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2D chemical drawings correlate to bioactivities: MIA-QSAR modelling of antimalarial activities of 2,5-diaminobenzophenone derivatives
Cormanich, Rodrigo A.;Freitas, Matheus P.;Rittner, Roberto;
Journal of the Brazilian Chemical Society , 2011, DOI: 10.1590/S0103-50532011000400004
Abstract: two-dimensional chemical structures of a series of 2,5-diaminobenzophenone derivatives, some farnesyltransferase inhibitors, have shown to correlate with the corresponding antimalarial activities. the descriptors in this qsar analysis are pixels of the chemical structures (two dimensional images) transformed into binaries and, therefore, the data variance explaining the variance in the activities block corresponds to the coordinates of each pixel in each molecule. this method, named multivariate image analysis applied to quantitative structure-activity relationship (mia-qsar), was applied to model the antimalarial activities of the titled compounds and the results were compared to well known three-dimensional qsar techniques for the same class of compounds. in addition to the simplicity and high predictive performance of the mia-qsar modelling, this 2d image-based method has the potential of working well when equally simple, classical analysis fails. overall, the present qsar analysis based on 2d chemical drawings (constrained structures) dispensed conformational screening and 3d alignment to provide a reliable qsar model; the physicochemical description about e.g. steric effects and chiral centers is all contained in the way in which substituents in a congeneric series are drawn, and the method can serve as a tool to introduce those who are planning to deal with drug design.
Immunochemical Analysis of the Antimalarial Drugs Artemisinin and Artesunate  [PDF]
Hiroyuki Tanaka,Madan K. Paudel,Ayako Takei,Junichi Sakoda,Thaweesak Juengwatanatrakul,Kaori Sasaki-Tabata,Waraporn Putalun,Wanchai De-Eknamkul,Oraphan Matangkasombut,Yukihiro Shoyama,Satoshi Morimoto
Antibodies , 2012, DOI: 10.3390/antib1030273
Abstract: We prepared a monoclonal antibody (mAb 1C1) showing specificity for artemisinin (AM) and artesunate (AS), and we developed an indirect competitive enzyme-linked immunosorbent assay (icELISA) using this novel mAb. Moreover, we prepared a recombinant antibody derived from mAb 1C1 in order to overcome insufficient mAb production by hybridoma culture. A recombinant antigen-binding fragment (Fab) was easily constructed using antibody manipulation technologies and was produced by microorganisms in high yield. We herein review immunochemical approaches for analysis of the antimalarial drugs AM and AS that were able to yield analysis results for multiple samples in a short period of time using simple and reliable protocols.
Exploring MIA-QSARs for farnesyltransferase inhibitory effect of antimalarial compounds refined by docking simulations  [PDF]
Omar Deeb, Sherin Alfalah, Matheus P. Freitas, Elaine F. F. da Cunha, Teodorico C. Ramalho
Journal of Biophysical Chemistry (JBPC) , 2012, DOI: 10.4236/jbpc.2012.31008
Abstract: Two series of farnesyltransferase (FTase) inhibitors were grouped and their antimalarial activi-ties modeled by means of multivariate image analysis applied to quantitative structure-activity relationship (MIA-QSAR). A reliable model was achieved, with r2 for calibration, external prediction and leave-one-out cross-validation of 0.96, 0.87 and 0.83, respectively. Therefore, biological activities of congeners can be estimated using the QSAR model. The bioactivities of new compounds based on the miscellany of substructures of the two classes of FTase inhibitors were predicted using the MIA-QSAR model and the most promising ones were submitted to ADME (absorption, distribution, metabolism and excretion) and docking evaluation. Despite the smaller interaction energy of the two most promising, predicted compounds in comparison to the two most active compounds of the data set, one of the proposed structures did not violate any Lipinski’s rule of five. Therefore, it is either a potential drug or may drive synthesis of similar, improved compounds.
Prediction of potential antimalarial targets of artemisinin based on protein information from whole genome of Plasmodium falciparum
LiPing Han,Qiang Huang,Peng Nan,Yang Zhong
Chinese Science Bulletin , 2009, DOI: 10.1007/s11434-009-0634-0
Abstract: On the basis of the genomic data and protein pathway information about Plasmodium falciparum clone 3D7 from the NCBI taxonomy database and the KEGG database, eight key protein enzymes in the signal pathways were selected to perform molecular docking with artemisinin. The binding modes obtained from the molecular docking suggested that purine nucleoside phosphorylase (pfPNP), peptide deformylase (pfPDF), and ribose 5-phosphate isomerase (pfRpiA) may be involved in the antimalarial mode of action of artemisinin. Artemisinin exhibited its antimalarial activity probably by interfering with the metabolic pathways of purine, pyrimidine, methionine, glyoxylate and dicarboxylate, or pentose phosphate.
