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4-Aminoquinolines: Chloroquine, Amodiaquine and Next-Generation Analogues

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Treatment and Prevention of Malaria

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

For several decades, the 4-aminoquinolines chloroquine (CQ) and amodiaquine (AQ) were considered the most important drugs for the control and eradication of malaria. The success of this class has been based on excellent clinical efficacy, limited host toxicity, ease of use and simple, cost-effective synthesis. Importantly, chloroquine therapy is affordable enough for use in the developing world. However, its value has seriously diminished since the emergence of widespread parasite resistance in every region where P. falciparum is prevalent. Recent medicinal chemistry campaigns have resulted in the development of short-chain chloroquine analogues (AQ-13), organometallic antimalarials (ferroquine) and the “fusion” antimalarial trioxaquine (SAR116242). Projects to reduce the toxicity of AQ have resulted in the development of metabolically stable AQ analogues (isoquine/N-tert-butyl isoquine). In addition to these developments, older 4-aminoquinolines such as piperaquine and the related aza-acridine derivative pyronaridine continue to be developed. It is the aim of this chapter to review 4-aminoquinoline structure–activity relationships and medicinal chemistry developments in the field and consider the future therapeutic value of CQ and AQ.

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References

  1. Phillipson JD, O’Neill MJ (1986) Novel antimalarial drugs from plants? Parasitol Today 2:355–359

    Article  PubMed  CAS  Google Scholar 

  2. Jensen M, Mehlhorn H (2009) Seventy-five years of Resochin in the fight against malaria. Parasitol Res 105:609–627

    Article  PubMed  Google Scholar 

  3. Loeb LF, Clarke WM, Coatney GR, Coggeshall LT, Dieuaide FR, Dochez AR (1946) Activity of a new antimalarial agent, Chloroquine (SN 7618). JAMA 130:1069–1070

    Article  Google Scholar 

  4. Wells TN, Poll EM (2010) When is enough enough? The need for a robust pipeline of high-quality antimalarials. Discov Med 9:389–398

    PubMed  Google Scholar 

  5. Winstanley PA, Ward SA, Snow RW (2002) Clinical status and implications of antimalarial drug resistance. Microb Infect 4:157–164

    Article  CAS  Google Scholar 

  6. Foley M, Tilley L (1998) Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol Ther 79:55–87

    Article  PubMed  CAS  Google Scholar 

  7. Egan TJ (2001) Quinoline antimalarials. Expert Opin Ther Patents 11:185–209

    Article  Google Scholar 

  8. Tilley L, Loria P, Foley M (2001) Chloroquine and other quinoline antimalarials. In: Rosenthal PJ (ed) Antimalarial chemotherapy: mechanisms of action, resistance and new direction in drug discovery. Humana, Totowa, NJ, pp 87–121

    Google Scholar 

  9. Olliaro P (2001) Mode of action and mechanisms of resistance for antimalarial drugs. Pharmacol Ther 89:207–219

    Article  PubMed  CAS  Google Scholar 

  10. Surolia N, Padmanaban G (1991) Chloroquine inhibits heme-dependent protein synthesis in Plasmodium falciparum. Proc Natl Acad Sci USA 88:4786–4790

    Article  PubMed  CAS  Google Scholar 

  11. Ginsburg H, Geary TG (1987) Current concepts and new ideas on the mechanism of action of quinoline-containing antimalarials. Biochem Pharmacol 36:1567–1576

    Article  PubMed  CAS  Google Scholar 

  12. Vander Jagt DL, Hunsaker LA, Campos NM (1986) Characterization of a hemoglobin-degrading, low molecular weight protease from Plasmodium falciparum. Mol Biochem Parasitol 18:389–400

    Article  PubMed  CAS  Google Scholar 

  13. Cohen SN, Yielding KL (1965) Inhibition of DNA and RNA polymerase reactions by chloroquine. Proc Natl Acad Sci USA 54:521–527

    Article  PubMed  CAS  Google Scholar 

  14. Meshnick SR (1990) Chloroquine as intercalator: a hypothesis revived. Parasitol Today 6:77–79

    Article  PubMed  CAS  Google Scholar 

  15. Peters W (1970) Chemotherapy and drug resistance in malaria. Academic, London

    Google Scholar 

  16. Egan TJ (2008) Recent advances in understanding the mechanism of hemozoin (malaria pigment) formation. J Inorg Biochem 102:1288–1299

