• Parasites, Hosts and Diseases
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• v.62 no.1
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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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• v.60 no.6
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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.

• Tuberculosis and Respiratory Diseases
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• v.40 no.2
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• pp.112-122
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• 1993

Backgrounds : The goal of drug therapy in pneumoconiosis is to inhibit the progression of pulmonary fibrosis related to a toxic effect of the inhaled substance. Although there have been many studies on the therapy of pneumoconiosis, it is still elusive. Quinolyl piperazine phosphate (QP), a derivative of chloroquine, is less toxic, more effective, and longer action than chloroquine. This investigation was performed to examine the effect of the quinolyl piperazine phosphate in silicotic rats. Methods : The silica group was administered intratracheally by 40 mg free silica dust with 0.5 ml normal saline, and the QP group was orally administered QP 10 mg per week after free silica instillation. The animals in the silica group and the QP group were killed at the 1st, 3rd, 8th and 20th week after free silica instillation. We observed the total cell count in bronchoalveolar lavage fluid, luminol-dependent chemiluminescence by viable alveolar inflammatory cells, the dry weights and the amount of hydroxyproline in the left lung and the histopathologic examination in the right lung. Results : 1) The total number of cells of bronchoalveolar lavage fluid in the QP group tended to be decreased in comparison with the silical group. But, It was not significant. 2) Luminol-induced chemiluminescence by viable alveolar inflammatory cells in the QP group was similiar to that in the silical group. 3) The dry weights in the left lung at the 3th and 8th week in the QP group were significantly decreased compared to the silical group. 4) The total amount of hydroxyproline at the 3rd week of the QP group were significantly decreased compared to the silical group. In the silica group, the total amount of hydroxyproline was significantly increased at the 3rd week compared with the 1st group. But, in the QP group, it was significantly increased at the 8th week. 5) In tissue pathology, the infiltration of inflammatory cells around bronchiole, and the number and the size of silicotic nodule in the QP group were similar to the silica group. But, the extent of fibrosis is less than the silica group. Especially we observed progressive massive fibrosis which located in the periphery in 3 cases among the silica group, but couldn't observe in the QP group. Conclusions : QP doesn't significantly suppress the pulmonary fibrosis consequent to the intratracheal instillation of free silica dust, but delay the progression of fibrosis.