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Novel Quinoline Antimalarials

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Antimalarial Chemotherapy

Part of the book series: Infectious Disease ((ID))

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Abstract

Since the first total synthesis of a quinoline-based antimalarial in the early part of this century, thousands of chemical analogs have been synthesized and screened for biological activity against malaria (1). However, despite the evaluation of such a vast library of potential drug candidates we are still unsure about the essential pharmacophore and our understanding of their mechanisms of action are rudimentary and surrounded in controversy. So, as we move into the 21st century, we find ourselves relying on quinoline-based treatments for malaria that are empirically derived and based on original leads from the 1930s and 1940s. In addition, the emergence of pervasive strains of Plasmodium falciparum resistant to quinoline-based drugs has further brought into question the utility of this class of drug as a global solution to malaria infection (2). In defense of this class of drug, it is clear that they target a biological process that is totally unique to the malarial parasite, resulting in selectivity and limited host toxicity. Further, if we look at chloroquine, it is clear that the parasite has found it difficult to acquire resistance to this drug (resistance first reported some 15–20 yr after its introduction into use and following many millions of parasite drug exposures) (3). The degree of in vitro chloroquine resistance appears to peak in the 250- to 300-nM range as reported as early as the mid 1970s, and despite the continued geographical spread of resistant isolates and the continued widespread use of the drug in many parts of the world, the degree of resistance never exceeds these values. This may suggest that the resistance mechanism(s) is already operational at its maximal potential.

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References

  1. Hofheinz W, Merkli B. Quinine and quinine analogues. In: Peters W, Richards WHG, (eds). Handbook of Experimental Pharmacology, Vol 68/II, Antimalarial Drugs II. New York: Springer-Verlag, 1984, pp. 61–81.

    Chapter  Google Scholar 

  2. Peters W. Drug resistance in malaria parasites of animals and man. Adv Parasitol 1998; 41: 1–62.

    Article  PubMed  CAS  Google Scholar 

  3. Peters W. Chemotherapy and Drug Resistance in Malaria. London: Academic, 1987.

    Google Scholar 

  4. Guttman P, Ehrlich P. Uber die wirkung des methyebleu bei malaria. Berl Klin Wochensclir 1891; 28: 953–956.

    Google Scholar 

  5. Geary TG, Divo AA, Jensen JB. Activity of quinoline-containing antimalarials against chloroquine-sensitive and -resistant strains of Plasmodium falciparum in vitro. Trans R Soc Trop Med Hyg 1987; 81 (3): 499–503.

    Article  PubMed  CAS  Google Scholar 

  6. Carson PE, Hohl R, Nora MV, Parkhurst GW, Ahmad T, Scanlan S, et al. Toxicology of the 8-aminoquinolines and genetic factors associated with their toxicology in man. Bull WHO 1981; 59: 427–437.

    PubMed  CAS  Google Scholar 

  7. ’Neill PM. The effect of chemical substitution on the metabolism and antimalarial activity of amodiaquine and primaquine. PhD thesis, The University of Liverpool, 1995.

    Google Scholar 

  8. Nodiff EA, Chatterjee S, Masallani HA. Antimalarial activity of the 8-aminoquinolines. Prog Med Chem 1991; 28: 1–40.

    Article  PubMed  CAS  Google Scholar 

  9. Bhatt BK, Seth M, Bhaduri AP. Recent developments in 8-aminoquinoline antimalarials. Prog Drug Res 1984; 28: 197–231.

    Google Scholar 

  10. Brueckner RP, Lasseter KC, Lin ET, Schuster BG. First-time-in-humans safety and pharmacokinetics of WR 238605: a new antimalarial. Am J Trop Med Hyg 1998; 58 (5): 645–649.

    PubMed  CAS  Google Scholar 

  11. Brueckner RP, Coster T, Wesche DL, Shmuklarsky M, Schuster BG. Prophylaxis of Plasmodium falciparum infection in a human challenge model with WR 238605, a new 8-aminoquinoline antimalarial. Antimicrob Agents Chemother 1998; 42 (5): 1293–1294.

    PubMed  CAS  Google Scholar 

  12. Peters W, Robinson BL, Milhous WK. The chemotherapy of rodent malaria. LI. Studies on a new 8-aminoquinoline, WR 238,605. Ann Trop Med Parasitol 1993; 87 (6): 547–552.