    Article  PubMed  CAS  Google Scholar 

  17. Slater AF, Cerami A (1992) Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature 355:167–169

    Article  PubMed  CAS  Google Scholar 

  18. Egan TJ, Ross DC, Adams PA (1994) Quinoline anti-malarial drugs inhibit spontaneous formation of beta-haematin (malaria pigment). FEBS Lett 352:54–57

    Article  PubMed  CAS  Google Scholar 

  19. Raynes K, Foley M, Tilley L, Deady LW (1996) Novel bisquinoline antimalarials. Synthesis, antimalarial activity, and inhibition of haem polymerisation. Biochem Pharmacol 52:551–559

    Article  PubMed  CAS  Google Scholar 

  20. Adams PA, Berman PA, Egan TJ, Marsh PJ, Silver J (1996) The iron environment in heme and heme-antimalarial complexes of pharmacological interest. J Inorg Biochem 63:69–77

    Article  PubMed  CAS  Google Scholar 

  21. Egan TJ, Mavuso WW, Ross DC, Marques HM (1997) Thermodynamic factors controlling the interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX. J Inorg Biochem 68:137–145

    Article  PubMed  CAS  Google Scholar 

  22. Egan TJ, Helder MM (1999) The role of haem in the activity of chloroquine and related antimalarial drugs. Coord Chem Rev 190–192:493–517

    Article  Google Scholar 

  23. Vippagunta SR, Dorn A, Matile H, Bhattacharjee AK, Karle JM, Ellis WY, Ridley RG, Vennerstrom JL (1999) Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth. J Med Chem 42:4630–4639

    Article  PubMed  CAS  Google Scholar 

  24. Dorn A, Vippagunta SR, Matile H, Jaquet C, Vennerstrom JL, Ridley RG (1998) An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochem Pharmacol 55:727–736

    Article  PubMed  CAS  Google Scholar 

  25. Sullivan DJ, Gluzman IY, Russell DG, Goldberg DE (1996) On the molecular mechanism of chloroquine’s antimalarial action. Proc Natl Acad Sci USA 93:11865–11870

    Article  PubMed  CAS  Google Scholar 

  26. Buller R, Peterson ML, Almarsson O, Leiserowitz L (2002) Quinoline binding site on malaria pigment crystal: a rational pathway for antimalaria drug design. Cryst Growth Des 2:553–562

    Article  CAS  Google Scholar 

  27. Hawley SR, Bray PG, Park BK, Ward SA (1996) Amodiaquine accumulation in Plasmodium falciparum as a possible explanation for its superior antimalarial activity over chloroquine. Mol Biochem Parasitol 80:15–25

    Article  PubMed  CAS  Google Scholar 

  28. Geary TG, Divo AD, Jensen JB, Zangwill M, Ginsburg H (1990) Kinetic modelling of the response of Plasmodium falciparum to chloroquine and its experimental testing in vitro. Implications for mechanism of action of and resistance to the drug. Biochem Pharmacol 40:685–691

    Article  PubMed  CAS  Google Scholar 

  29. Ferrari V, Cutler DJ (1991) Simulation of kinetic data on the influx and efflux of chloroquine by erythrocytes infected with Plasmodium falciparum. Evidence for a drug-importer in chloroquine-sensitive strains. Biochem Pharmacol 42(Suppl):S167–179

    Article  PubMed  CAS  Google Scholar 

  30. Ferrari V, Cutler DJ (1991) Kinetics and thermodynamics of chloroquine and hydroxychloroquine transport across the human erythrocyte membrane. Biochem Pharmacol 41:23–30

    Article  PubMed  CAS  Google Scholar 

  31. Sanchez CP, Wunsch S, Lanzer M (1997) Identification of a chloroquine importer in Plasmodium falciparum. Differences in import kinetics are genetically linked with the chloroquine-resistant phenotype. J Biol Chem 272:2652–2658

