Malaria-infected Mice Live Until at Least Day 30 After a New Monomeric Trioxane Combined with Mefloquine Are Administered Together in a Single Low Oral Dose

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2009 Jul 10

PMID 19586052

Citations 14

Authors

Lauren E Woodard

Wonsuk Chang

Xiaochun Chen

Jun O Liu

Theresa A Shapiro

Gary H Posner

Affiliations

Soon will be listed here.

Abstract

In only five simple steps and 48% overall yield from the natural trioxane artemisinin, the thermally and hydrolytically stable trioxane fluoroanilide 4b has been prepared. Upon one oral dose of only 6.8 mg/kg of monomeric trioxane 4b combined with 20 mg/kg of mefloquine hydrochloride, all of the malaria-infected mice lived until at least day 30 post infection. Of the five mice in this surviving group, four (80%) were completely cured (no parasites in their blood) and one mouse had 4% blood parasitemia. Importantly, the efficacy of this ACT chemotherapy using monomeric trioxane 4b plus mefloquine hydrochloride is considerably better than the efficacy under the same conditions using the popular trioxane drug artemether plus mefloquine hydrochloride.

Citing Articles

Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity.

Pepe D, Toumpa D, Andre-Barres C, Menendez C, Mouray E, Baltas M ACS Med Chem Lett. 2020; 11(5):921-927.

PMID: 32435406 PMC: 7236259. DOI: 10.1021/acsmedchemlett.9b00669.

Malaria-Infected Mice Are Cured by a Single Low Dose of a New Silylamide Trioxane Plus Mefloquine.

Woodard L, Mott B, Singhal V, Kumar N, Shapiro T, Posner G Pharmaceuticals (Basel). 2016; 2(3):228-235.

PMID: 27713236 PMC: 3978545. DOI: 10.3390/ph2030228.

Antimalarial chemotherapy: artemisinin-derived dimer carbonates and thiocarbonates.

Mazzone J, Conyers R, Tripathi A, Sullivan D, Posner G Bioorg Med Chem Lett. 2014; 24(11):2440-3.

PMID: 24775306 PMC: 4074917. DOI: 10.1016/j.bmcl.2014.04.025.

The survival times of malaria-infected mice are prolonged more by several new two-carbon-linked artemisinin-derived dimer carbamates than by the trioxane antimalarial drug artemether.

Conyers R, Mazzone J, Siegler M, Tripathi A, Sullivan D, Mott B Bioorg Med Chem Lett. 2014; 24(5):1285-9.

PMID: 24508128 PMC: 3943161. DOI: 10.1016/j.bmcl.2014.01.059.

Synthesis and antimalarial efficacy of two-carbon-linked, artemisinin-derived trioxane dimers in combination with known antimalarial drugs.

Mott B, Tripathi A, Siegler M, Moore C, Sullivan D, Posner G J Med Chem. 2013; 56(6):2630-41.

PMID: 23425037 PMC: 3630999. DOI: 10.1021/jm400058j.

References

Ashley E, White N . Artemisinin-based combinations. Curr Opin Infect Dis. 2005; 18(6):531-6. DOI: 10.1097/01.qco.0000186848.46417.6c. View

Guthmann J, Cohuet S, Rigutto C, Fortes F, Saraiva N, Kiguli J . High efficacy of two artemisinin-based combinations (artesunate + amodiaquine and artemether + lumefantrine) in Caala, Central Angola. Am J Trop Med Hyg. 2006; 75(1):143-5. View

de Pilla Varotti F, Botelho A, Andrade A, De Paula R, Fagundes E, Valverde A . Synthesis, antimalarial activity, and intracellular targets of MEFAS, a new hybrid compound derived from mefloquine and artesunate. Antimicrob Agents Chemother. 2008; 52(11):3868-74. PMC: 2573098. DOI: 10.1128/AAC.00510-08. View

Sirima S, Tiono A, Gansane A, Diarra A, Ouedraogo A, Konate A . The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum. Malar J. 2009; 8:48. PMC: 2662869. DOI: 10.1186/1475-2875-8-48. View

Jung M, Lee S, Ham J, Lee K, Kim H, Kim S . Antitumor activity of novel deoxoartemisinin monomers, dimers, and trimer. J Med Chem. 2003; 46(6):987-94. DOI: 10.1021/jm020119d. View

Vennerstrom J, Arbe-Barnes S, Brun R, Charman S, Chiu F, Chollet J . Identification of an antimalarial synthetic trioxolane drug development candidate. Nature. 2004; 430(7002):900-4. DOI: 10.1038/nature02779. View

Sagara I, Rulisa S, Mbacham W, Adam I, Sissoko K, Maiga H . Efficacy and safety of a fixed dose artesunate-sulphamethoxypyrazine-pyrimethamine compared to artemether-lumefantrine for the treatment of uncomplicated falciparum malaria across Africa: a randomized multi-centre trial. Malar J. 2009; 8:63. PMC: 2678145. DOI: 10.1186/1475-2875-8-63. View

Sagara I, Diallo A, Kone M, Coulibaly M, Diawara S, Guindo O . A randomized trial of artesunate-mefloquine versus artemether-lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Mali. Am J Trop Med Hyg. 2008; 79(5):655-61. View

Adjuik M, Babiker A, Garner P, Olliaro P, Taylor W, White N . Artesunate combinations for treatment of malaria: meta-analysis. Lancet. 2004; 363(9402):9-17. DOI: 10.1016/s0140-6736(03)15162-8. View

10.

Rosenthal A, Chen X, Liu J, West D, Hergenrother P, Shapiro T . Malaria-infected mice are cured by a single oral dose of new dimeric trioxane sulfones which are also selectively and powerfully cytotoxic to cancer cells. J Med Chem. 2009; 52(4):1198-203. PMC: 2698029. DOI: 10.1021/jm801484v. View

11.

Gautam A, Ahmed T, Batra V, Paliwal J . Pharmacokinetics and pharmacodynamics of endoperoxide antimalarials. Curr Drug Metab. 2009; 10(3):289-306. DOI: 10.2174/138920009787846323. View

12.

Myint H, Ashley E, Day N, Nosten F, White N . Efficacy and safety of dihydroartemisinin-piperaquine. Trans R Soc Trop Med Hyg. 2007; 101(9):858-66. DOI: 10.1016/j.trstmh.2007.05.018. View

13.

Chen X, Chong C, Shi L, Yoshimoto T, Sullivan Jr D, Liu J . Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity. Proc Natl Acad Sci U S A. 2006; 103(39):14548-53. PMC: 1599997. DOI: 10.1073/pnas.0604101103. View

14.

Posner G, Paik I, Sur S, McRiner A, Borstnik K, Xie S . Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy. J Med Chem. 2003; 46(6):1060-5. DOI: 10.1021/jm020461q. View