Next‐generation antimalarial drugs: hybrid molecules as a new strategy in drug design

Abstract

Malaria is a disease that affects nearly 40% of the global population, and chemotherapy remains the mainstay of its control strategy. The global malaria situation is increasingly being exacerbated by the emergence of drug resistance to most of the available antimalarials, necessitating search for novel drugs. A recent rational approach of antimalarial drug design characterized as “covalent bitherapy” involves linking two molecules with individual intrinsic activity into a single agent, thus packaging dual‐activity into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next‐generation antimalarial drugs. If the selective toxicity of hybrid prodrugs can be demonstrated in vivo with good bioavailability at the target site in the parasite, it would offer various advantages including dosage compliance, minimized toxicity, ability to design better drug combinations, and cheaper preclinical evaluation while achieving the ultimate object of delaying or circumventing the development of resistance. This review is focused on several hybrid molecules that have been developed, with particular emphasis on those deemed to have high potential for development for clinical use. Drug Dev Res 71: 20–32, 2010. © 2009 Wiley‐Liss, Inc.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 59

1. 1.

   Araújo NC, Barton V, Jones M, Stocks PA, Ward SA, Davies J, Bray PG, Shone AE, Cristiano ML, O'Neill PM. 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. 2009;19:2038-2043.

   Not in our library10.1016/j.bmcl.2009.02.013

2. 2.

   Atamna H, Ginsburg H. The malaria parasite supplies glutathione to its host cell: investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodium falciparum. Eur J Biochem. 1997;250:670-679.

   Not in our library10.1111/j.1432-1033.1997.00670.x

3. 3.

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

   Not in our library10.1186/1475-2875-6-81

4. 4.

   Basco LK, Dechy-Cabaret O, Ndounga M, Meche FS, Robert A, Meunier B. In vitro activities of DU-1102, a new trioxaquine derivative, against Plasmodium falciparum isolates. Antimicrob Agents Chemother. 2001;45:1886-1888.

   Not in our library10.1128/aac.45.6.1886-1888.2001

5. 5.

   Becker K, Rahlfs S, Nickel C, Schirmer RH. Glutathione: functions and metabolism in the malarial parasite Plasmodium falciparum. Biol Chem. 2003;384:551-566.

   Not in our library10.1515/bc.2003.063

6. 6.

   Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois MC, Demoitie MA, Stallaert JF, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Ballou WR, Cohen J, Riley EM, Lemnge MM, Marsh K, von Seidlein L. Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N Engl J Med. 2008;359:2521-2532.

   Not in our library10.1056/nejmoa0807381

7. 7.

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

   Not in our library10.1128/aac.00967-06

8. 8.

   Biot C, Dessolin J, Ricard I, Dive D. Easily synthesized antimalarial ferrocene triazacyclononane quinoline conjugates. J Organomet Chem. 2004;689:4678-4682.

   Not in our library

9. 9.

   Biot C, Pradines B, Sergeant MH, Gut J, Rosenthal PJ, Chibale K. Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues. Bioorg Med Chem Lett. 2007;17:6434-6438.

   Not in our library10.1016/j.bmcl.2007.10.003

10. 10.

    Bloland PB. Drug resistance in malaria. 2001;1-23.

    Not in our library

11. 11.

    Bray PG, Martin RE, Tilley L, Ward SA, Kirk K, Fidock DA. Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. Mol Microbiol. 2005;56:323-333.

    Not in our library10.1111/j.1365-2958.2005.04556.x

12. 12.

    Burgess SJ, Selzer A, Kelly JX, Smilkstein MJ, Riscoe MK, Peyton DH. A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum. J Med Chem. 2006;49:5623-5625.

    Not in our library10.1021/jm060399n

13. 13.

    Capela R, Oliveira R, Goncalves LM, Domingos A, Gut J, Rosenthal PJ, Lopes F, Moreira R. Artemisinin-dipeptidyl vinyl sulfone hybrid molecules: design, synthesis and preliminary SAR for antiplasmodial activity and falcipain-2 inhibition. Bioorg Med Chem Lett. 2009;19:3229-3232.

    Not in our library10.1016/j.bmcl.2009.04.100

14. 14.