    Article  PubMed  CAS  Google Scholar 

  32. Chou AC, Chevli R, Fitch CD (1980) Ferriprotoporphyrin IX fulfills the criteria for identification as the chloroquine receptor of malaria parasites. Biochemistry 19:1543–1549

    Article  PubMed  CAS  Google Scholar 

  33. Bray PG, Janneh O, Raynes KJ, Mungthin M, Ginsburg H, Ward SA (1999) Cellular uptake of chloroquine is dependent on binding to ferriprotoporphyrin IX and is independent of NHE activity in Plasmodium falciparum. J Cell Biol 145:363–376

    Article  PubMed  CAS  Google Scholar 

  34. D’Alessandro U, Buttiëns H (2001) History and importance of antimalarial drug resistance. Trop Med Int Health 6:845–848

    Article  PubMed  Google Scholar 

  35. Bray PG, Mungthin M, Ridley RG, Ward SA (1998) Access to hematin: the basis of chloroquine resistance. Mol Pharmacol 54:170–179

    PubMed  CAS  Google Scholar 

  36. Sidhu ABS, Verdier-Pinard D, Fidock DA (2002) Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Science 298:210–213

    Article  PubMed  CAS  Google Scholar 

  37. Fidock DA, Nomura T, Talley AK, Cooper RA, Dzekunov SM, Ferdig MT, Ursos LMB, Sidhu ABS, Naude B, Deitsch KW (2000) Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Mol Cell 6:861–871

    Article  PubMed  CAS  Google Scholar 

  38. Krogstad DJ, Gluzman IY, Kyle DE, Oduola AMJ, Martin SK, Milhous WK, Schlesinger PH (1987) Efflux of chloroquine from Plasmodium falciparum – mechanism of chloroquine resistance. Science 238:1283–1285

    Article  PubMed  CAS  Google Scholar 

  39. Hayward R, Saliba KJ, Kirk K (2006) The pH of the digestive vacuole of Plasmodium falciparum is not associated with chloroquine resistance. J Cell Sci 119:1016–1025

    Article  PubMed  CAS  Google Scholar 

  40. Bray PG, Mungthin M, Hastings IM, Biagini GA, Saidu DK, Lakshmanan V, Johnson DJ, Hughes RH, Stocks PA, O’Neill PM (2006) PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX. Mol Microbiol 62:238–251

    Article  PubMed  CAS  Google Scholar 

  41. Warhurst DC, Craig JC, Adagu IS (2002) Lysosomes and drug resistance in malaria. Lancet 360:1527–1529

    Article  PubMed  Google Scholar 

  42. Sanchez CP, Stein WD, Lanzer M (2007) Is PfCRT a channel or a carrier? Two competing models explaining chloroquine resistance in Plasmodium falciparum. Trends Parasitol 23:332–339

    Article  PubMed  CAS  Google Scholar 

  43. Martin RE, Marchetti RV, Cowan AI, Howitt SM, Broer S, Kirk K (2009) Chloroquine transport via the malaria parasite’s chloroquine resistance transporter. Science 325:1680–1682

    Article  PubMed  CAS  Google Scholar 

  44. Sanchez CP, Dave A, Stein WD, Lanzer M (2010) Transporters as mediators of drug resistance in Plasmodium falciparum. Int J Parasitol 40:1109–1118

    Article  PubMed  CAS  Google Scholar 

  45. van Es HH, Karcz S, Chu F, Cowman AF, Vidal S, Gros P, Schurr E (1994) Expression of the plasmodial pfmdr1 gene in mammalian cells is associated with increased susceptibility to chloroquine. Mol Cell Biol 14:2419–2428

    Article  PubMed  Google Scholar 

  46. Sanchez CP, Rotmann A, Stein WD, Lanzer M (2008) Polymorphisms within PfMDR1 alter the substrate specificity for anti-malarial drugs in Plasmodium falciparum. Mol Microbiol 70:786–798

    PubMed  CAS  Google Scholar 

  47. WHO (2010) Guidelines for the treatment of malaria, 2nd edn. WHO (World Health Organization), Geneva

    Google Scholar 

  48. Laufer MK, Thesing PC, Eddington ND, Masonga R, Dzinjalamala FK, Takala SL, Taylor TE, Plowe CV (2006) Return of chloroquine antimalarial efficacy in Malawi. New Engl J Med 355:1959–1966