    PubMed  CAS  Google Scholar 

  13. de Alencar FE, Cerutti C Jr, Durlacher RR, Boulos M, Alves FP, Milhous W, et al. Atovaquone and proguanil for the treatment of malaria in Brazil. J Infect Dis 1997;175(6):1544–1547.

    Article  PubMed  Google Scholar 

  14. Srivastava P, Pandey VC, Misra AP, Gupta P, Raj K, Bhaduri AP. Potential inhibitors of plasmodial heme oxygenase; an innovative approach for combating chloroquine resistant malaria. Bioorg Med Chem 1998; 6 (2): 181–187.

    Article  PubMed  CAS  Google Scholar 

  15. Sweeney TR. Drugs with quinine-like action. In: Peters W, Richards WHG (eds). Antimalarial Drugs II: Current Antimalarials and New Drug Developments. Berlin: Springer-Verlag, 1984, pp. 267–313.

    Google Scholar 

  16. Oduola AM, Milhous WK, Weatherly NF, Bowdre JH, Desjardins RE. Plasmodium falciparum: induction of resistance to mefloquine in cloned strains by continuous drug exposure in vitro. Exp Parasitol 1988; 67 (2): 354–360.

    Article  PubMed  CAS  Google Scholar 

  17. Vennerstrom JL, Nuzum EO, Miller RE, Dorn A, Gerena L, Dande PA, Ellis WY, et al. 8-Aminoquinolines active against blood stage Plasmodium falciparum in vitro inhibit hematin polymerization. Antimicrob Agents Chemother. 1998; 43 (3): 598–602.

    Google Scholar 

  18. Loeb LF, Clarke WM, Coatney GR, Coggeshall LT, Dieuaide FR, Dochez AR, et al. Activity of a new antimalarial agent chloroquine (SN 7618). J Am Med Assoc 1946; 130: 1069–1070.

    Article  Google Scholar 

  19. Bray PG, Hawley SR, Ward SA. 4-Aminoquinoline resistance of Plasmodium falciparum: insights from the study of amodiaquine uptake. Mol Pharmacol 1996; 50: 1551–1558.

    PubMed  CAS  Google Scholar 

  20. Bray PG, Raynes KJ, Mungthin M, Ginsburg H, Ward SA. Cellular uptake of chloroquine is dependant on binding to ferriprotoporphyrin IX, is independent of NHE activity in Plasmodium falciparum. J Cell Biol. 1999; 145 (2): 363–376.

    Article  PubMed  CAS  Google Scholar 

  21. Raynes KJ, Bray PG, Ward SA. Altered binding of chloroquine to ferriprotoporphyrin IX is the basis for chloroquine resistance. Drug Resist Updates 1999; 2: 97–103.

    Article  CAS  Google Scholar 

  22. Hawley SR, Bray PG, Mungthin M, Atkinson JD, O’Neill PM, Ward SA. Relationship between antimalarial drug activity, accumulation and inhibition of heme polymerization in Plasmodium falciparum in vitro. Antimicrob Agents Chemotherap 1998; 42 (3): 682–686.

    CAS  Google Scholar 

  23. Ekweozer C, Aderounmu AF, Sodeinde O. Comparison of the relative in vitro activity of chloroquine and amodiaquine against chloroquine-sensitive strains of P falciparum. Ann Trop Med Parasitol. 1987; 81: 95–99.

    Google Scholar 

  24. Greenwood D. Conflicts of interest: the genesis of synthetic antimalarial agents in peace and war. J Antimicrob Chemother 1995; 36: 857–872.

    Article  PubMed  CAS  Google Scholar 

  25. Watkins WM, Sixsmith DG, Spencer HG, Boriga DA, Karjuki DM, Kipingor T, et al. Effectiveness of amodiaquine as a treatment for chloroquine-resistant Plasmodium falciparum infections in Kenya. Lancet 1984; 1: 357–359.

    Article  PubMed  CAS  Google Scholar 

  26. Koh HL, Go ML, Ngiam TL, Mak JW. Conformational and Structural Features determining in vitro antimalarial activity in some indolo[3,2-c.1 quinolines, anilinoquinolines and tetrahydroindolo[3,2-d] benzazepeines. Eur J Med Chem 1994; 29: 107–113.

    Article  CAS  Google Scholar 

  27. Vippagunta SR, Dorn A, Matile H, Bhattacharjee AK, Karle JM, Ellis WY, et al. Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth. J Med Chem 1999; 42 (22): 4630–4639.

