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A study on antimalarial artemisinin derivatives using MEP maps and multivariate QSAR

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Abstract

Artemisinin and some derivatives with activity against D-6 strains of Plasmodium falciparum were studied. Molecular electrostatic potential (MEP) maps were used in an attempt to identify key features of the compounds that are necessary for their activities, and then use those to propose new artemisinin derivatives. The partial least squares (PLS) method was then used to generate a predictive model. The PLS model with three latent variables explaining 88.9% of total variance, with Q2 = 0.839 and R2 = 0.935, was obtained for 15/6 compounds in the training/external validation set. For construction of the model, the most important descriptors were the highest occupied molecular orbital (HOMO) energy, atomic charges on the atoms O1 (Q1) and C3 (Q3), molecular volume (VOL), and hydrophilic index (HYF). From a set of 20 proposed artemisinin derivatives, one new compound (39) with higher antimalarial activity than the molecules initially studied was predicted. Synthesis of these new derivatives may follow the results of the MEP maps studied and the PLS modeling.

Molecular electrostatic potential (MEP) (values in au) map computed from electronic density to the novel proposed artemisinin derivative (39). The red color indicates the 1,2,4-trioxane ring in the region of most negative MEPdue to the peroxide linkage characteristic of compounds active against D-6 strains of Plasmodium falciparum.

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References

  1. Bowman S, Lawson D, Basham D, Brow D, Chillingworth T, Churcher CM, Craig A, Davies RM, Devlin K, Feltwell T, Gentles S, Gwillinam R, Hamlin N, Harris D, Holroyd S, Hornsby T, Horrocks P, Jagels K, Jassal B, Kyes SJ, McLean S, Moule S, Mungall K, Murphy L, Olive RK, Quail MA, Rajadream M-A, Rutter S, Skelton J, Squares R, Squares S, Sulston JE, Whitehead S, Woodward JR, Newbold C, Barrell BG (1999) Nature 400:532–538

    Article  CAS  Google Scholar 

  2. Pandey AV, Tekwani BL, Singh RL, Chaudan SV (1999) J Biol Chem 274:19383–19388

    Article  CAS  Google Scholar 

  3. Kamchonwonggpaisan S, Samoff E, Meschinck SR (1997) Mol Biochem Parasitol 86:179–186

    Article  Google Scholar 

  4. Olliaro P (2001) Pharmacol Ther 89:207–219

    Article  CAS  Google Scholar 

  5. Ridley RG (2002) Nature 415:686–692

    Article  CAS  Google Scholar 

  6. White NJ (2004) J Clin Invest 113:1084–1092

    Article  CAS  Google Scholar 

  7. Arav-Boger R, Shapiro TA (2005) Annu Rev Pharmacol Toxicol 45:565–585

    Article  CAS  Google Scholar 

  8. Cheng F, Shen J, Luo X, Zhu W, Gu J, Ji R, Jiang H, Chen K (2002) Bioorg Med Chem 10:2883–2891

    Article  CAS  Google Scholar 

  9. Bhattacharjee AK, Hartell MG, Nichols DA, Hicks RP, Stanton B, van Hamont JE, Milhous WK (2004) Eur J Med Chem 39:59–67

    Article  CAS  Google Scholar 

  10. Jefford CW (2001) Curr Med Chem 8:1803–1826

    CAS  Google Scholar 

  11. Haynes RK, Vonwiller SC (1997) Acc Chem Res 30:73–79

    Article  CAS  Google Scholar 

  12. Bernardinelli G, Jefford CW, Maric D, Thomson C, Weber J (1994) Int J Quant Chem: Quant Biol Symp 21:117–131

    Article  CAS  Google Scholar 

  13. Posner GH, Cumming JN, Ploypradith P, Oh CH (1995) J Am Chem Soc 117:5885–5886

    Article  CAS  Google Scholar 

  14. Posner GH, Wang D, Cumming JN, Oh CH, French AN, Bodley AL, Shapiro TA (1995) J Med Chem 38:2273–2275

    Article  CAS  Google Scholar 

  15. Haynes RK, Vonwiller SC (1996) Tetrahedron Lett 37:253–256

    Article  CAS  Google Scholar 

  16. Rafiee MA, Hadipour NL, Naderi-manesh H (2005) J Chem Inf Model 45:366–370

    Article  CAS  Google Scholar 

  17. Wu WM, Wu YK, Wu YL, Yao ZJ, Zhou CM, Li Y, Shan F (1998) J Am Chem Soc 120:3316–3325

    Article  CAS  Google Scholar 

  18. Meshnick SR (2002) Int J Parasitol 32:1655–1660

    Article  CAS  Google Scholar 

  19. Hynes RK, Krishna S (2004) Microb Infect 6:1339–1346

    Article  Google Scholar 

  20. Kannan R, Kumar K, Sahal D, Kukreti S, Chauhan VS (2005) Biochem J 385:409–418

    Article  CAS  Google Scholar 

  21. Kamchonwongpaisan S, Samoff E, Meschinck SR (1997) Mol Biochem Parasitol 86:179–186

    Article  CAS  Google Scholar 

  22. Hon YL, Yang YZ, Meschnick SR (1998) Mol Biochem Parasitol 63:121–128

    Google Scholar 

  23. Wang DY, Wu YL (2000) Chem Commun 22:2193–2194

    Article  Google Scholar 

  24. Hynes RK, Ho W-Y, Chen H-W, Fugmann B, Stetter J, Croft SL, Vivas L, Peters W, Robinson BR (2004) Angew Chem Int Ed 43:1381–1385

