef

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In Vitro Evaluation of Two Novel Antimalarial Derivatives of SKM13: SKM13-MeO and SKM13-F: Thuy-Tien Thi Trinh, Young-ah Kim, Hyelee Hong, Linh Thi Thuy Le, Hayoung Jang, Soon-Ai Kim, Hyun Park, Hak Sung Kim, Seon-Ju Yeo; Korean J Parasitol 2022;60(6):401-407.
Published online December 22, 2022; DOI: https://doi.org/10.3347/kjp.2022.60.6.401

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.

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Design, Synthesis and in vitro Evaluation of Primaquine and Diaminoquinazoline Hybrid Molecules Against the Malaria Parasite
Mukul Kore, Anjani G. Rao, Dimple Acharya, Shrikant S. Kirwale, Amritansh Bhanot, Abhishek Govekar, Ajeet Kumar Mohanty, Aniruddha Roy, Shruthi S. Vembar, Sandeep Sundriyal
Chemistry – An Asian Journal.2025;[Epub] CrossRef
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
Hyelee Hong, Kwonmo Moon, Thuy-Tien Thi Trinh, Tae-Hui Eom, Hyun Park, Hak Sung Kim, Seon-Ju Yeo
Parasites, Hosts and Diseases.2024; 62(1): 42. CrossRef

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Brief Communication

Antimalarial Activity of C-10 Substituted Triazolyl Artemisinin: Gab-Man Park, Hyun Park, Sangtae Oh, Seokjoon Lee; Korean J Parasitol 2017;55(6):661-665.
Published online December 31, 2017; DOI: https://doi.org/10.3347/kjp.2017.55.6.661

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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.

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Novel frontiers through nitrogen substitution at 6th, 10th and 11th position of artemisinin: Synthetic approaches and antimalarial activity
Priyanka Yadav, Varun Rawat, Shalini Kaushik Love, Ved Prakash Verma
European Journal of Medicinal Chemistry.2025; 281: 117032. CrossRef
Identification of potential bi-triazole based antimalarial compounds and their effects against asexual stages of Plasmodium isolates
Marcinete Latorre Almeida, Leandro do Nascimento Martinez, Welington da Silva Paula do Nascimento, Guilherme Matos Passarini, Daniel Sol Sol de Medeiros, Minelly Azevedo da Silva, Saara Neri Fialho, Amália do Santos Ferreira, Norton Rubens Diunior Lucas P
Caderno Pedagógico.2024; 21(13): e12709. CrossRef
In silico screening, synthesis, and antimalarial evaluation of PABA substituted 1,3,5-triazine derivatives as Pf-DHFR inhibitors
Ashmita Saha, Ayesha Aktar Khanam Choudhury, Nayana Adhikari, Surajit Kumar Ghosh, Anshul Shakya, Saurav Jyoti Patgiri, Udaya Pratap Singh, Hans Raj Bhat
Experimental Parasitology.2023; 250: 108546. CrossRef
Current development of 1,2,3-triazole derived potential antimalarial scaffolds: Structure- activity relationship (SAR) and bioactive compounds
S. Maheen Abdul Rahman, Jasvinder Singh Bhatti, Suresh Thareja, Vikramdeep Monga
European Journal of Medicinal Chemistry.2023; 259: 115699. CrossRef
Exploration of artemisinin derivatives and synthetic peroxides in antimalarial drug discovery research
Om P.S. Patel, Richard M. Beteck, Lesetja J. Legoabe
European Journal of Medicinal Chemistry.2021; 213: 113193. CrossRef

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Original Article

Sensitivity of Plasmodium falciparum to Antimalarial Drugs in Hainan Island, China: Shan-Qing Wang, Guang-Ze Wang, Yu-Chun Li, Feng Meng, Shi-Gan Lin, Zhen-Hu Zhu, Ding-Wei Sun, Chang-Hua He, Xi-Min Hu, Jian-Wei Du; Korean J Parasitol 2015;53(1):35-41.
Published online February 27, 2015; DOI: https://doi.org/10.3347/kjp.2015.53.1.35

