Antischistosomal Activity of Trioxaquines: In Vivo Efficacy and Mechanism of Action on Schistosoma mansoni

Schistosomiasis is among the most neglected tropical diseases, since its mode of spreading tends to limit the contamination to people who are in contact with contaminated waters in endemic countries. Here we report the in vitro and in vivo anti-schistosomal activities of trioxaquines. These hybrid molecules are highly active on the larval forms of the worms and exhibit different modes of action, not only the alkylation of heme. The synergy observed with praziquantel on infected mice is in favor of the development of these trioxaquines as potential anti-schistosomal agents.

[1]  Yves Moné,et al.  An example of molecular co-evolution: reactive oxygen species (ROS) and ROS scavenger levels in Schistosoma mansoni/Biomphalaria glabrata interactions. , 2011, International journal for parasitology.

[2]  J. Boissier,et al.  Trioxaquine PA1259 Alkylates Heme in the Blood-Feeding Parasite Schistosoma mansoni , 2011, Antimicrobial Agents and Chemotherapy.

[3]  N. Baddour,et al.  Miltefosine, a promising novel agent for schistosomiasis mansoni. , 2011, International journal for parasitology.

[4]  J. Keiser,et al.  Schistosoma mansoni: antischistosomal activity of the four optical isomers and the two racemates of mefloquine on schistosomula and adult worms in vitro and in vivo. , 2011, Experimental parasitology.

[5]  E. Reisinger,et al.  Schistosoma mansoni: schistosomicidal effect of mefloquine and primaquine in vitro. , 2011, Experimental parasitology.

[6]  M. Tanner,et al.  ACTs for schistosomiasis: do they act? , 2010, The Lancet. Infectious diseases.

[7]  B. Meunier,et al.  Heme as trigger and target for trioxane-containing antimalarial drugs. , 2010, Accounts of chemical research.

[8]  S. Xiao,et al.  Further observation on histopathological alterations of adult Schistosoma japonicum harbored in mice following treatment with mefloquine at a smaller single dose , 2010, Parasitology Research.

[9]  J. Utzinger,et al.  Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against Schistosoma haematobium: randomized, exploratory open-label trial. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[10]  J. Keiser,et al.  Praziquantel analogs with activity against juvenile Schistosoma mansoni. , 2010, Bioorganic & medicinal chemistry letters.

[11]  S. Xiao,et al.  Transmission electron microscopic observation on ultrastructural alterations in Schistosoma japonicum caused by mefloquine , 2010, Parasitology Research.

[12]  J. Keiser,et al.  Morphological effects and tegumental alterations induced by mefloquine on schistosomula and adult flukes of Schistosoma mansoni , 2009, Parasitology.

[13]  A. Jadhav,et al.  Structure mechanism insights and the role of nitric oxide donation guide the development of oxadiazole-2-oxides as therapeutic agents against schistosomiasis. , 2009, Journal of medicinal chemistry.

[14]  J. Boissier,et al.  In Vitro Activities of Trioxaquines against Schistosoma mansoni , 2009, Antimicrobial Agents and Chemotherapy.

[15]  T. Egan,et al.  Interference with Hemozoin Formation Represents an Important Mechanism of Schistosomicidal Action of Antimalarial Quinoline Methanols , 2009, PLoS neglected tropical diseases.

[16]  Conor R. Caffrey,et al.  Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening , 2009, PLoS neglected tropical diseases.

[17]  Sandra D. Melman,et al.  Towards an understanding of the mechanism of action of praziquantel. , 2009, Molecular and biochemical parasitology.

[18]  M. Tanner,et al.  Mefloquine—An Aminoalcohol with Promising Antischistosomal Properties in Mice , 2009, PLoS neglected tropical diseases.

[19]  M. Tanner,et al.  Effect of single-dose oral artemether and tribendimidine on the tegument of adult Clonorchis sinensis in rats , 2009, Parasitology Research.

[20]  B. Mordmüller,et al.  Selection of a trioxaquine as an antimalarial drug candidate , 2008, Proceedings of the National Academy of Sciences.

[21]  Jozef Vercruysse,et al.  Schistosomicidal activity of the antimalarial drug, mefloquine, in Schistosoma mansoni-infected mice. , 2008, Travel medicine and infectious disease.

[22]  B. Meunier,et al.  The Antimalarial Trioxaquine DU1301 Alkylates Heme in Malaria-Infected Mice , 2008, Antimicrobial Agents and Chemotherapy.

[23]  John M. Pisciotta,et al.  Hemozoin: oil versus water. , 2008, Parasitology international.

[24]  B. Meunier,et al.  Hybrid molecules with a dual mode of action: dream or reality? , 2008, Accounts of chemical research.

[25]  Anton Simeonov,et al.  Identification of oxadiazoles as new drug leads for the control of schistosomiasis , 2008, Nature Medicine.

[26]  S. Laurent,et al.  Synthesis of "Trioxaquantel" ® Derivatives as Potential New Antischistosomal Drugs , 2008 .

[27]  J. Keiser,et al.  Fasciola hepatica: tegumental alterations in adult flukes following in vitro and in vivo administration of artesunate and artemether. , 2008, Experimental parasitology.

[28]  D. McManus,et al.  Pumping iron: a potential target for novel therapeutics against schistosomes , 2007, Trends in parasitology.

[29]  J. Lelièvre,et al.  Trioxaquines and Heme-Artemisinin Adducts Inhibit the In Vitro Formation of Hemozoin Better than Chloroquine , 2007, Antimicrobial Agents and Chemotherapy.