    Article  PubMed  CAS  Google Scholar 

  49. Djimde A, Doumbo OK, Cortese JF, Kayentao K, Doumbo S, Diourte Y, Dicko A, Su XZ, Nomura T, Fidock DA et al (2001) A molecular marker for chloroquine-resistant falciparum malaria. New Engl J Med 344:257–263

    Article  PubMed  CAS  Google Scholar 

  50. Read AF, Huijben S (2009) Evolutionary biology and the avoidance of antimicrobial resistance. Evol Appl 2:40–51

    Article  Google Scholar 

  51. Ursing J, Kofoed PE, Rodrigues A, Blessborn D, Thoft-Nielsen R, Bjorkman A, Rombo L (2011) Similar efficacy and tolerability of double-dose chloroquine and artemether-lumefantrine for treatment of Plasmodium falciparum infection in guinea-bissau: a randomized trial. J Infect Dis 203:109–116

    Article  PubMed  CAS  Google Scholar 

  52. Ursing J, Rombo L, Kofoed PE, Gil JP (2008) Carriers, channels and chloroquine efficacy in Guinea-Bissau. Trends Parasitol 24:49–51

    Article  PubMed  CAS  Google Scholar 

  53. Kofoed PE, Ursing J, Poulsen A, Rodrigues A, Bergquist Y, Aaby P, Rombo L (2007) Different doses of amodiaquine and chloroquine for treatment of uncomplicated malaria in children in Guinea-Bissau: implications for future treatment recommendations. Trans R Soc Trop Med Hyg 101:231–238

    Article  PubMed  CAS  Google Scholar 

  54. Hand CC, Meshnick SR (2011) Is chloroquine making a comeback? J Infect Dis 203:11–12

    Article  PubMed  CAS  Google Scholar 

  55. Ursing J, Schmidt BA, Lebbad M, Kofoed PE, Dias F, Gil JP, Rombo L (2007) Chloroquine resistant P.falciparum prevalence is low and unchanged between 1990 and 2005 in Guinea-Bissau: an effect of high chloroquine dosage? Infect Genet Evol 7:555–561

    Article  PubMed  CAS  Google Scholar 

  56. Kaur K, Jain M, Reddy RP, Jain R (2010) Quinolines and structurally related heterocycles as antimalarials. Eur J Med Chem 45:3245–3264

    Article  PubMed  CAS  Google Scholar 

  57. De D, Krogstad FM, Cogswell FB, Krogstad DJ (1996) Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro. Am J Trop Med Hyg 55:579–583

    PubMed  CAS  Google Scholar 

  58. Ridley RG, Hofheinz W, Matile H, Jaquet C, Dorn A, Masciadri R, Jolidon S, Richter WF, Guenzi A, Girometta MA (1996) 4-aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquine-resistant Plasmodium falciparum. Antimicrob Agents Chemother 40:1846–1854

    PubMed  CAS  Google Scholar 

  59. Ramanathan-Girish S, Catz P, Creek MR, Wu B, Thomas D, Krogstad DJ, De D, Mirsalis JC, Green CE (2004) Pharmacokinetics of the antimalarial drug, AQ-13, in rats and cynomolgus Macaques. Int J Toxicol 23:179–189

    Article  PubMed  CAS  Google Scholar 

  60. Mzayek F, Deng H, Mather FJ, Wasilevich EC, Liu H, Hadi CM, Chansolme DH, Murphy HA, Melek BH, Tenaglia AN (2007) Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin Trials 2:e6

    Article  PubMed  CAS  Google Scholar 

  61. Mzayek F, Deng HY, Hadi MA, Mave V, Mather FJ, Goodenough C, Mushatt DM, Lertora JJ, Krogstad D (2009) Randomized clinical trial (RCT) with a crossover study design to examine the safety and pharmacokinetics of a 2100 mg dose of AQ-13 and the effects of a standard fatty meal on its bioavailability. Am J Trop Med Hyg 81:S252