    Article  PubMed  CAS  Google Scholar 

  28. Heindel ND, Molnar J. Synthesis and antimalarial activity of amodiaquine analogs. J Med Chem 1970; 13 (1): 156–157.

    Article  PubMed  CAS  Google Scholar 

  29. Heindel ND, Bechara IS, Ohnmacht CJ, Molnar J, Lemke TF, Kennewell PD. Diaminoquinoline antimalarials. J Med Chem 1969; 12 (5): 797–801.

    Article  PubMed  CAS  Google Scholar 

  30. Werbel LM, Kesten SJ, Turner WR. Structure-activity relationships of antimalarial indolo[3,2-clquinolines [1,2]. Eur J Med Chem 1993; 28: 837–852.

    Article  CAS  Google Scholar 

  31. Go ML, Koh, HL, Ngiam TL, Phillipson JD, Kirby GC, O’Neill MJ, et al. Synthesis and in vitro antimalarial activity of some indolo[3,2-c]quinolines. Eur J Biochem 1992; 27: 391–394.

    CAS  Google Scholar 

  32. Bray PG, Ward SA, Ginsburg. H. Na+/H+ antiporter, chloroquine uptake and drug resistance: inconsistencies in a newly proposed model. Parasitol Today 1999; 15 (9): 360–363.

    Article  PubMed  CAS  Google Scholar 

  33. Schraufstatler E. Arch Pharmacol (Weinheim) 1965; 298: 655.

    Article  Google Scholar 

  34. Werbel LM, Cook PD, Elslager EF, Hung JH, Johnson JL, Kesten SJ, et al. Synthesis, antimalarial activity, and quantitative structure-activity relationships of tebuquine and a series of related 5-[(7-chloro-4-quinolinyl)amino]-3-[(alkylamino)methyl] [1,1’-biphenyl]2-ols and N-oxides. J Med Chem 1986; 29: 924–939.

    Article  PubMed  CAS  Google Scholar 

  35. O’Neill PM, Willock DJ, Hawley SR, Bray PG, Storr RC, Ward SA, et al. Synthesis, antimalarial activity and molecular modeling of tebuquine analogues. J Med Chem 1997; 40: 437–448.

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  37. Kesten SJ, Johnson J, Werbel LM. Synthesis and antimalarial effects of 4-[(7-chloro-4quinolinyl)amino]-2-[(diethylamino)methyl]-6-alkylphenols and their N-oxides. J Med Chem 1987; 30: 906–911.

    Article  PubMed  CAS  Google Scholar 

  38. Ward SA, Bray PG, Mungthin M, Hawley SR. Current views on the mechanisms of resistance to quinoline-containing drugs in Plasmodium falciparum. Ann Trop Med Parasitol 1995; 89: 121–124.

    PubMed  CAS  Google Scholar 

  39. Peters W. Pyronaridine against multiresistant falciparum malaria. Lancet 1996; 347 (9001): 625.

    Article  PubMed  CAS  Google Scholar 

  40. Ringwald P, Eboumbou EC, Bickii J, Basco LK. In vitro activities of pyronaridine, alone and in combination with other antimalarial drugs, against Plasmodium falciparum. Antimicrob Agents Chemother 1999; 43 (6): 1525–1527.

    PubMed  CAS  Google Scholar 

  41. Ringwald P, Meche FS, Basco LK. Short report: effects of pyronaridine on gametocytes in patients with acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1999; 61 (3): 446–448.

    PubMed  CAS  Google Scholar 

  42. Peters W, Robinson BL. The Chemotherapy of Rodent Malaria. XLVII. Studies on pyronaridine and other mannich base antimalarials. Ann Trop Med Parasitol 1992; 86: 455.

    PubMed  CAS  Google Scholar 

  43. Ruscoe JE, Jewell H, Maggs JL, O’Neill PM, Storr RC, Ward SA, et al. The effect of chemical substitution on the metabolic activation, metabolic detoxification, and pharmacological activity of amodiaquine in the mouse. J Pharm Exp Ther 1995; 273 (1): 393–404.

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  45. O’Neill PM, Willock DJ, Hawley SR, Bray PG, Storr RC, Park BK. Synthesis, antimalarial activity and molecular modelling of tebuquine analogues. J Med Chem. 1997; 40 (4): 437.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  47. Barlin GB, Nguyen TMT, Kotecka B, Rieckmenn KH. Potential antimalarials XV. Di-mannich bases of 4-[7-chloroquinolin-4-ylamino]phenol and 2-[7-bromo(and trifluormethyl)-1–5naphthiridin-4-ylamino]phenol. Aust J Chem 1992; 45: 1651–1662.

