Advertisement

Antiplasmodial Activity

  • Nubia Boechat
  • Luiz Carlos da Silva Pinheiro
  • Flavia Fernandes da Silveira
Chapter

Abstract

According to the World Health Organization, malaria is one of the most serious public health problems globally. Malaria is a parasitic disease caused by protozoa of the genus Plasmodium, which are predominant in tropical and subtropical regions. Currently, the number of safe medications for this disease is limited, mainly due to the development of drug resistance. Combination therapy is recommended by the World Health Organization to either prevent or to delay the onset of resistance. Implementing projects in the medicinal chemistry area, which include organic chemistry and biological activity investigations, is essential for the discovery of new drugs. Sesquiterpene lactones have been demonstrated to be important antimalarial drugs. Artemisinin and its derivatives are some of the most widely used sesquiterpene lactone drugs and contain an endoperoxide bridge. Due to their antimalarial properties, several new sesquiterpene lactones have been tested in clinical trials and are being studied as a new class of antimalarial agents. The activity of sesquiterpene lactones is primarily attributed to the α-methylene-γ-lactone group that is present in their structure. Molecular hybridization is a strategy that is employed by medicinal chemists for the discovery of new drugs which involves combining pharmacophore fragments with a single hybrid molecule. Several synthetic hybrid sesquiterpene lactones have shown significant antiplasmodial activity. The aim of this work is to review antiplasmodial agents featuring a sesquiterpene lactone scaffold. Particularly, the sesquiterpene lactones that are currently being used or those that are still in the development process as well as those from natural or semisynthetic origins are highlighted.

Keywords

Malaria Artemisinin Antiplasmodial activity Drug resistance Asteraceae Sesquiterpene lactone Hybrid Clinical trials 

