Volume 91, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Because of emerging resistance to existing drugs, new chemical classes of antimalarial drugs are urgently needed. We have rationally designed a library of compounds that were predicted to accumulate in the digestive vacuole and then decrystallize hemozoin by breaking the iron carboxylate bond in hemozoin. We report the synthesis of 16 naphthothiazolium salts with amine-bearing side chains and their activities against the erythrocytic stage of . KSWI-855, the compound with the highest efficacy against the asexual stages of , also had activity against gametocytes and activity against in a murine malaria model.


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  1. World Health Organization. World Malaria Report 2011. Available at: http://www.who.int/malaria/world_malaria_report_2011/en/. Accessed August 13, 2012.
  2. Price RN, Dorsey G, Ashley EA, Barnes KI, Baird JK, d'Alessandro U, Guerin PJ, Laufer MK, Naidoo I, Nosten F, Olliaro P, Plowe CV, Ringwald P, Sibley CH, Stepniewska K, White NJ, , 2007. World Antimalarial Resistance Network I: clinical efficacy of antimalarial drugs. Malar J 6: 119.[Crossref]
  3. Valderramos SG, Fidock DA, , 2006. Transporters involved in resistance to antimalarial drugs. Trends Pharmacol Sci 27: 594601.[Crossref]
  4. Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K, Lim P, Zhou C, Mao S, Anderson JM, Lindegardh N, Jiang H, Song J, Su X, White NJ, Dondorp AM, Anderson TJC, Fay MP, Mu J, Duong S, Fairhurst RM, , 2012. Artemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis 12: 851858.[Crossref]
  5. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, Lwin KM, Ariey F, Hanpithakpong W, Lee SJ, Ringwald P, Silamut K, Imwong M, Chotivanich K, Lim P, Herdman T, An SS, Yeung S, Singhasivanon P, Day NPJ, Lindegardh N, Socheat D, White NJ, , 2009. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med 361: 455467.[Crossref]
  6. Dondorp AM, Fairhurst RM, Slutsker L, Macarthur JR, Breman JG, Guerin PJ, Wellems TE, Ringwald P, Newman RD, Plowe CV, , 2011. The threat of artemisinin-resistant malaria. N Engl J Med 365: 10731075.[Crossref]
  7. Kyaw MP, Nyunt MH, Chit K, Aye MM, Aye KH, Aye MM, Lindegardh N, Tarning J, Imwong M, Jacob CG, Rasmussen C, Perin J, Ringwald P, Nyunt MM, , 2013. Reduced susceptibility of Plasmodium falciparum to artesunate in southern Myanmar. PLoS ONE 8: e57689.[Crossref]
  8. Carrara VI, Zwang J, Ashley EA, Price RN, Stepniewska K, Barends M, Brockman A, Anderson T, McGready R, Phaiphun L, Proux S, van Vugt M, Hutagalung R, Lwin KM, Phyo AP, Preechapornkul P, Imwong M, Pukrittayakamee S, Singhasivanon P, White NJ, Nosten F, , 2009. Changes in the treatment responses to artesunate-mefloquine on the northwestern border of Thailand during 13 years of continuous deployment. PLoS ONE 4: e4551.[Crossref]
  9. Yang H, Liu D, Yang Y, Fan B, Yang P, Li X, Li C, Dong Y, Yang C, , 2003. Changes in susceptibility of Plasmodium falciparum to artesunate in vitro in Yunnan Province, China. Trans R Soc Trop Med Hyg 97: 226228.[Crossref]
  10. Anthony MP, Burrows JN, Duparc S, Moehrle JJ, Wells TNC, , 2012. The global pipeline of new medicines for the control and elimination of malaria. Malar J 11: 316.[Crossref]
  11. Ding XC, Ubben D, Wells TNC, , 2012. A framework for assessing the risk of resistance for anti-malarials in development. Malar J 11: 292.[Crossref]
  12. Francis SE, Sullivan DJ, Jr Goldberg DE, , 1997. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum . Annu Rev Microbiol 51: 97123.[Crossref]
  13. Becker K, Tilley L, Vennerstrom JL, Roberts D, Rogerson S, Ginsburg H, , 2004. Oxidative stress in malaria parasite-infected erythrocytes: host-parasite interactions. Int J Parasitol 34: 163189.[Crossref]
  14. Fitch CD, Chevli R, Kanjananggulpan P, Dutta P, Chevli K, Chou AC, , 1983. Intracellular ferriprotoporphyrin IX is a lytic agent. Blood 62: 11651168.
  15. Hebbel RP, Eaton JW, , 1989. Pathobiology of heme interaction with the erythrocyte membrane. Semin Hematol 26: 136149.