    Chipeleme A, Gut J, Rosenthal PJ, Chibale K. Synthesis and biological evaluation of phenolic Mannich bases of benzaldehyde and (thio)semicarbazone derivatives against the cysteine protease falcipain-2 and a chloroquine resistant strain of Plasmodium falciparum. Bioorg Med Chem. 2007;15:273-282.

    Not in our library10.1016/j.bmc.2006.09.055

15. 15.

    Chiyanzu I, Clarkson C, Smith PJ, Lehman J, Gut J, Rosenthal PJ, Chibale K. Design, synthesis and anti-plasmodial evaluation in vitro of new 4-aminoquinoline isatin derivatives. Bioorg Med Chem. 2005;13:3249-3261.

    Not in our library10.1016/j.bmc.2005.02.037

16. 16.

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

    Not in our library10.1073/pnas.0804338105

17. 17.

    Creek DJ, Charman WN, Chiu FCK, Prankerd RJ, Dong Y, Vennerstrom JL, Charman SA. Relationship between antimalarial activity and heme alkylation for spiro- and dispiro-1,2,4-trioxolane antimalarials. Antimicrob Agents Chemother. 2008;52:1291-1296.

    Not in our library10.1128/aac.01033-07

18. 18.

    Davioud-Charvet E, Delarue S, Biot C, Schwöbel B, Boehme CC, Müssigbrodt A, Maes L, Sergheraert C, Grellier P, Schirmer RH, Becker K. A prodrug form of a Plasmodium falciparum glutathione reductase inhibitor conjugated with a 4-anilinoquinoline. J Med Chem. 2001;44:4268-4276.

    Not in our library10.1021/jm010268g

19. 19.

    Eckstein-Ludwig U, Webb RJ, Van Goethem ID, East JM, Lee AG, Kimura M, O'Neill PM, Bray PG, Ward SA, Krishna S. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424:957-961.

    Not in our library10.1038/nature01813

20. 20.

    Ellis GL, Amewu R, Hall C, Rimmer K, Ward SA, O'Neill PM. An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity. Bioorg Med Chem Lett. 2008;18:1720-1724.

    Not in our library10.1016/j.bmcl.2008.01.053

21. 21.

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

    Not in our library10.1016/s0163-7258(98)00012-6

22. 22.

    Gautam A, Ahmed T, Batra V, Paliwal J. Pharmacokinetics and pharmacodynamics of endoperoxide antimalarials. Curr Drug Metab. 2009;10:289-306.

    Not in our library10.2174/138920009787846323

23. 23.

    Gómez ZM, Rathod PK. Antimalarial activity of a combination of 5-fluoroorotate and uridine in mice. Antimicrob Agents Chemother. 1990;34:1371-1375.

    Not in our library10.1128/aac.34.7.1371

24. 24.

    Jones M, Mercer AE, Stocks PA, La Pensee LJ, Cosstick R, Park BK, Kennedy ME, Piantanida I, Ward SA, Davies J, Bray PG, Rawe SL, Baird J, Charidza T, Janneh O, O'Neill PM. Antitumour and antimalarial activity of artemisinin-acridine hybrids. Bioorg Med Chem Lett. 2009;19:2033-2037.

    Not in our library10.1016/j.bmcl.2009.02.028

25. 25.

    Kelly JX, Smilkstein MJ, Cooper RA, Lane KD, Johnson RA, Janowsky A, Dodean RA, Hinrichs DJ, Winter R, Riscoe M. Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum. Antimicrob Agents Chemother. 2007;51:4133-4140.

    Not in our library10.1128/aac.00669-07

26. 26.

    Kelly JX, Smilkstein MJ, Brun R, Wittlin S, Cooper RA, Lane KD, Janowsky A, Johnson RA, Dodean RA, Winter R, Hinrichs DJ, Riscoe MK. An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity. Nature. 2009;459:270-273.

    Not in our library

27. 27.

    Kouznetsov VV, Gómez-Barrio A. Recent developments in the design and synthesis of hybrid molecules based on aminoquinoline ring and their antiplasmodial evaluation. Eur J Med Chem. 2009;44:3091-3113.

    Not in our library10.1016/j.ejmech.2009.02.024

28. 28.

    Loup C, Lelievre J, Benoit-Vical F, Meunier B. Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. Antimicrob Agents Chemother. 2007;51:3768-3770.