References

  1. Achan J, Talisuna AO, Erhart A et al (2011) Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J 10:144–156CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adjei GO, Kudzi W, Dodoo A et al (2010) Artesunate plus amodiaquine combination therapy: reviewing the evidence. Drug Dev Res 71:33–43Google Scholar
  3. Aquino I (2010) Efeito genotóxico da artemisinina e do artesunato em células de mamíferos. Dissertation, University of São PauloGoogle Scholar
  4. Arantes FFP, Barbosa LCA, Maltha CRA et al (2011) A quantum chemical and chemometric study of sesquiterpene lactones with cytotoxicity against tumor cells. J Chemom 25(8):401–407Google Scholar
  5. Araujo NCP, Barton V, Jones M (2009) Semi-synthetic and synthetic 1,2,4-trioxaquines and 1,2,4-trioxolaquines: synthesis, preliminary SAR and comparison with acridine endoperoxide conjugates. Bioorg Med Chem Lett 19:2038–2043CrossRefPubMedGoogle Scholar
  6. Baio PA (2011) A importância do conhecimento clínico e epidemiológico da malária nos países não endémicos: perspectivas futuras para Europa. Dissertation, University of Porto, PortugalGoogle Scholar
  7. Balaich JN, Mathias DK, Torto B et al (2016) The nonartemisinin sesquiterpene lactones parthenin and parthenolide block Plasmodium falciparum sexual stage transmission. Antimicrob Agents Chemother 60(4):2108–2117CrossRefPubMedPubMedCentralGoogle Scholar
  8. Barnett DS, Guy RK (2014) Antimalarials in development in 2014. Chem Rev 114:11221–11241CrossRefPubMedGoogle Scholar
  9. Bassat Q, Mulenga M, Tinto H et al (2009) Dihydroartemisinin-piperaquine and artemether-lumefantrine for treating uncomplicated malaria in african children: a randomised, non-inferiority trial. PLoS One 4(11):e7871. https://doi.org/10.1371/journal.pone.0007871 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Boechat N, Souza MVN, Valverde AL et al (2014) Compounds derived from artesunate, preparation process, pharmaceutical composition and use of the respective medicine. Us Patent 8,802,701 B2, 12 Aug 2014Google Scholar
  11. Capela R, Cabal GG, Rosenthal PJ et al (2011) Design and evaluation of primaquine-artemisinin hybrids as a multistage antimalarial strategy. Antimicrob Agents Chemother 55:4698–4706CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chaturvedi D (2011) Sesquiterpene lactones: structural diversity and their biological activities. In: Tiwari V, Mishra B (eds) Opportunity, challenge and scope of natural products in medicinal chemistry. Research Signpost, Kerala, pp 313–334Google Scholar
  13. Chaturvedi D, Goswami A, Saikia PP et al (2010) Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents. Chem Soc Rev 39:435–454CrossRefPubMedGoogle Scholar
  14. Coura JR (2013) Dinâmica das doenças infecciosas e parasitarias, 2nd edn. Guanabara Koogan, Rio de JaneiroGoogle Scholar
  15. Croft SL, Duparc S, Arbe-Barnes SJ et al (2012) Review of pyronaridine anti-malarial properties and product characteristics. Malar J 11:270–298CrossRefPubMedPubMedCentralGoogle Scholar
  16. Cunico W, Carvalho SA, Gomes CRB et al (2008) Fármacos antimalariais – história e perspectivas. Rev Bras Farm 89:49–55Google Scholar
  17. European Medicines Agency (EMA) Science Medicine Health (2017a) http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_for_use_outside_EU/2012/06/WC500129288.pdf. Accessed 31 Jan 2017
  18. European Medicines Agency (EMA) Science Medicine Health (2017b) Eurartesim (dihydroartemisinin/ piperaquine) 20 mg/160 mg and 40 mg/320 mg film-coated tablets: EU summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001199/WC500118113.pdf. Accessed 10 Jan 2017
  19. Feng TS, Guantai EM, Nell M et al (2011) Effects of highly active novel artemisinin–chloroquinoline hybrid compounds on b-hematin formation, parasite morphology and endocytosis in Plasmodium falciparum. Biochem Pharmacol 82:236–247CrossRefPubMedGoogle Scholar
  20. França TCC, Santos MG, Figueroa-Villar JD (2008) Malária: aspectos históricos e quimioterapia. Quim Nova 31(5):1271–1278CrossRefGoogle Scholar
  21. Gangjee A, Jain HD, Phan J et al (2006) Dual inhibitors of thymidylate synthase and dihydrofolate reductase as antitumour agents: design, synthesis and biological evaluation of classical and nonclassical pyrrolo[2,3-d] pyrimidine antifolates. J Med Chem 49:1055–1065CrossRefPubMedPubMedCentralGoogle Scholar
  22. Garcia LS (2010) Clinics in laboratory. Medicine 30:93–129Google Scholar
  23. Ghantous A, Sinjab A, Herceg Z, Darwiche N (2013) Parthenolide: from plant shoots to cancer roots. Drug Discov Today 18:894–905CrossRefPubMedGoogle Scholar
  24. Instituto de Tecnologia de Farmacos (ITF), Farmanguinhos/Fiocruz (2017) https://facilbula.com.br/pesquisabula/arquivopdf?nomeArquivo=5133402015_2673917_PROFISSIONAL.PDF. Accessed 30 Jan 2017
  25. Kaur K, Jain M, Kaur T, Jain R (2009) Antimalarials from nature. Bioorg Med Chem 17:3229–3256CrossRefPubMedGoogle Scholar
  26. Kaur K, Jain M, Reddy RP et al (2010) Quinolines and structurally related heterocycles as antimalarials. Eur J Med Chem 45:3245–3264CrossRefPubMedGoogle Scholar