    Article  CAS  Google Scholar 

  48. Kotecka BM, Barlin GB, Edstein MD, Rieckmann KH. New quinoline di-Mannich base compounds with greater antimalarial activity than chloroquine, amodiaquine or pyronaridine. Antimicrob Agents Chemotherap. 1997; 41: 1369–1374.

    CAS  Google Scholar 

  49. Raynes KJ, Stocks PA, O’Neill PM, Park BK, Ward SA. New 4-aminoquinolines Mannich base antimalarials I. Effect of an alkyl substituent in the 5’-position of the 4’-hydroxyanilino sidechain. J Med Chem 1999; 42: 2747–2751.

    Article  PubMed  CAS  Google Scholar 

  50. De D, Krogstad FM, Cogswell FB, Krogstad DL. Aminoquinolines that circumvent resistance in Plasmodium falciparum in vitro. Am J Trop Med Hyg 1996; 55: 597–583.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  52. Ridley RG, Hofheinz W, Matile H, Jaquet C, Dorn A, Masciadri R, et al. 4-Aminoquinoline analogs of chloroquine with shortened side chains retain activity against chloroquineresistant Plasmodium falciparum. Antimicrob Agents Chemotherap 1996; 40 (8): 1846–1854.

    CAS  Google Scholar 

  53. Li Y, Hu Y, Huang HZ, Zhu DQ, Huang WJ, Wu DL, et al. Hydroxylpiperaquine in the treatment of falciparum malaria. Chin Med J 1981; 94: 301–302.

    PubMed  CAS  Google Scholar 

  54. Lin C, Feny-yi Q, Yan-chang Z. Field observations on the antimalarial piperaquine. Chin Med J. 1982; 95: 281–286.

    Google Scholar 

  55. Lin C. Recent studies on the antimalarial efficacy of piperaquine and hydroxyl piperaquine. Chin Med J. 1991; 104: 161–164.

    CAS  Google Scholar 

  56. Vennerstrom J, Ellis WY, Ager AL, Anderson SL, Gerena L, Milhous WK. Bisquinolines, N,N’-bis[7-chloroquinoline-4-yl]alkanediamines with potential against chloroquine resistant malaria. J Med Chem 1992; 35: 2129–2134.

    Article  PubMed  CAS  Google Scholar 

  57. Basco LK, Anderson SL, Milhous WK, Vennerstrom J. In vitro activity of Bisquinoline WR 268,668 against African clones and isolates of Plasmodium falciparum. Am J Trop Med Hyg 1994; 50: 200–205.

    PubMed  CAS  Google Scholar 

  58. Le Bras J, Deloron P, Charmot G. Dichloroquinazine[4-aminoquinoline], effective in vitro against chloroquine resistance Plasmodium falciparum. Lancet 1983; 1: 73–74.

    PubMed  Google Scholar 

  59. Ridley RG, Matile H, Jaquet C, Dorn A, Hofheinz W, Luepin W, et al. Antimalarial activity of the bisquinoline trans N,N-Bis[7-chloroquinolin-4-yl]cyclohexan-1,2-diamine: comparison of the two steroisomers and detailed evaluation of the S,S enantiomer, Ro 477737. Antimicrob Agents Chemother 1997; 41: 677–686.

    PubMed  CAS  Google Scholar 

  60. Hofheinz W, Leupin W. N,N-Bis[quinolin-4-yl]diamine derivatives, their preparation and their use as antimalarials. Chem Abstr 1996; 124: 260860f.

    Google Scholar 

  61. Hofheinz W, Masciadri R. Bisquinolines for the treatment of malaria. Chem Abstr 1996; 124: 260861g.

    Google Scholar 

  62. Raynes KJ, Galatis D, Cowman AF, Tilley L, Deady LW. Synthesis and activity of some antimalarial bisquinolines. J Med Chem 1995; 38: 204–206.

    Article  PubMed  CAS  Google Scholar 

  63. Raynes KJ, Foley M, Tilley L. Novel bisquinoline antimalarials, antimalarial activity and inhibition of haem polymerization. Mol Biochem Parasitol 1996; 52: 551–559.