[30]  Tony J Collins,et al.  ImageJ for microscopy. , 2007, BioTechniques.

[31]  R. Fetter,et al.  Proteomic analysis of adult S. mansoni gut contents. , 2007, Molecular and biochemical parasitology.

[32]  M. Tanner,et al.  In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species , 2007, Antimicrobial Agents and Chemotherapy.

[33]  J. Lelièvre,et al.  Trioxaquines Are New Antimalarial Agents Active on All Erythrocytic Forms, Including Gametocytes , 2007, Antimicrobial Agents and Chemotherapy.

[34]  D. McManus,et al.  Tracking the fate of iron in early development of human blood flukes , 2007, The international journal of biochemistry & cell biology.

[35]  P. Sobhon,et al.  Schistosoma mekongi: the in vitro effect of praziquantel and artesunate on the adult fluke. , 2006, Experimental parasitology.

[36]  Elke Hacker,et al.  Two Isoforms of a Divalent Metal Transporter (DMT1) in Schistosoma mansoni Suggest a Surface-associated Pathway for Iron Absorption in Schistosomes* , 2006, Journal of Biological Chemistry.

[37]  E. Hempelmann,et al.  Structural and morphological characterization of hemozoin produced by Schistosoma mansoni and Rhodnius prolixus , 2005, FEBS letters.

[38]  B. Meunier,et al.  The antimalarial drug artemisinin alkylates heme in infected mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  S. Laurent,et al.  C10-modified artemisinin derivatives: efficient heme-alkylating agents. , 2005, Angewandte Chemie.

[40]  D. Cioli,et al.  Sex- and stage-related sensitivity of Schistosoma mansoni to in vivo and in vitro praziquantel treatment. , 2004, International journal for parasitology.

[41]  Shun-ke Zhang,et al.  Schistosoma japonicum: isolation and identification of peptides mimicking ferritin epitopes from phage display library. , 2004, Acta biochimica et biophysica Sinica.

[42]  D. McManus,et al.  The ultrastructural architecture of the adult Schistosoma japonicum tegument. , 2003, International journal for parasitology.

[43]  T. Wellems Plasmodium Chloroquine Resistance and the Search for a Replacement Antimalarial Drug , 2002, Science.

[44]  M. Tanner,et al.  Ultrastructural alterations in adult Schistosoma mansoni caused by artemether. , 2002, Memorias do Instituto Oswaldo Cruz.

[45]  B. Meunier,et al.  From mechanistic studies on artemisinin derivatives to new modular antimalarial drugs. , 2002, Accounts of chemical research.

[46]  S. D. de Vlas,et al.  Are poor responses to praziquantel for the treatment of Schistosoma mansoni infections in Senegal due to resistance? An overview of the evidence , 2001, Tropical medicine & international health : TM & IH.

[47]  J. Boissier,et al.  Male-female larval interactions in Schistosoma mansoni-infected Biomphalaria glabrata. , 2001, International journal for parasitology.

[48]  M. Tanner,et al.  Artemether administered together with haemin damages schistosomes in vitro. , 2001, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[49]  A. Ruppel,et al.  [Studies on the activity and immunohistochemistry of heme oxygenase in Schistosoma japonicum]. , 2001, Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases.

[50]  B. Meunier,et al.  Preparation and Antimalarial Activities of “Trioxaquines”, New Modular Molecules with a Trioxane Skeleton Linked to a 4‐Aminoquinoline , 2000, Chembiochem : a European journal of chemical biology.

[51]  F. Rumjanek,et al.  Haemozoin in Schistosoma mansoni. , 2000, Molecular and biochemical parasitology.

[52]  M. Tanner,et al.  Tegumental changes in adult Schistosoma mansoni harboured in mice treated with praziquantel enantiomers. , 2000, Acta tropica.

[53]  J. Karle,et al.  Structural specificity of chloroquine-hematin binding related to inhibition of hematin polymerization and parasite growth. , 1999, Journal of medicinal chemistry.

[54]  T. Day,et al.  Resistance to praziquantel: direct evidence from Schistosoma mansoni isolated from Egyptian villagers. , 1999, The American journal of tropical medicine and hygiene.

[55]  B. Meunier,et al.  Alkylating Properties of Antimalarial Artemisinin Derivatives and Synthetic Trioxanes when Activated by a Reduced Heme Model , 1998 .

[56]  P. Fallon,et al.  Praziquantel: an urgent and exciting challenge. , 1996, Parasitology today.

[57]  P. Schüssler,et al.  An isoform of ferritin as a component of protein yolk platelets in Schistosoma mansoni , 1995, Molecular reproduction and development.

[58]  W. Kunz,et al.  Ferritins of Schistosoma mansoni: sequence comparison and expression in female and male worms. , 1992, Molecular and biochemical parasitology.

[59]  C. Le,et al.  Schistosoma mansoni: effect of transferrin and growth factors on development of schistosomula in vitro. , 1989 .

[60]  L. E. Clemens,et al.  Schistosoma mansoni: effect of transferrin and growth factors on development of schistosomula in vitro. , 1989, The Journal of parasitology.

[61]  R. Wilson,et al.  Synthesis of macromolecules by the epithelial surfaces of Schistosoma mansoni: an autoradiographic study , 1979, Parasitology.

[62]  F. Cox Death of a schistosome , 1979, Nature.

[63]  P. W. Pappas,et al.  Membrane transport in helminth parasites: a review. , 1975, Experimental parasitology.