    Google Scholar 

  62. De D, Krogstad FM, Byers LD, Krogstad DJ (1998) Structure-activity relationships for antiplasmodial activity among 7-substituted 4-aminoquinolines. J Med Chem 41:4918–4926

    Article  PubMed  CAS  Google Scholar 

  63. Ward SA, Bray PG, Hawley SR, Mungthin M (1996) Physicochemical properties correlated with drug resistance and the reversal of drug resistance in Plasmodium falciparum. Mol Pharmacol 50:1559–1566

    PubMed  Google Scholar 

  64. Farrel N (1989) Transition metal complexes as drugs and chemotherapeutic agents. Kluwer Academic, Dordrecht

    Book  Google Scholar 

  65. Sanchez-Delgado RA, Navarro M, Perez H, Urbina JA (1996) Toward a novel metal-based chemotherapy against tropical diseases. 2. Synthesis and antimalarial activity in vitro and in vivo of new ruthenium- and rhodium-chloroquine complexes. J Med Chem 39:1095–1099

    Article  PubMed  CAS  Google Scholar 

  66. Sanchez-Delgado RA, Navarro M, Perez H (1997) Toward a novel metal-based chemotherapy against tropical diseases. 3. Synthesis and antimalarial activity in vitro and in vivo of the new gold-chloroquine complex [Au(PPh3)(CQ)]PF6. J Med Chem 40:1937–1939

    Article  PubMed  Google Scholar 

  67. Biot C, Glorian G, Maciejewski LA, Brocard JS, Domarle O, Blampain G, Millet P, Georges AJ, Abessolo H, Dive D (1997) Synthesis and antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue. J Med Chem 40:3715–3718

    Article  PubMed  CAS  Google Scholar 

  68. Biot C, Delhaes L, N’Diaye CM, Maciejewski LA, Camus D, Dive D, Brocard JS (1999) Synthesis and antimalarial activity in vitro of potential metabolites of ferrochloroquine and related compounds. Biorg Med Chem 7:2843–2847

    Article  CAS  Google Scholar 

  69. Dubar F, Khalife J, Brocard J, Dive D, Biot C (2008) Ferroquine, an ingenious antimalarial drug – thoughts on the mechanism of action. Molecules 13:2900–2907

    Article  PubMed  CAS  Google Scholar 

  70. Barends M, Jaidee A, Khaohirun N, Singhasivanon P, Nosten F (2007) In vitro activity of ferroquine (SSR 97193) against Plasmodium falciparum isolates from the Thai-Burmese border. Malar J 6:81

    Article  PubMed  CAS  Google Scholar 

  71. Leimanis ML, Jaidee A, Sriprawat K, Kaewpongsri S, Suwanarusk R, Barends M, Phyo AP, Russell B, Renia L, Nosten F (2010) Plasmodium vivax susceptibility to ferroquine. Antimicrob Agents Chemother 54:2228–2230

    Article  PubMed  CAS  Google Scholar 

  72. Sanofi-Aventis (2000) Dose ranging study of ferroquine with artesunate in african adults and children with uncomplicated Plasmodium falciparum malaria (FARM). In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD). http://clinicaltrials.gov/ct2/show/NCT00988507. Accessed 23 May 2011. NLM Identifier: NCT00988507

  73. Davis TME, Hung TY, Sim IK, Karunajeewa HA, Ilett KF (2005) Piperaquine – a resurgent antimalarial drug. Drugs 65:75–87

    Article  PubMed  CAS  Google Scholar 

  74. Hung TY, Davis TME, Ilett KF, Karunajeewa H, Hewitt S, Denis MB, Lim C, Socheat D (2004) Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria. Br J Clin Pharmacol 57:253–262

    Article  PubMed  CAS  Google Scholar 

  75. Hien TT, Dolecek C, Mai PP, Dung NT, Truong NT, Thai LH, An DTH, Thanh TT, Stepniewska K, White NJ (2004) Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomised clinical trial. Lancet 363:18–22

    Article  CAS  Google Scholar 

  76. Olliaro P, Wells TNC (2009) The global portfolio of new antimalarial medicines under development. Clin Pharmacol Ther 85:584–595

