Antimalarial Properties of Isoquinoline Derivative from Streptomyces hygroscopicus subsp. Hygroscopicus: An In Silico Approach.

Malaria is one of the life-threatening diseases in the world. The spread of resistance to antimalarial drugs is a major challenge, and resistance to artemisinin has been reported in the Southeast Asian region. In the previous study, the active compound of Streptomyces hygroscopicus subsp. Hygroscopicus (S. hygroscopicus), eponemycin, has been shown to have antimalarial effects. To further analyze the effects of other active compounds on the Plasmodium parasite, identifying and analyzing the effectiveness of compounds contained in S. hygroscopicus through instrumentation of liquid chromatography/mass spectrometry (LC/MS) and in silico studies were very useful. This study aimed at identifying other derivative compounds from S. hygroscopicus and screening the antimalarial activity of the compound by assessing the binding affinity, pharmacokinetic profile, and bond interaction. The derivative compounds were identified using LC/MS. Protein targets for derivative compounds were found through literature studies, and the results of identification of compounds and protein targets were reconstructed into three-dimensional models. Prediction of pharmacokinetic profiles was carried out using Swiss ADME. Screening of protein targets for the derivative compound was carried out using the reverse molecular docking method. Analyzing bond interaction was done by LigPlot. One compound from S. hygroscopicus, i.e., 6,7-dinitro-2-[1, 2, 4]triazole-4-yl-benzo[de]isoquinoline-1,3-dione, was successfully identified using LC/MS. This compound was an isoquinoline derivative compound. Through literature studies with inclusion criteria, thirteen protein targets were obtained for reverse molecular docking. This isoquinoline derivative had the potential to bind to each protein target. The pharmacokinetic profile showed that this compound had the drug-likeness criteria. Conclusion. 6,7-Dinitro-2-[1, 2, 4]triazole-4-yl-benzo[de]isoquinoline-1,3-dione has antimalarial activity as shown by reverse molecular docking studies and pharmacokinetic profiles. The best inhibitory ability of compounds based on bond affinity is with adenylosuccinate synthetase.

Comparative study of antimalarial effect of sambiloto (Andrographis paniculata) extract, chloroquine and artemisinin and their combination against plasmodium falciparum in-vitro.

AIM: to compare the anti-malarial effect among sambiloto extract, chloroquine and artemisinin-only as well as those of their combination. METHODS: the study was conducted in Central Biomedical Laboratory, Faculty of Medicine, Brawijaya University, Malang, Indonesia from January to February 2006. Malaria culture used Plasmodium falciparum of Papua strain (2300) that was obtained from Namru-2 Jakarta. Five drugs applied in this test; those were chloroquine, artemisinin, the extract of sambiloto, the combination of sambiloto and chloroquine, and the combination of sambiloto and artemisinin. Parasite density was determined by counting the number of Plasmodium falciparum infected erythrocyte in 5,000 erythrocytes of the culture. Single drug (Chloroquine-only or artemisinin only) and either combination with sambiloto at dose 0.5 ug/ml had killing-effect against the parasite, measured by the appearance of "crisis form" on the infected erythrocytes. This killing-effect was dose dependent, and reached its optimum effect of 200 ug/ml. RESULTS: treatment of single sambiloto extract with dose 0.5 ug/ml increased the density of the parasite, however after every 1ug increasing dose of sambiloto extract, the killing effect also increased. The reduction of the parasite density was also seen by increasing the Sambiloto dose in the group of combination of sambiloto-chloroquine as well as the group of combination of sambiloto and artemisinin. Statistically, there was no difference in the anti-malaria efficacy among of five test drugs (p=1.00). The correlation between the reduction of the parasite with the increasing of dose in all groups is statistically significance (p=0.001). CONCLUSION: the extract of sambiloto in a single dose or in a combination evidently has the effect of anti-falciparum malaria.

Diversity of the var gene family of Indonesian Plasmodium falciparum isolates.

BACKGROUND: The large polymorphic protein PfEMP1 is encoded by the var gene family. PfEMP1 has been shown to play an important role as cytoadherence ligand on the surface of infected erythrocytes and thereby contributes to the distinct pathogenesis of malaria. The study explored the diversity of the DBL1α and DBL2ß-C2 domains of the protein from Indonesian Plasmodium falciparum field isolates. METHODS: Samples of patients with severe and uncomplicated malaria from two different malaria-endemic areas in Indonesia were collected and DNA directly extracted. Dried blood on filter paper was prepared for RNA extraction. PCR amplicons were either cloned and subsequently sequenced or directly sequenced for analysis on nucleotide and amino acid level. Recently published as well as self-designed primers were used for amplification. RESULTS: Blood from eight patients was finally used for analysis. Seventy-one different sequences out of over 500 DBL1α sequenced clones were observed, resulting in an average of 8.9 different DBL1α sequences per isolate. The average DBL1α sequence similarity within isolates was similar to between isolates. Phylogenetic analysis demonstrated no clustering of sequences regarding strain or geographical origin. The DBL1α sequences were analysed by distribution of semi-conserved features (cysteine/PoLV1-4 grouping) and classified into six sequence groups. The DBL1α cys2 type was observed in all expressed sequences in vivo. Expression of certain DBL sequences implied potential involvement in the pathogenesis. As expected, the DBL2ß-C2 domains showed high to moderate homology among each other. CONCLUSION: The DBL1α domains of PfEMP1 from clinical Indonesian isolates showed high divergence among same isolates and some similarities with other Asia-Pacific strains. Further investigations of important var gene domains with a larger sample size are required to confirm with statistical significance observed associations with severe malaria in Indonesian samples.