  27. Keating GM (2012) Dihydroartemisinin/Piperaquine: a review of its use in the treatment of uncomplicated Plasmodium falciparum malaria. Adis Drug Eval 72(7):937–961Google Scholar
  28. Leite FHA, Fonseca A, Nunes RR et al (2013) Malaria: from old drugs to new molecular targets. Biochem Biotechnol Rep 2:59–76CrossRefGoogle Scholar
  29. Li J, Zhou B (2010) Biological actions of artemisinin: insights from medicinal chemistry studies. Molecules 15:1378–1397CrossRefPubMedGoogle Scholar
  30. Lombard MC, N’Da DD, Breytenbach JC et al (2011) Synthesis, in vitro antimalarial and cytotoxicity of artemisinin-aminoquinoline hybrids. Bioorg Med Chem Lett 21:1683–1686CrossRefPubMedGoogle Scholar
  31. Majdi M, Ashengroph M, Abdollahi MR (2016) Sesquiterpene lactone engineering in microbial and plant platforms: parthenolide and artemisinin as case studies. Appl Microbiol Biotechnol 100:1041–1059CrossRefPubMedGoogle Scholar
  32. Manda H, Gouagna LC, Foster WA et al (2007) Effect of discriminative plant-sugar feeding on the survival and fecundity of Anopheles gambiae. Malar J 6:113–124CrossRefPubMedPubMedCentralGoogle Scholar
  33. Matar KM, Awad AI, Elamin SB (2014) Pharmacokinetics of artesunate alone and in combination with sulfadoxine/Pyrimethamine in healthy sudanese volunteers. Am J Trop Med Hyg 90(6):1087–1093CrossRefPubMedPubMedCentralGoogle Scholar
  34. Medicines for malária venture (MMV) (2017a) http://www.mmv.org/access/products-projects/eurartesim-dihydroartemisinin-piperaquine. Accessed 28 Jan 2017
  35. Medicines for malaria venture (MMV) (2017c) http://www.mmv.org/access/products-projects/artesun-injectable-artesunate. Accessed 29 Jan 2017
  36. Medicines for malária venture (MMV) (2017d) http://www.mmv.org/access/products-projects/pyramax-pyronaridine-artesunate. Accessed 01 Dec 2016
  37. Medicines for malaria venture (MMV) (2017e) https://www.mmv.org/access/products-projects/asaq-winthrop-artesunate-amodiaquine. Accessed 20 Jan 2017
  38. Midha K, Mohit, Nagpal M, Sharma A (2015) Drug-resistant malaria in south Asian countries: a review of evidence and future prospects of nanomedicine based strategies for prophylaxis and treatment. Eur J Pharm Med Res 2(5):231–248Google Scholar
  39. Misra H, Mehta D, Mehta BK, Jain DC (2014) Extraction of artemisinin, an active antimalarial phytopharmaceutical from dried leaves of Artemisia annua L., using microwaves and a validated HPTLC-visible method for its quantitative determination. Chromatogr Res Int 2014, Article ID 361405. https://doi.org/10.1155/2014/361405
  40. Muregi FW, Ishih A (2010) Next-generation antimalarial drugs: hybrid molecules as a new strategy in drug design. Drug Dev Res 71:20–32PubMedPubMedCentralGoogle Scholar
  41. Na-Bangchang K, Karbwang J (2009) Review: current status of malaria chemotherapy and the role of pharmacology in antimalarial drug research and development. Fundam Clin Pharmacol 23:387–409CrossRefPubMedGoogle Scholar
  42. Navaratnam V, Ramanathan S, Wahab MSA et al (2009) Tolerability and pharmacokinetics of non-fixed and fixed combinations of artesunate and amodiaquine in Malaysian healthy normal volunteers. Eur J Clin Pharmacol 65:809–821CrossRefPubMedPubMedCentralGoogle Scholar
  43. Nguyen DVH, Nguyen QP, Nguyen ND et al (2009) Pharmacokinetics and ex vivo pharmacodynamics antimalarial activity of dihydroartemisinin-piperaquine in patients with uncomplicated falciparum malaria in Vietnam. Antimicrob Agents Chemother 53(8):3534–3537CrossRefPubMedPubMedCentralGoogle Scholar
  44. Nyunt MM, Plowe CV (2007) Pharmacologic advances in the global control and treatment of malaria: combination therapy and resistance. Clin Pharmacol Ther 82(5):601–605CrossRefPubMedGoogle Scholar
  45. O’Neill PM, Barton VE, Ward SA (2010) The molecular mechanism of action of artemisinin-the debate continues. Molecules 15:1705–1721CrossRefPubMedGoogle Scholar
  46. Okell LC, Drakeley CJ, Ghani AC et al (2008) Reduction of transmission from malaria patients by artemisinin combination therapies: a pooled analysis of six randomized trials. Malar J 7:125–138CrossRefPubMedPubMedCentralGoogle Scholar
  47. Paik IH, Xie S, Shapiro TA et al (2006) Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity. J Med Chem 49:2731–2734CrossRefPubMedGoogle Scholar
  48. Penna-Coutinho J, Almela MJ, Miguel-Blanco C et al (2016) Transmission-blocking potential of MEFAS, a hybrid compound derived fromartesunate and mefloquine. Antimicrob Agents Chemother 60(5):3145–3147CrossRefPubMedPubMedCentralGoogle Scholar
  49. Raj DK, Nixon CP, Nixon CE et al (2014) Antibodies to pfsea-1 block parasite egress from rbcs and protect against malaria infection. Science 344:871–877CrossRefPubMedPubMedCentralGoogle Scholar
  50. Rappuoli R, Aderem A (2011) A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature 473:463–469CrossRefPubMedGoogle Scholar
  51. Schmidt TJ (2006) Structure-activity relationships of sesquiterpene lactones. Stud Nat Prod Chem 33:309–392CrossRefGoogle Scholar