Abstract
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Pyronaridine and artesunate have been shown to be effective in falciparum malaria treatment. However, pyronaridine is rarely used in Hainan Island clinically, and artesunate is not widely used as a therapeutic agent. Instead, conventional antimalarial drugs, chloroquine and piperaquine, are used, explaining the emergence of chloroquine-resistant Plasmodium falciparum. In this article, we investigated the sensitivity of P. falciparum to antimalarial drugs used in Hainan Island for rational drug therapy. We performed in vivo (28 days) and in vitro tests to determine the sensitivity of P. falciparum to antimalarial drugs. Total 46 patients with falciparum malaria were treated with dihydroartemisinin/piperaquine phosphate (DUO-COTECXIN) and followed up for 28 day. The cure rate was 97.8%. The mean fever clearance time (22.5±10.6 hr) and the mean parasite clearance time (27.3±12.2 hr) showed no statistical significance with different genders, ages, temperatures, or parasite density (P>0.05). The resistance rates of chloroquine, piperaquine, pyronarididine, and artesunate detected in vitro were 71.9%, 40.6%, 12.5%, and 0%, respectively (P<0.0001). The resistance intensities decreased as follows: chloroquine>piperaquine>pyronarididine>artesunate. The inhibitory dose 50 (IC₅₀) was 3.77×10^-6 mol/L, 2.09×10^-6 mol/L, 0.09×10^-6 mol/L, and 0.05×10^-6 mol/L, and the mean concentrations for complete inhibition (CIMC) of schizont formation were 5.60×10^-6 mol/L, 9.26×10^-6 mol/L, 0.55×10^-6 mol/L, and 0.07×10^-6 mol/L, respectively. Dihydroartemisinin showed a strong therapeutic effect against falciparum malaria with a low toxicity.

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Evaluation Algorithm of Volleyball Players’ Competitive Ability Based on the Random Matrix Model
Tailin Wang, Hua Zheng, Fangshu Li, Nian Jia, Zengliang Cai, Ning Cao
Mathematical Problems in Engineering.2022; 2022: 1. CrossRef

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Brief Communication

Antimalarial activity of thiophenyl- and benzenesulfonyl-dihydroartemisinin: Seokjoon Lee, Sangtae Oh, Gab-Man Park, Tong-Soo Kim, Jae-Sook Ryu, Han-Kyu Choi; Korean J Parasitol 2005;43(3):123-126.
Published online September 20, 2005; DOI: https://doi.org/10.3347/kjp.2005.43.3.123

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Each diastereomer of 10-thiophenyl- and 10-benzenesulfonyl-dihydroartemisinin was synthesized from artemisinin in three steps, and screened against chloroquine-resistance and chloroquine-sensitive Plasmodium falciparum. Three of the four tested compounds were found to be effective. Especially, 10β-benzenesulfonyl-dihydroartemisinin showed stronger antimalarial activity than artemisinin.

Citations

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Chemical transformations of artemisinin
A. V. Semakov, S. V. Afanasyeva, S. A. Pukhov
Russian Chemical Bulletin.2024; 74(6): 1604. CrossRef
Design, synthesis and molecular docking studies of novel N-arylsulfonyl-benzimidazoles with anti Trypanosoma cruzi activity
Gisele E. Miana, Sergio R. Ribone, Domingo M.A. Vera, Manuel Sánchez-Moreno, María R. Mazzieri, Mario A. Quevedo
European Journal of Medicinal Chemistry.2019; 165: 1. CrossRef
Antimalarial Activity of C-10 Substituted Triazolyl Artemisinin
Gab-Man Park, Hyun Park, Sangtae Oh, Seokjoon Lee
The Korean Journal of Parasitology.2017; 55(6): 661. CrossRef
TD-DFT calculations of UV absorption bands and their intensities in the spectra of some tetrahydroquinolines
María V. Cooke, Ivana Malvacio, Walter J. Peláez, Ana J. Pepino, María R. Mazzieri, Gustavo A. Argüello
RSC Advances.2015; 5(33): 26255. CrossRef
Malaria-Infected Mice Live Until at Least Day 30 after a New Artemisinin-Derived Thioacetal Thiocarbonate Combined with Mefloquine Are Administered Together in a Single, Low, Oral Dose
Alexander M. Jacobine, Jennifer R. Mazzone, Rachel D. Slack, Abhai K. Tripathi, David J. Sullivan, Gary H. Posner
Journal of Medicinal Chemistry.2012; 55(17): 7892. CrossRef
Synthesis, stereoelectronic characterization and antiparasitic activity of new 1-benzenesulfonyl-2-methyl-1,2,3,4-tetrahydroquinolines
Romina J. Pagliero, Sabrina Lusvarghi, Adriana B. Pierini, Reto Brun, María R. Mazzieri
Bioorganic & Medicinal Chemistry.2010; 18(1): 142. CrossRef

