Prediction of anti-plasmodial activity of Artemisia annua extracts: application of 1H NMR spectroscopy and chemometrics.

We describe the application of 1H NMR spectroscopy and chemometrics to the analysis of extracts of Artemisia annua. This approach allowed the discrimination of samples from different sources, and to classify them according to anti-plasmodial activity without prior knowledge of this activity. The use of partial least squares analysis allowed the prediction of actual values for anti-plasmodial activities for independent samples not used in producing the models. The models were constructed using approximately 70% of the samples, with 30% used as a validation set for which predictions were made. Models generally explained >90% of the variance, R(2) in the model, and had a predictive ability, Q(2) of >0.8. This approach was also able to correlate 1H NMR spectra with cytotoxicity (R2=0.9, Q2=0.8). This work demonstrates the potential of NMR spectroscopy and chemometrics for the development of predictive models of anti-plasmodial activity.

[1]  J. Phillipson,et al.  Plants as sources of antimalarial drugs. Part 1. In vitro test method for the evaluation of crude extracts from plants. , 1985, Planta medica.

[2]  G. Bàlint,et al.  Artemisinin and its derivatives: an important new class of antimalarial agents. , 2001, Pharmacology & therapeutics.

[3]  Jae-Hoon Kim,et al.  In vitro antiprotozoal effects of artemisinin on Neospora caninum. , 2002, Veterinary parasitology.

[4]  Elaine Holmes,et al.  Metabolomic analysis of the consequences of cadmium exposure in Silene cucubalus cell cultures via 1H NMR spectroscopy and chemometrics. , 2003, Phytochemistry.

[5]  H. Kessler.  Structure–Activity Relationships by NMR: A New Procedure for Drug Discovery by a Combinatorial–Rational Approach , 1997 .

[6]  J. Haynes,et al.  Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique , 1979, Antimicrobial Agents and Chemotherapy.

[7]  J. Nicholson,et al.  Multi-component metabolic classification of commercial feverfew preparations via high-field 1H-NMR spectroscopy and chemometrics. , 2002, Planta medica.

[8]  Jon G. Wilkes,et al.  Models of Polychlorinated Dibenzodioxins, Dibenzofurans, and Biphenyls Binding Affinity to the Aryl Hydrocarbon Receptor Developed Using 13C NMR Data , 2001, J. Chem. Inf. Comput. Sci..

[9]  M. Saraste,et al.  FEBS Lett , 2000 .

[10]  R. Wilson,et al.  Potentiation of the antimalarial activity of qinghaosu by methoxylated flavones. , 1987, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[11]  Jon G. Wilkes,et al.  Use of 13C NMR Spectrometric Data To Produce a Predictive Model of Estrogen Receptor Binding Activity , 2001, J. Chem. Inf. Comput. Sci..

[12]  Dan A. Buzatu,et al.  13C NMR Quantitative Spectrometric Data-Activity Relationship (QSDAR) Models of Steroids Binding the Aromatase Enzyme , 2001, J. Chem. Inf. Comput. Sci..

[13]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[14]  J G Bundy,et al.  An NMR‐based metabonomic approach to the investigation of coelomic fluid biochemistry in earthworms under toxic stress , 2001, FEBS letters.

[15]  Jon G. Wilkes,et al.  Developing 13C NMR quantitative spectrometric data-activity relationship (QSDAR) models of steroid binding to the corticosteroid binding globulin , 2001, J. Comput. Aided Mol. Des..

[16]  Bernard Sandler,et al.  AID , 1978 .

[17]  P. Benias,et al.  A novel one-step, highly sensitive fluorometric assay to evaluate cell-mediated cytotoxicity. , 1998, Journal of immunological methods.

[18]  P. Gretener,et al.  Differential effects of orally versus parenterally administered qinghaosu derivative artemether in dogs , 1999, Experimental and Toxicologic Pathology.

[19]  I. Kubo,et al.  Structure-activity relationship of alkanols as mosquito larvicides with novel findings regarding their mode of action. , 1999, Bioorganic & medicinal chemistry.

[20]  E. Wemakor,et al.  The potential of Artemisia annua L. as a locally produced remedy for malaria in the tropics: agricultural, chemical and clinical aspects. , 2000, Journal of ethnopharmacology.

[21]  R. Glen,et al.  Quantitative structure-metabolism relationships for substituted benzoic acids in the rat. Computational chemistry, NMR spectroscopy and pattern recognition studies. , 1992, Biochemical pharmacology.

[22]  D. L. Klayman,et al.  Qinghaosu (artemisinin): an antimalarial drug from China , 1985 .

[23]  M. Narasu,et al.  Current status of artemisinin and its derivatives as antimalarial drugs. , 1999, Life sciences.

[24]  N Aranìbar,et al.  Automated mode-of-action detection by metabolic profiling. , 2001, Biochemical and biophysical research communications.

[25]  W. Quax,et al.  Seasonal Variations of Artemisinin and its Biosynthetic Precursors in Tetraploid Artemisia annua Plants Compared with the Diploid Wild-Type , 1999, Planta medica.

[26]  R. Haynes.  Artemisinin and derivatives: the future for malaria treatment? , 2001, Current opinion in infectious diseases.

[27]  B. Gilbert,et al.  Synergy in plant medicines. , 2003, Current medicinal chemistry.

[28]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[29]  Buffhirko.  VET , 2006 .

[30]  E Holmes,et al.  NMR spectroscopy based metabonomic studies on the comparative biochemistry of the kidney and urine of the bank vole (Clethrionomys glareolus), wood mouse (Apodemus sylvaticus), white toothed shrew (Crocidura suaveolens) and the laboratory rat. , 2000, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[31]  R. Lathe.  Phd by thesis , 1988, Nature.

[32]  Diagnosis of inborn errors of metabolism using 1H NMR spectroscopic analysis of urine , 1999, Journal of Inherited Metabolic Disease.

[33]  L. Messori,et al.  Simple and rapid physico-chemical methods to examine action of antimalarial drugs with hemin: its application to Artemisia annua constituents. , 2002, Life sciences.

[34]  W. Quax,et al.  Seasonal Variation of Artemisinin and its Biosynthetic Precursors in Plants of Artemisia annua of Different Geographical Origin: Proof for the Existence of Chemotypes , 2000, Planta medica.