Synthesis and Antimalarial Activity of Novel Dihydro-Artemisinin Derivatives  [PDF]
Yang Liu,Kunqiang Cui,Weiqiang Lu,Wei Luo,Jian Wang,Jin Huang,Chun Guo
Molecules , 2011, DOI: 10.3390/molecules16064527
Abstract: The Plasmodium falciparum cysteine protease falcipain-2, one of the most promising targets for antimalarial drug design, plays a key role in parasite survival as a major peptide hydrolase within the hemoglobin degradation pathway. In this work, a series of novel dihydroartemisinin derivatives based on (thio)semicarbazone scaffold were designed and synthesized as potential falcipain-2 inhibitors. The in vitro biological assay indicated that most of the target compounds showed excellent inhibition activity against P. falciparum falcipain-2, with IC50 values in the 0.29–10.63 μM range. Molecular docking studies were performed to investigate the binding affinities and interaction modes for the inhibitors. The preliminary SARs were summarized and could serve as a foundation for further investigation in the development of antimalarial drugs.
Substandard artemisinin-based antimalarial medicines in licensed retail pharmaceutical outlets in Ghana  [PDF]
M. El-Duah & K. Ofori-Kwakye
Journal of Vector Borne Diseases , 2012,
Abstract: Background & objectives: The artemisinin-based antimalarial medicines are first line medicines in the treatmentof severe and uncomplicated falciparum malaria. Numerous brands of these medicines manufactured in variouscountries are available in the Ghanaian market. The study was aimed at evaluating the authenticity and qualityof selected brands of artemisinin-based antimalarial medicines marketed in Ghana.Methods: In all, 14 artemisinin-based antimalarial medicines were purchased from pharmacies (P) and licensedchemical shops (LCSs) in the Kumasi metropolis, Ghana. Simple field tests based on colorimetry and thin layerchromatography were employed in determining the authenticity of the samples. Important quality assessmenttests, namely uniformity of mass, crushing strength, disintegration time, and the percentage content of activepharmaceutical ingredients (APIs) were determined.Results: All the brands tested contained the stipulated APIs. Artesunate tablet AT2 failed the uniformity of masstest while artesunate tablets AT3 & AT4 as well as amodiaquine tablets AM4 & AM6 failed the crushing strengthtest. All the six artemether-lumefantrine tablet brands passed the uniformity of mass, crushing strength anddisintegration tests. Only artemether-lumefantrine tablet brand AL1 contained the correct amount of the drugs.The other 13 artemisinin products contained either a lower (underdose) or higher (overdose) amount of thespecified drug. Artesunate monotherapy tablets were readily available in pharmacies and licensed chemicalshops.Interpretation & conclusion: All the artemisinin-based medicines tested (except AL1) were of substandardquality. The results demonstrate the need for continuous monitoring and evaluation of the quality of artemisininbased antimalarials in the Ghanaian market. Also, the practice of artemisinin antimalarial monotherapy is prevalentin Ghana. Determined efforts should, therefore, be made to eradicate the practice to prevent the development ofresistance to the artemisinins.
Interaction of Artemisinin Based Antimalarial Drugs with Hemin in Water-DMSO Mixture  [PDF]
P.T. Mpiana,B.K. Mavakala,Yu Zhi-Wu
International Journal of Pharmacology , 2007,
Abstract: The interaction of hemin with artemisinin, artesunate and dihydroartemisinin was investigated by UV-Visible Spectroscopy at pH 9 and High Performance Liquid Chromatography/Diode Array Detector/Mass Spectrometry (HPLC/DAD/MS) for their reactivity with hemin. It has been showed that artesunate and dihydroartemisinin interacted more strongly with Fe (III) PPIX that artemisinin did. The reported results showed too that hemin and endoperoxide lactone derived antimalarials slowly react to give rise to several stereoisomers supramolecular adducts (three for artesunate, seven for artemisinin and eight isomers for dihydroartemisinin) while in contrast, only heme (Fe2) was found to react with artemisinin based drugs in previous studies. Based on this result, our work confirmed the mechanism in which the artemisinin derivates approach hemin by pointing O1 at the endoperoxide linkage toward iron center, a mechanism that is controlled by steric hindrance. After that C3-C4 bond is cleaved to give rise carbon radical at C4 as predicted by automated calculation of docking of artemisinin to heme.