    Article  PubMed  CAS  Google Scholar 

  77. Zwang J, Ashley EA, Karema C, D’Alessandro U, Smithuis F, Dorsey G, Janssens B, Mayxay M, Newton P, Singhasivanon P (2009) Safety and efficacy of dihydroartemisinin-piperaquine in falciparum malaria: a prospective multi-centre individual patient data analysis. PLoS ONE 4:e6358

    Article  PubMed  CAS  Google Scholar 

  78. Price RN, Hasugian AR, Ratcliff A, Siswantoro H, Purba HLE, Kenangalem E, Lindegardh N, Penttinen P, Laihad F, Ebsworth EP (2007) Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin-piperaquine for drug-resistant malaria. Antimicrob Agents Chemother 51:4090–4097

    Article  PubMed  CAS  Google Scholar 

  79. Khanh NX, de Vries PJ, Ha LD, van Boxtel CJ, Koopmans R, Kager PA (1999) Declining concentrations of dihydroartemisinin in plasma during 5-day oral treatment with artesunate for falciparum malaria. Antimicrob Agents Chemother 43:690–692

    PubMed  CAS  Google Scholar 

  80. Charman SA (2007) Synthetic peroxides: a viable alternative to artemisinins for the treatment of uncomplicated malaria? In: American Society of Tropical Medicine and Hygiene (ASTMH) 56th Annual Meeting, Philadelphia, Pennsylvania, USA, 4–8 Nov 2007

    Google Scholar 

  81. Snyder C, Chollet J, Santo-Tomas J, Scheurer C, Wittlin S (2007) In vitro and in vivo interaction of synthetic peroxide RBx11160 (OZ277) with piperaquine in Plasmodium models. Exp Parasitol 115:296–300

    Article  PubMed  CAS  Google Scholar 

  82. White NJ (2008) Qinghaosu (Artemisinin): the price of success. Science 320:330–334

    Article  PubMed  CAS  Google Scholar 

  83. Meunier B (2008) Hybrid molecules with a dual mode of action: dream or reality? Acc Chem Res 41:69–77

    Article  PubMed  CAS  Google Scholar 

  84. Muregi FW, Ishih A (2010) Next-generation antimalarial drugs: hybrid molecules as a new strategy in drug design. Drug Dev Res 71:20–32

    PubMed  CAS  Google Scholar 

  85. Benoit-Vical F, Lelievre J, Berry A, Deymier C, Dechy-Cabaret O, Cazelles J, Loup C, Robert A, Magnaval JF, Meunier B (2007) Trioxaquines are new antimalarial agents active on all erythrocytic forms, including gametocytes. Antimicrob Agents Chemother 51:1463–1472

    Article  PubMed  CAS  Google Scholar 

  86. Cosledan F, Fraisse L, Pellet A, Guillou F, Mordmuller B, Kremsner PG, Moreno A, Mazier D, Maffrand JP, Meunier B (2008) Selection of a trioxaquine as an antimalarial drug candidate. Proc Natl Acad Sci USA 105:17579–17584

    Article  PubMed  CAS  Google Scholar 

  87. O’Neill PM, Bray PG, Hawley SR, Ward SA, Park BK (1998) 4-aminoquinolines – past, present, and future: a chemical perspective. Pharmacol Ther 77:29–58

    Article  PubMed  Google Scholar 

  88. Daily EB, Aquilante CL (2009) Cytochrome P450 2 C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics 10:1489–1510

    Article  PubMed  CAS  Google Scholar 

  89. Fu S, Bjorkman A, Wahlin B, Ofori-Adjei D, Ericsson O, Sjoqvist F (1986) In vitro activity of chloroquine, the two enantiomers of chloroquine, desethylchloroquine and pyronaridine against Plasmodium falciparum. Br J Clin Pharmacol 22:93–96

    PubMed  CAS  Google Scholar 

  90. White NJ, Looareesuwan S, Edwards G, Phillips RE, Karbwang J, Nicholl DD, Bunch C, Warrell DA (1987) Pharmacokinetics of intravenous amodiaquine. Br J Clin Pharmacol 23:127–135

    Article  PubMed  CAS  Google Scholar 

  91. Jewell H, Maggs JL, Harrison AC, O’Neill PM, Ruscoe JE, Park BK (1995) Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica 25:199–217