    CAS  Google Scholar 

  64. Cowman AF, Deady LW, Deharo E, Desevnes J, Tilley L. Synthesis and activity of some antimalarial bisquinoline methanols. Aust J Chem 1997; 50: 1091–1096.

    Article  CAS  Google Scholar 

  65. Dorn A, Vippagunta SR, Matile H, Jaquet C, Vennerstrom JL, Ridley RG. An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerization by quinoline antimalarials. Biochem Pharmacol 1998; 55 (6): 727–36.

    Article  PubMed  CAS  Google Scholar 

  66. Watt G, Loesuttivibool L, Shanks GD, Bordreau EF, Brown AE, Pavanand K, et al. Quinine with tetracycline for the treatment of drug-resistant falciparum malaria in Thailand. Am J Trop Med Hyg 1992; 47: 108–111.

    PubMed  CAS  Google Scholar 

  67. Hofheinz W, Merkli B. Quinine and quinine analogues. In: Peters W. and Richards WHG. (eds). Antimalarial Drugs II. Berlin: Springer-Verlag, 1984, pp. 61–81.

    Chapter  Google Scholar 

  68. Pullman TNK, Eichelberger L, Alving AS, Jones R, Craige B, and Whorton CM. The use of SN-10,275 in the prophylaxis and treatment of sporozoite-induced vivax malaria (Chesson strain). J Clin Invest 1948; 27: 12–16.

    Article  CAS  Google Scholar 

  69. Ohnmacht CJ, Patel AR, Lutz RE, Antimalarials. 7. Bis[trifluoromethyl]-[2-piperidyl]-4quinolinemethanols. J Med Chem 1971; 14: 926–928.

    Article  PubMed  CAS  Google Scholar 

  70. Palmer KJ, Holliday SM, Brogden RN. Mefloquine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1993; 45: 430–475.

    Article  PubMed  CAS  Google Scholar 

  71. Mockenhaupt FP. Mefloquine resistance in Plasmodium falciparum. Parasitol Today 1995; 11: 248–253.

    Article  PubMed  CAS  Google Scholar 

  72. Riffkin C, Chung R, Wall D, Zalcberg JR, Cowman AF, Foley M, et al. Modulation of the function of human MDR-1 P-glycoprotein by the antimalarial drug mefloquine. Biochem Pharmacol 1996; 52: 1545–1552.

    Article  PubMed  CAS  Google Scholar 

  73. Bhattacharjee AK, Karle JM. Functional correlation of molecular electronic properties with potency of synthetic carbinolamine antimalarial agents. Bioorg Med Chem 1998; 6: 1927–1933.

    Article  PubMed  CAS  Google Scholar 

  74. Bryson HM, Goa KL. Halofantrine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic potential. Drugs 1992; 43: 236–258.

    Article  PubMed  CAS  Google Scholar 

  75. Ringwald P, Bickii J, Basco LK. In vitro activity of antimalarials against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon. Am J Trop Med Hyg 1996; 55 (3): 254–258.

    PubMed  CAS  Google Scholar 

  76. Falade CO, Salako LA, Sowunmi A, Oduola AM, Larcier P. Comparative efficacy of halofantrine, chloroquine and sulfadoxine-pyrimethamine for treatment of acute uncomplicatedfalciparum malaria in Nigerian children, Ann Trop Med Parasitol 1997; 91 (1): 7–16.

    Google Scholar 

  77. Fryauff DJ, Baird JK, Basri H, Wiady I, Purnomo, Bangs MJ, et al. Halofantrine and primaquine for radical cure of malaria in Irian Jaya, Indonesia. Ann Trop Med Parasitol 1997; 91 (1): 7–16.

    PubMed  CAS  Google Scholar 

  78. Wernsdorfer WH, Landgraf B, Kilimali VA, Wernsdorfer G. Activity of benflumetol and its enantiomers in fresh isolates of Plasmodium falciparum from East Africa. Acta Trop 1998; 70 (1): 9–15.

    Article  PubMed  CAS  Google Scholar 

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  1. Paul A. Stocks
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  2. Kaylene J. Raynes
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  3. Stephen A. Ward
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  1. School of Medicine, University of California, San Francisco, CA, USA

    Philip J. Rosenthal MD

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Stocks, P.A., Raynes, K.J., Ward, S.A. (2001). Novel Quinoline Antimalarials. In: Rosenthal, P.J. (eds) Antimalarial Chemotherapy. Infectious Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-111-4_13

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  • DOI: https://doi.org/10.1007/978-1-59259-111-4_13

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