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Original Article

Aspartic proteases of Plasmodium vivax are highly conserved in wild isolates: Byoung-Kuk Na, Eung-Goo Lee, Hyeong-Woo Lee, Shin-Hyeong Cho, Young-An Bae, Yoon Kong, Jong-Koo Lee, Tong-Soo Kim; Korean J Parasitol 2004;42(2):61-66.
Published online June 20, 2004; DOI: https://doi.org/10.3347/kjp.2004.42.2.61

Abstract
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The plasmepsins are the aspartic proteases of malaria parasites. Treatment of aspartic protease inhibitor inhibits hemoglobin hydrolysis and blocks the parasite development in vitro suggesting that these proteases might be exploited their potentials as antimalarial drug targets. In this study, we determined the genetic variations of the aspartic proteases of Plasmodium vivax (PvPMs) of wild isolates. Two plasmepsins (PvPM4 and PvPM5) were cloned and sequenced from 20 P. vivax Korean isolates and two imported isolates. The sequences of the enzymes were highly conserved except a small number of amino acid substitutions did not modify key residues for the function or the structure of the enzymes. The high sequence conservations between the plasmepsins from the isolates support the notion that the enzymes could be reliable targets for new antimalarial chemotherapeutics.

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The Effect of Aqueous Extract of Cinnamon on the Metabolome ofPlasmodium falciparumUsing1HNMR Spectroscopy
Shirin Parvazi, Sedigheh Sadeghi, Mehri Azadi, Maryam Mohammadi, Mohammad Arjmand, Farideh Vahabi, Somye Sadeghzadeh, Zahra Zamani
Journal of Tropical Medicine.2016; 2016: 1. CrossRef
Use of multiplex real-time PCR for detection of common diarrhea causing protozoan parasites in Egypt
John T. Nazeer, Khalifa El Sayed Khalifa, Heidrun von Thien, Mahmoud Mohamed El-Sibaei, Magda Youssef Abdel-Hamid, Ranya Ayman Samir Tawfik, Egbert Tannich
Parasitology Research.2013; 112(2): 595. CrossRef
Imperfect Duplicate Insertions Type of Mutations in Plasmepsin V Modulates Binding Properties of PEXEL Motifs of Export Proteins in Indian Plasmodium vivax
Manmeet Rawat, Sonam Vijay, Yash Gupta, Pramod Kumar Tiwari, Arun Sharma, Rajvir Dahiya
PLoS ONE.2013; 8(3): e60077. CrossRef
Sequence homology and structural analysis of plasmepsin 4 isolated from Indian Plasmodium vivax isolates
Manmeet Rawat, Sonam Vijay, Yash Gupta, Rajnikant Dixit, P.K. Tiwari, Arun Sharma
Infection, Genetics and Evolution.2011; 11(5): 924. CrossRef
Single nucleotide polymorphisms, putatively neutral DNA markers and population genetic parameters in IndianPlasmodium vivaxisolates
BHAVNA GUPTA, ADITYA P. DASH, NALINI SHRIVASTAVA, APARUP DAS
Parasitology.2010; 137(12): 1721. CrossRef
Characterization of plasmepsin V, a membrane-bound aspartic protease homolog in the endoplasmic reticulum of Plasmodium falciparum
Michael Klemba, Daniel E. Goldberg
Molecular and Biochemical Parasitology.2005; 143(2): 183. CrossRef
Purification and Characterization of a Hemoglobin Degrading Aspartic Protease from the Malarial Parasite Plasmodium vivax
Arun Sharma, Alex Eapen, Sarala K. Subbarao
The Journal of Biochemistry.2005; 138(1): 71. CrossRef