  16. Ulrich P, Cerami A, , 1982. Potential antitrypanosomal agents. 1,N2-disubstituted 2-amino-5-hydroxy-4-methylnaphtho[1,2-d]thiazolium salts and related compounds. J Med Chem 25: 654657.[Crossref]
  17. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD, , 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16: 710718.[Crossref]
  18. Buchholz K, Burke TA, Williamson KC, Wiegand RC, Wirth DF, Marti M, , 2011. A high-throughput screen targeting malaria transmission stages opens new avenues for drug development. J Infect Dis 203: 14451453.[Crossref]
  19. Franke-Fayard B, Trueman H, Ramesar J, Mendoza J, van der Keur M, van der Linden R, Sinden RE, Waters AP, Janse CJ, , 2004. A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle. Mol Biochem Parasitol 137: 2333.[Crossref]
  20. Daher W, Biot C, Fandeur T, Jouin H, Pelinski L, Viscogliosi E, Fraisse L, Pradines B, Brocard J, Khalife J, Dive D, , 2006. Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure. Malar J 5: 11.[Crossref]
  21. Van Schalkwyk DA, Walden JC, Smith PJ, , 2001. Reversal of chloroquine resistance in Plasmodium falciparum using combinations of chemosensitizers. Antimicrob Agents Chemother 45: 31713174.[Crossref]
  22. Pratt-Riccio LR, Chehuan YF, Siqueira MJ, das Graças Alecrim M, Bianco-Junior C, Druilhe P, Brasseur P, de Fatima Ferreira-da-Cruz M, Carvalho LJ, Danile-Ribeiro CT, , 2013. Use of a colorimetric (DELI) test for the evaluation of chemoresistance of Plasmodium falciparum and Plasmodium vivax to commonly used anti-plasmodial drugs in the Brazilian Amazon. Malar J 12: 281.[Crossref]
  23. Wang Z, Liu M, Liang X, Siriwat S, Li X, Chen X, Parker DM, Miao J, Cui L, , 2014. A flow cytometry-based quantitative drug sensitivity assay for all Plasmodium falciparum gametocyte stages. PLoS ONE 9: e93825.[Crossref]
  24. Fidock DA, Rosenthal PJ, Croft SL, Brun R, Nwaka S, , 2004. Antimalarial drug discovery: efficacy models for compound screening. Nat Rev Drug Discov 3: 509520.[Crossref]
  25. Noland GS, Briones N, Sullivan DJ, Jr, 2003. The shape and size of hemozoin crystals distinguishes diverse Plasmodium species. Mol Biochem Parasitol 130: 9199.[Crossref]
  26. Gorka AP, de Dios AC, Roepe PD, , 2013. Quinoline drug-heme interactions and implications for antimalarial cytostatic versus cytocidal activities. J Med Chem.
  27. Krugliak M, Zhang J, Ginsburg H, , 2002. Intraerythrocytic Plasmodium falciparum utilizes only a fraction of the amino acids derived from the digestion of host cell cytosol for the biosynthesis of its proteins. Mol Biochem Parasitol 119: 249256.[Crossref]
  28. Moura PA, Dame JB, Fidock DA, , 2009. Role of Plasmodium falciparum digestive vacuole plasmepsins in the specificity and antimalarial mode of action of cysteine and aspartic protease inhibitors. Antimicrob Agents Chemother 53: 49684978.[Crossref]
  29. Chugh M, Sundararaman V, Kumar S, Reddy VS, Siddiqui WA, Stuart KD, Malhotra P, , 2013. Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum . Proc Natl Acad Sci USA 110: 53925397.[Crossref]
  30. Mauritz JM, Esposito A, Ginsburg H, Kaminski CF, Tiffert T, Lew VL, , 2009. The homeostasis of Plasmodium falciparum-infected red blood cells. PLOS Comput Biol 5: e1000339.[Crossref]
  31. Campanale N, Nickel C, Daubenberger CA, Wehlan DA, Gorman JJ, Klonis N, Becker K, Tilley L, , 2003. Identification and characterization of heme-interacting proteins in the malaria parasite, Plasmodium falciparum . J Biol Chem 278: 2735427361.[Crossref]
  32. Pisciotta JM, Sullivan D, , 2008. Hemozoin: oil versus water. Parasitol Int 57: 8996.[Crossref]
  33. Pagola S, Stephens PW, Bohle DS, Kosar AD, Madsen SK, , 2000. The structure of malaria pigment beta-haematin. Nature 404: 307310.[Crossref]
  34. Slater AF, Swiggard WJ, Orton BR, Flitter WD, Goldberg DE, Cerami A, Henderson GB, , 1991. An iron-carboxylate bond links the heme units of malaria pigment. Proc Natl Acad Sci USA 88: 325329.[Crossref]

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  • Received : 29 Sep 2013
  • Accepted : 06 May 2014

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