    Article  Google Scholar 

  25. Hynes RK (2005) Angew Chem Int Ed 44:2064–2065

    Article  Google Scholar 

  26. Pinheiro JC, Kiralj R, Ferreira MMC, Romero OAS (2003) QSAR Comb Sci 22:830–842

    Article  CAS  Google Scholar 

  27. Roothaan CCJ (1951) Rev Mod Phys 23:69–89

    Article  CAS  Google Scholar 

  28. Binkley JS, Pople JA, Hehre WJ (1980) J Am Chem Soc 102:939–946

    Article  CAS  Google Scholar 

  29. Lin AJ, Zikry AB, Kyle DE (1997) J Med Chem 40:1396–1400

    Article  CAS  Google Scholar 

  30. Lin AJ, Miller RE (1995) J Med Chem 38:764–770

    Article  CAS  Google Scholar 

  31. Beebe KR, Pell JR, Seasholtt MB (1998) Chemometrics: a pratical guide. Wiley, New York, pp 81–278

    Google Scholar 

  32. Ferreira MMC (2002) J Braz Chem Soc 13:742–753

    CAS  Google Scholar 

  33. Kubinyi H (1993) QSAR: Hansch analysis and related approaches. In: Mannhold R, Krogsgaard-Larsen P, Timmerman H (eds) Methods and principles in medicinal chemistry, vol 1. VHC, Weinheim, pp 1–240

    Google Scholar 

  34. GaussView 1.0 (1997) Gaussian Inc., Pittsburgh, PA

  35. Pinheiro JC, Ferreira MMC, Romero OAS (2001) J Mol Struct (Theochem) 572:35–44

    Article  CAS  Google Scholar 

  36. Leban I, Golic L, Japelj M (1998) Acta Pharm Jugosl 38:71–77

    Google Scholar 

  37. Lisgarten JN, Potter BS, Bantuzeko C, Palmer RA (1998) J Chem Cryst 28:539–543

    Article  CAS  Google Scholar 

  38. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Millam MA, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi Barone JV, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson GA, Ayala PY, Cui Q, Morokuma K, Salvador P, Dannenberg JJ, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Baboul AG, Sefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, A-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andes JL, Gonzalez C, Head-Gordon M, Replogle ES, Pople JA (2001) Gaussian 98 - Revision A.11. Gaussian Inc, Pittsburgh PA

    Google Scholar 

  39. Flukiger P, Luthi HP, Portmann S, Weber J (2000–2001) MOLEKEL. Swiss Center for Scientific Computing, Mano, Switzerland

  40. Todeschine R, Gramatica P (1997) WHIM-3D 3.3. Milan

  41. ChemPlus (2000) Modular extensions to hyperChem release 6.02, molecular modeling for windows. HyperCube Inc, Gainesvillem FL

    Google Scholar 

  42. Infometrix, Pirouette 3.01, Woodinville WA, 2001

Download references

Acknowledgments

We gratefully acknowledge the financial support of the Brazilian agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. The authors would like to thank the Instituto de Química-Araraquara for the use of the GaussView software, and the Swiss Center for Scientific Computing for the use of the MOLEKEL software. We employed computing facilities at the Centro Nacional de Processamento de Alto Desempenho-Universidade Estadual de Campinas and at the Laboratório de Química Teórica e Computacional-Universidade Federal do Pará.

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Authors and Affiliations

  1. Laboratório de Química Teórica e Computacional, Departamento de Química, Centro de Ciências Exatas e Naturais, Universidade Federal do Pará, CP 101101, 66075-110, Belém, PA, Amazônia, Brazil

    Fábio José B. Cardoso, Antonio Florêncio de Figueiredo, Maycon da Silva Lobato, Ricardo Moraes de Miranda, Ruth Catarine O. de Almeida & José Ciríaco Pinheiro

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  1. Fábio José B. Cardoso
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  2. Antonio Florêncio de Figueiredo
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  3. Maycon da Silva Lobato
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  4. Ricardo Moraes de Miranda
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  5. Ruth Catarine O. de Almeida
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  6. José Ciríaco Pinheiro
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Correspondence to José Ciríaco Pinheiro.

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Cardoso, F.J.B., de Figueiredo, A.F., da Silva Lobato, M. et al. A study on antimalarial artemisinin derivatives using MEP maps and multivariate QSAR. J Mol Model 14, 39–48 (2008). https://doi.org/10.1007/s00894-007-0249-9

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  • DOI: https://doi.org/10.1007/s00894-007-0249-9

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