Ancient Chinese Methods Are Remarkably Effective for the Preparation of Artemisinin-Rich Extracts of Qing Hao with Potent Antimalarial Activity  [PDF]
Colin W. Wright,Peter A. Linley,Reto Brun,Sergio Wittlin,Elisabeth Hsu
Molecules , 2010, DOI: 10.3390/molecules15020804
Abstract: Ancient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions.
Expanding the Antimalarial Drug Arsenal—Now, But How?  [PDF]
Brian T. Grimberg,Rajeev K. Mehlotra
Pharmaceuticals , 2011, DOI: 10.3390/ph4050681
Abstract: The number of available and effective antimalarial drugs is quickly dwindling. This is mainly because a number of drug resistance-associated mutations in malaria parasite genes, such as crt, mdr1, dhfr/ dhps, and others, have led to widespread resistance to all known classes of antimalarial compounds. Unfortunately, malaria parasites have started to exhibit some level of resistance in Southeast Asia even to the most recently introduced class of drugs, artemisinins. While there is much need, the antimalarial drug development pipeline remains woefully thin, with little chemical diversity, and there is currently no alternative to the precious artemisinins. It is difficult to predict where the next generation of antimalarial drugs will come from; however, there are six major approaches: (i) re-optimizing the use of existing antimalarials by either replacement/rotation or combination approach; (ii) repurposing drugs that are currently used to treat other infections or diseases; (iii) chemically modifying existing antimalarial compounds; (iv) exploring natural sources; (v) large-scale screening of diverse chemical libraries; and (vi) through parasite genome-based (“targeted”) discoveries. When any newly discovered effective antimalarial treatment is used by the populus, we must maintain constant vigilance for both parasite-specific and human-related factors that are likely to hamper its success. This article is neither comprehensive nor conclusive. Our purpose is to provide an overview of antimalarial drug resistance, associated parasite genetic factors (1. Introduction; 2. Emergence of artemisinin resistance in P. falciparum), and the antimalarial drug development pipeline (3. Overview of the global pipeline of antimalarial drugs), and highlight some examples of the aforementioned approaches to future antimalarial treatment. These approaches can be categorized into “short term” (4. Feasible options for now) and “long term” (5. Next generation of antimalarial treatment—Approaches and candidates). However, these two categories are interrelated, and the approaches in both should be implemented in parallel with focus on developing a successful, long-lasting antimalarial chemotherapy.
Simple Field Assays to Check Quality of Current Artemisinin-Based Antimalarial Combination Formulations  [PDF]
Jean-Robert Ioset, Harparkash Kaur
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0007270
Abstract: Introduction Malaria continues to be one of the major public health problems in Africa, Asia and Latin America. Artemisinin derivatives (ARTs; artesunate, artemether, and dihydroartemisinin) derived from the herb, Artemisia annua, are the most effective antimalarial drugs available providing rapid cures. The World Health Organisation (WHO) has recommended that all antimalarials must be combined with an artemisinin component (artemisinin-based combination therapy; ACT) for use as first line treatment against malaria. This class of drugs is now first-line policy in most malaria-endemic countries. Reports of ad hoc surveys from South East Asia show that up to 50% of the artesunate currently sold is counterfeit. Drug quality is rarely assessed in resource poor countries in part due to lack of dedicated laboratory facilities which are expensive to build, equip and maintain. With a view to address this unmet need we developed two novel colour reaction assays that can be used in the field to check the quality of ARTs. Methods and Findings Our assays utilise thin layer chromatography silica gel sheets and 2, 4 dinitrophenylhydrazine or 4-Benzoylamino-2, 5-dimethoxybenzenediazonium chloride hemi (zinc chloride) salt as the reagents showing a pink or blue product respectively only in the presence ARTs. We are able to detect as low as 10% of ARTs in ACTs (WINTHROP - artesunate/amodiaquine, Coartem?-artemether/lumefantrine and Duocortexcin - dihydroartemisinin/piperaquine). The assays have been validated extensively by testing eighty readily accessible and widely used drugs in malaria endemic countries. None of the other antimalarial drugs or a range of commonly used excipients, antiretroviral drugs or other frequently used drugs from the WHO essential drugs list such as analgesics or antibiotics are detected with our assays. Conclusions Our two independent assays requiring no specialist training are specific, simple to use, rapid, robust, reproducible, inexpensive and, have successfully resulted in detecting two counterfeit drugs within a small scale screening survey of over 100 declared artemisinin-containing drugs collected from various Asian and African countries. These promising results indicate that the assays will provide a useful first test to assure the quality of the ACTs formulations in resource poor malaria endemic areas when there is an absence of dedicated medicines quality laboratory facilities.
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