  52. Seder RA, Chang LJ, Enama ME et al (2013) Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 341:1359–1365CrossRefPubMedGoogle Scholar
  53. Sirima SB, Ogutu B, Lusingu JPA et al (2016) Comparison of artesunate–mefloquine and artemether–lumefantrine fixed-dose combinations for treatment of uncomplicated Plasmodium falciparum malaria in children younger than 5 years in sub-Saharan Africa: a randomised, multicentre, phase 4 trial. Lancet 16:1123–1133CrossRefPubMedGoogle Scholar
  54. Srivastava V, Lee H (2015) Chloroquine-based hybrid molecules as promising novel chemotherapeutic agents. Eur J Pharmacol 762:472–486CrossRefPubMedGoogle Scholar
  55. Staines HM, Krishna S (2012) Treatment and prevention of malaria: antimalarial drug chemistry, action and use. Springer, LondonCrossRefGoogle Scholar
  56. Stover KR, King ST, Robinson J (2012) Artemether-Lumefantrine: an option for malaria. Ann Pharmacother 46:567–577CrossRefPubMedGoogle Scholar
  57. Sülsen V, Gutierrez Yappu D, Laurella L et al (2011) In vitro antiplasmodial activity of sesquiterpene lactones from Ambrosia tenuifolia. Evid Based Complement Alternat Med 2011:352938. https://doi.org/10.1155/2011/352938 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tan BS (2009) Population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin. Thesis, University of IowaGoogle Scholar
  59. Teixeira JRM (2011) Avaliação da terapêutica da malária por Plasmodium vivax: perfil cinético da cloroquina e primaquina. Ph.D. thesis, University Federal of Pará, BrazilGoogle Scholar
  60. Teixeira C, Vale N, Pérez B et al (2014) Recycling classical drugs for malaria. Chem Rev 114:1164–11220CrossRefGoogle Scholar
  61. The Nobel Foundation (2015) The Nobel prize in physiology or medicine 2015. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2015/press.pdf. Accessed 10 Jan 2016
  62. Unger C, Kiss I, Vasas A et al (2015) The germacranolide sesquiterpene lactone neurolenin B of the medicinal plant Neurolaena lobata (L.) R.Br. ex Cass inhibits NPM/ALK-driven cell expansion and NF-κB-driven tumour intravasation. Phytomedicine 22:862–874CrossRefPubMedGoogle Scholar
  63. Valecha N, Phyo AP, Mayxay M et al (2010) An open-label, randomised study of dihydroartemisinin-piperaquine versus artesunate-mefloquine for falciparum malaria in Asia. PLoS One 5(7):e11880. https://doi.org/10.1371/journal.pone.0011880 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Vandekerckhove S, D’hooghe M (2015) Quinoline-based antimalarial hybrid compounds. Bioorg Med Chem 23:5098–5119CrossRefPubMedGoogle Scholar
  65. Varotti FP, Botelho ACC, Andrade AA et al (2008) Synthesis, antimalarial activity, and intracellular targets of Mefas, a new hybrid compound derived from mefloquine and artesunate. Antimicrob Agents Chemother 52:3868–3874CrossRefGoogle Scholar
  66. Walsh JJ, Coughlan D, Heneghan N et al (2007) A novel artemisinin-quinine hybrid with potent antimalarial activity. Bioorg Med Chem Lett 17:3599–3602CrossRefPubMedGoogle Scholar
  67. Wells S, Diap G, Kiechel JR et al (2013) The story of artesunate–mefloquine (ASMQ), innovative partnerships in drug development: case study. Malar J 12:68–78CrossRefPubMedPubMedCentralGoogle Scholar
  68. World Health Organization (WHO) (2014) World malaria report. WHO, Geneva. http://www.who.int/malaria/publications/world_malaria_report_2014/report/en/. Accessed 02 Dec 2016
  69. World Health Organization (WHO) (2015a) World malaria report. http://www.who.int/malaria/publications/world-malaria-report-2015/report/en/. Accessed 10 Jan 2016
  70. World Health Organization (WHO) (2015b) Guidelines for the treatment of malaria, 3rd edn. World Health Organization, Geneva. http://www.who.int/malaria/publications/atoz/9789241549127/en/ Accessed 12 Jan 2017Google Scholar
  71. World Health Organization (WHO) (2016) World malaria report. http://www.who.int/malaria/publications/world-malaria-report-2016/report/en/. Accessed 16 Jan 2017
  72. WorldWide Antimalarial Resistance Network (WWARN) Lumefantrine PK/PD Study Group (2015) Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data. BMC Med 13:227–246CrossRefGoogle Scholar
  73. Wright CW, Linley PA, Brun R et al (2010) Ancient chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity. Molecules 15:804–812CrossRefPubMedGoogle Scholar
  74. Wyrebska A, Gach K, Szemraj J et al (2012) Comparison of anti-invasive activity of parthenolide and 3-isopropyl-2-methyl-4-methyleneisoxazolidin-5-one (MZ-6) – a new compound with a-methylene-c-lactone motif – on two breast cancer cell lines. Chem Biol Drug Des 79:112–120CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Nubia Boechat
    • 1
  • Luiz Carlos da Silva Pinheiro
    • 1
  • Flavia Fernandes da Silveira
    • 1
    • 2
  1. 1.Fundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos Farmanguinhos-FiocruzRio de JaneiroBrazil
  2. 2.Programa de Pós-graduação em Química da Universidade Federal do Rio de JaneiroRio de JaneiroBrazil

Personalised recommendations