    Not in our library10.1128/aac.00239-07

29. 29.

    Maher B. Malaria: the end of the beginning. Nature. 2008;451:1042-1046.

    Not in our library10.1038/4511042a

30. 30.

    Maude RJ, Woodrow CJ, White LJ. The artemisinin antimalarials: preserving the “magic bullet.”. Drug Dev Res. 2010;71:12-19.

    Not in our library10.1002/ddr.20344

31. 31.

    Meierjohann S, Walter RD, Muller S. Regulation of intracellular glutathione levels in erythrocytes infected with chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum. Biochem J. 2002;368:761-768.

    Not in our library10.1042/bj20020962

32. 32.

    Meshnick SR, Yang YZ, Lima V, Kuypers F, Kamchonwongpaisan S, Yuthavong Y. Iron-dependent free radical generation from the antimalarial agent artemisinin (qinghaosu). Antimicrob Agents Chemother. 1993;37:1108-1114.

    Not in our library10.1128/aac.37.5.1108

33. 33.

    Morphy R, Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005;48:6523-6543.

    Not in our library10.1021/jm058225d

34. 34.

    Muregi FW, Kano S, Kino H, Ishih A. Plasmodium berghei: efficacy of 5-fluoroorotate in combination with commonly used antimalarial drugs in a mouse model. Exp Parasitol. 2009;121:376-380.

    Not in our library10.1016/j.exppara.2009.01.009

35. 35.

    Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008;359:2619-2620.

    Not in our library10.1056/nejmc0805011

36. 36.

    Nzila A. The past, present and future of antifolates in the treatment of Plasmodium falciparum infection. J Antimicrob Chemother. 2006;57:1043-1054.

    Not in our library10.1093/jac/dkl104

37. 37.

    Nzila A, Ward SA, Marsh K, Sims PF, Hyde JE. Comparative folate metabolism in humans and malaria parasites (part I): pointers for malaria treatment from cancer chemotherapy. Trends Parasitol. 2005;21:292-298.

    Not in our library10.1016/j.pt.2005.04.002

38. 38.

    Olliaro P, Wells TN. The global portfolio of new antimalarial medicines under development. Clin Pharmacol Ther. 2009;85:584-595.

    Not in our library10.1038/clpt.2009.51

39. 39.

    Olson JE, Lee GK, Semenov A, Rosenthal PJ. Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors. Bioorg Med Chem. 1999;7:633-638.

    Not in our library10.1016/s0968-0896(99)00004-8

40. 40.

    Pandey AV, Tekwani BL, Singh RL, Chauhan VS. Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite. J Biol Chem. 1999;274:19383-19388.

    Not in our library10.1074/jbc.274.27.19383

41. 41.

    Perry CS, Charman SA, Prankerd RJ, Chiu FC, Dong Y, Vennerstrom JL, Charman WN. Chemical kinetics and aqueous degradation pathways of a new class of synthetic ozonide antimalarials. J Pharm Sci. 2006;95:737-747.

    Not in our library10.1002/jps.20568

42. 42.

    Pukrittayakamee S, Chotivanich K, Chantra A, Clemens R, Looareesuwan S, White NJ. Activities of artesunate and primaquine against asexual- and sexual-stage parasites in falciparum malaria. Antimicrob Agents Chemother. 2004;48:1329-1334.

    Not in our library10.1128/aac.48.4.1329-1334.2004

43. 43.

    Rajić Z, Kos G, Zorc B, Singh PP, Singh S. Macromolecular prodrugs. XII. Primaquine conjugates: synthesis and preliminary antimalarial evaluation. Acta Pharm. 2009;59:107-115.

    Not in our library10.2478/v10007-009-0007-x

44. 44.

    Rathod PK, Gómez ZM. Plasmodium yoelii: oral delivery of 5-fluoroorotate to treat malaria in mice. Exp Parasitol. 1991;73:512-514.

    Not in our library10.1016/0014-4894(91)90075-8

45. 45.

    Rathod PK, Khatri A, Hubbert T, Milhous WK. Selective activity of 5-fluoroorotic acid against Plasmodium falciparum in vitro. Antimicrob Agents Chemother. 1989;33:1090-1094.