    Article  PubMed  CAS  Google Scholar 

  92. Jewell H, Ruscoe JE, Maggs JL, O’Neill PM, Storr RC, Ward SA, Park BK (1995) The effect of chemical substitution on the metabolic activation, metabolic detoxication, and pharmacological activity of amodiaquine in the mouse. J Pharmacol Exp Ther 273:393–404

    PubMed  Google Scholar 

  93. Clarke JB, Neftel K, Kitteringham NR, Park BK (1991) Detection of antidrug IgG antibodies in patients with adverse drug reactions to amodiaquine. Int Arch Allergy Appl Immunol 95:369–375

    Article  PubMed  CAS  Google Scholar 

  94. Churchill FC, Mount DL, Patchen LC, Bjorkman A (1986) Isolation, characterization and standardization of a major metabolite of amodiaquine by chromatographic and spectroscopic methods. J Chromatogr B 377:307–318

    Article  CAS  Google Scholar 

  95. Laurent F, Saivin S, Chretien P, Magnaval JF, Peyron F, Sqalli A, Tufenkji AE, Coulais Y, Baba H, Campistron G et al (1993) Pharmacokinetic and pharmacodynamic study of amodiaquine and its two metabolites after a single oral dose in human volunteers. Arzneim-Forsch 43:612–616

    CAS  Google Scholar 

  96. Li XQ, Bjorkman A, Andersson TB, Ridderstrom M, Masimirembwa CM (2002) Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther 300:399–407

    Article  PubMed  CAS  Google Scholar 

  97. O’Neill PM, Harrison AC, Storr RC, Hawley SR, Ward SA, Park BK (1994) The effect of fluorine substitution on the metabolism and antimalarial activity of amodiaquine. J Med Chem 37:1362–1370

    Article  PubMed  Google Scholar 

  98. O’Neill PM, Willock DJ, Hawley SR, Bray PG, Storr RC, Ward SA, Park BK (1997) Synthesis, antimalarial activity, and molecular modeling of tebuquine analogues. J Med Chem 40:437–448

    Article  PubMed  Google Scholar 

  99. Barlin GB, Ireland SJ, Nguyen TMT, Kotecka B, Rieckmann KH (1994) Potential antimalarials. XXI. Mannich base derivatives of 4-[7-Chloro(and 7-trifluoromethyl)quinolin-4-ylamino]phenols. Aust J Chem 47:1553–1560

    Article  CAS  Google Scholar 

  100. Peters W, Robinson BL (1992) The chemotherapy of rodent malaria. XLVII. Studies on pyronaridine and other Mannich base antimalarials. Ann Trop Med Parasitol 86:455–465

    PubMed  CAS  Google Scholar 

  101. Ward SA, Hawley SR, Bray PG, O’Neill PM, Naisbitt DJ, Park BK (1996) Manipulation of the N-alkyl substituent in amodiaquine to overcome the verapamil-sensitive chloroquine resistance component. Antimicrob Agents Chemother 40:2345–2349

    PubMed  Google Scholar 

  102. Tingle MD, Ruscoe JE, O’Neill PM, Ward SA, Park BK (1998) Effect of disposition of Mannich antimalarial agents on their pharmacology and toxicology. Antimicrob Agents Chemother 42:2410–2416

    PubMed  Google Scholar 

  103. Biagini GA, O’Neill PM, Bray PG, Ward SA (2005) Current drug development portfolio for antimalarial therapies. Curr Opin Pharmacol 5:473–478

    Article  PubMed  CAS  Google Scholar 

  104. Looareesuwan S, Kyle DE, Viravan C, Vanijanonta S, Wilairatana P, Wernsdorfer WH (1996) Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand. Am J Trop Med Hyg 54:205–209

    PubMed  CAS  Google Scholar 

  105. Pradines B, Mabika Mamfoumbi M, Parzy D, Owono Medang M, Lebeau C, Mourou Mbina JR, Doury JC, Kombila M (1999) In vitro susceptibility of African isolates of Plasmodium falciparum from Gabon to pyronaridine. Am J Trop Med Hyg 60:105–108

