Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice

Overview

Journal Drug Dev Res

Specialty Pharmacology

Date 2011 Sep 28

PMID 20686674

Citations 4

Authors

Deuk Kyu Moon

Vandana Singhal

Nirbhay Kumar

Theresa A Shapiro

Gary H Posner

Affiliations

Soon will be listed here.

Abstract

Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure.

Citing Articles

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.

3-Alkoxy-1,2-Dioxolanes: Synthesis and Evaluation as Potential Antimalarial Agents.

Schiaffo C, Rottman M, Wittlin S, Dussault P ACS Med Chem Lett. 2011; 2(4):316-319.

PMID: 21666827 PMC: 3109996. DOI: 10.1021/ml100308d.

A single, low, oral dose of a 5-carbon-linked trioxane dimer orthoester plus mefloquine cures malaria-infected mice.

Moon D, Tripathi A, Sullivan D, Siegler M, Parkin S, Posner G Bioorg Med Chem Lett. 2010; 21(9):2773-5.

PMID: 20952197 PMC: 3037442. DOI: 10.1016/j.bmcl.2010.09.123.

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

Posner G, Paik I, Chang W, Borstnik K, Sinishtaj S, Rosenthal A . Malaria-infected mice are cured by a single dose of novel artemisinin derivatives. J Med Chem. 2007; 50(10):2516-9. DOI: 10.1021/jm070149m. 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

Posner G, Chang W, Hess L, Woodard L, Sinishtaj S, Usera A . Malaria-infected mice are cured by oral administration of new artemisinin derivatives. J Med Chem. 2008; 51(4):1035-42. DOI: 10.1021/jm701168h. View

Gelb M . Drug discovery for malaria: a very challenging and timely endeavor. Curr Opin Chem Biol. 2007; 11(4):440-5. PMC: 1993815. DOI: 10.1016/j.cbpa.2007.05.038. View

Woodard L, Chang W, Chen X, Liu J, Shapiro T, Posner G . 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. J Med Chem. 2009; 52(23):7458-62. PMC: 2788671. DOI: 10.1021/jm9005934. View

10.

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

11.

Jefford C . Synthetic peroxides as antimalarials. Curr Opin Investig Drugs. 2004; 5(8):866-72. View

12.

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

13.

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

14.

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

15.

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

16.

Begue J, Bonnet-Delpon D . Fluoroartemisinins: metabolically more stable antimalarial artemisinin derivatives. ChemMedChem. 2007; 2(5):608-24. DOI: 10.1002/cmdc.200600156. View

17.

Souares A, Lalou R, Sene I, Sow D, Le Hesran J . Factors related to compliance to anti-malarial drug combination: example of amodiaquine/sulphadoxine-pyrimethamine among children in rural Senegal. Malar J. 2009; 8:118. PMC: 2694834. DOI: 10.1186/1475-2875-8-118. View

18.

Chadwick J, Mercer A, Park B, Cosstick R, ONeill P . Synthesis and biological evaluation of extraordinarily potent C-10 carba artemisinin dimers against P. falciparum malaria parasites and HL-60 cancer cells. Bioorg Med Chem. 2009; 17(3):1325-38. DOI: 10.1016/j.bmc.2008.12.017. View

19.

Klayman D . Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985; 228(4703):1049-55. DOI: 10.1126/science.3887571. View

20.

ONeill P, Posner G . A medicinal chemistry perspective on artemisinin and related endoperoxides. J Med Chem. 2004; 47(12):2945-64. DOI: 10.1021/jm030571c. View