    Not in our library10.1128/aac.33.7.1090

46. 46.

    Rathod PK, Leffers NP, Young RD. Molecular targets of 5-fluoroorotate in the human malaria parasite, Plasmodium falciparum. Antimicrob Agents Chemother. 1992;36:704-711.

    Not in our library10.1128/aac.36.4.704

47. 47.

    Robert A, Meunier B. Is alkylation the main mechanism of action of the antimalarial drug artemisinin? Chem Soc Rev. 1998;27:273-279.

    Not in our library

48. 48.

    Rosenthal PJ. Antimalarial drug discovery: old and new approaches. J Exp Biol. 2003;206:3735-3744.

    Not in our library10.1242/jeb.00589

49. 49.

    Sabbani S, Stocks PA, Ellis GL, Davies J, Hedenstrom E, Ward SA, O'Neill PM. Piperidine dispiro-1,2,4-trioxane analogues. Bioorg Med Chem Lett. 2008;18:5804-5808.

    Not in our library10.1016/j.bmcl.2008.09.052

50. 50.

    Sajid M, McKerrow JH. Cysteine proteases of parasitic organisms. Mol Biochem Parasitol. 2002;120:1-21.

    Not in our library10.1016/s0166-6851(01)00438-8

51. 51.

    Solomon VR, Haq W, Smilkstein M, Srivastava K, Rajakumar S, Puri SK, Katti SB. Synthesis and antimalarial activity of novel side chain modified antimalarial agents derived from 4-aminoquinoline. Med Chem. 2008;4:446-456.

    Not in our library10.2174/157340608785700207

52. 52.

    Uhlemann AC, Wittlin S, Matile H, Bustamante LY, Krishna S. Mechanism of antimalarial action of the synthetic trioxolane RBX11160 (OZ277). Antimicrob Agents Chemother. 2007;51:667-672.

    Not in our library10.1128/aac.01064-06

53. 53.

    Vangapandu S, Sachdeva S, Jain M, Singh S, Singh PP, Kaul CL, Jain R. 8-quinolinamines and their pro prodrug conjugates as potent blood-schizontocidal antimalarial agents. Bioorg Med Chem. 2003;11:4557-4568.

    Not in our library10.1016/j.bmc.2003.07.003

54. 54.

    Van Schalkwyk DA, Egan TJ. Quinoline-resistance reversing agents for the malaria parasite Plasmodium falciparum. Drug Resist Updat. 2006;9:211-226.

    Not in our library10.1016/j.drup.2006.09.002

55. 55.

    Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FC, Chollet J, Dong Y, Dorn A, Hunziker D, Matile H, McIntosh K, Padmanilayam M, Santo Tomas J, Scheurer C, Scorneaux B, Tang Y, Urwyler H, Wittlin S, Charman WN. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature. 2004;430:900-904.

    Not in our library10.1038/nature02779

56. 56.

    Wang X, Dong Y, Wittlin S, Creek D, Chollet J, Charman SA, Tomas JS, Scheurer C, Snyder C, Vennerstrom JL. Spiro- and dispiro-1,2-dioxolanes: contribution of iron(II)-mediated one-electron vs two-electron reduction to the activity of antimalarial peroxides. J Med Chem. 2007;50:5840-5847.

    Not in our library10.1021/jm0707673

57. 57.

    Wei N, Sadrzadeh SM. Enhancement of hemin-induced membrane damage by artemisinin. Biochem Pharmacol. 1994;48:737-741.

    Not in our library10.1016/0006-2952(94)90051-5

58. 58.

    Wiwanitkit V. Plasmodium and host glutathione reductase: molecular function and biological process. Afr J Biotechnol. 2006;5:2009-2013.

    Not in our library

59. 59.

    Zhou L, Alker A, Ruf A, Wang X, Chiu FC, Morizzi J, Charman SA, Charman WN, Scheurer C, Wittlin S, Dong Y, Hunziker D, Vennerstrom JL. Characterization of the two major CYP450 metabolites of ozonide (1,2,4-trioxolane) OZ277. Bioorg Med Chem Lett. 2008;18:1555-1558.

    Not in our library10.1016/j.bmcl.2008.01.087

Cited by papers we hold 1

• New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics · 2013
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.