    PubMed  CAS  Google Scholar 

  106. Nosten FH (2010) Pyronaridine-artesunate for uncomplicated falciparum malaria. Lancet 375:1413–1414

    Article  PubMed  Google Scholar 

  107. Medicines for Malaria Venture. Pyramax dossier submitted to EMA. http://www.mmv.org/achievements-challenges/achievements/pyramax%C2%AE-dossier-submitted-ema?page=0. Accessed 24 May 2011

  108. O’Neill PM, Mukhtar A, Stocks PA, Randle LE, Hindley S, Ward SA, Storr RC, Bickley JF, O’Neil IA, Maggs JL (2003) Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials. J Med Chem 46:4933–4945

    Article  PubMed  CAS  Google Scholar 

  109. Delarue S, Girault S, Maes L, Debreu-Fontaine MA, Labaeid M, Grellier P, Sergheraert C (2001) Synthesis and in vitro and in vivo antimalarial activity of new 4-anilinoquinolines. J Med Chem 44:2827–2833

    Article  PubMed  CAS  Google Scholar 

  110. O’Neill PM, Park BK, Shone AE, Maggs JL, Roberts P, Stocks PA, Biagini GA, Bray PG, Gibbons P, Berry N (2009) Candidate selection and preclinical evaluation of N-tert-Butyl isoquine (GSK369796), an affordable and effective 4-Aminoquinoline antimalarial for the 21st century. J Med Chem 52:1408–1415

    Article  PubMed  CAS  Google Scholar 

  111. O’Neill PM, Shone AE, Stanford D, Nixon G, Asadollahy E, Park BK, Maggs JL, Roberts P, Stocks PA, Biagini G (2009) Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4-Fluoro and 4-Chloro analogues of amodiaquine. Identification of a suitable “back-up” compound for N-tert-butyl isoquine. J Med Chem 52:1828–1844

    Article  PubMed  CAS  Google Scholar 

  112. Schirmer RH, Coulibaly B, Stich A, Scheiwein M, Merkle H, Eubel J, Becker K, Becher H, Müller O, Zich T (2003) Methylene blue as an antimalarial agent. Redox Rep 8:272–275

    Article  PubMed  CAS  Google Scholar 

  113. Meissner PE, Mandi G, Coulibaly B, Witte S, Tapsoba T, Mansmann U, Rengelshausen J, Schiek W, Jahn A, Walter-Sack I (2006) Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine. Malar J 5:84

    Article  PubMed  CAS  Google Scholar 

  114. Chico RM, Pittrof R, Greenwood B, Chandramohan D (2008) Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy. Malar J 7:255

    Article  PubMed  CAS  Google Scholar 

  115. Pfizer (2000) Evaluate azithromycin plus chloroquine and sulfadoxine plus pyrimethamine combinations for intermittent preventive treatment of falciparum malaria infection in pregnant women In Africa. In: ClinicalTrials.gov [Internet]. National Library of Medicine (US), Bethesda (MD). http://clinicaltrials.gov/ct2/show/NCT01103063. Accessed 2011 May 23. NLM Identifier: NCT01103063

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Authors and Affiliations

  1. Department of Chemistry, Robert Robinson Laboratories, University of Liverpool, Liverpool, L69 7ZD, UK

    Paul M. O’Neill, Victoria E. Barton & James Chadwick

  2. Department of Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, L69 3GE, UK

    Paul M. O’Neill

  3. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK

    Stephen A. Ward

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  1. Paul M. O’Neill
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  2. Victoria E. Barton
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  3. Stephen A. Ward
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  4. James Chadwick
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Correspondence to Paul M. O’Neill .

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  1. Centre for Infection, Div. Cellular & Molecular Medicine, St. George's University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Henry M. Staines

  2. Medical School, Dept. Infectious Diseases, St. George´s Hospital, Cranmer Terrace, London, SW17 0RE, United Kingdom

    Sanjeev Krishna

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O’Neill, P.M., Barton, V.E., Ward, S.A., Chadwick, J. (2011). 4-Aminoquinolines: Chloroquine, Amodiaquine and Next-Generation Analogues. In: Staines, H., Krishna, S. (eds) Treatment and Prevention of Malaria. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-0346-0480-2_2

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