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

Ryan C Conyers; Jennifer R Mazzone; Maxime A Siegler; Abhai K Tripathi; David J Sullivan; Bryan T Mott; Gary H Posner

doi:10.1016/j.bmcl.2014.01.059

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

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1285-9. doi: 10.1016/j.bmcl.2014.01.059. Epub 2014 Jan 30.

Authors

Ryan C Conyers¹, Jennifer R Mazzone¹, Maxime A Siegler¹, Abhai K Tripathi², David J Sullivan², Bryan T Mott¹, Gary H Posner³

Affiliations

¹ Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, United States.
² W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States; The Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States.
³ Department of Chemistry, School of Arts and Sciences, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218, United States; The Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD 21205, United States. Electronic address: ghp@jhu.edu.

Abstract

Sixteen new artemisinin-derived 2-carbon-linked trioxane dimers were prepared to study chemical structure/antimalarial activity relationships (SAR). Administering a very low single oral dose of only 5mg/kg of dimer secondary alcohol 6a or 6b plus 15 mg/kg of mefloquine hydrochloride prolonged the lives of Plasmodium berghei-infected mice to an average of 25 days after infection. This ACT chemotherapy result is of high medicinal significance because the antimalarial efficacy of the popular trioxane drug artemether (2) plus mefloquine under the same conditions was significantly lower (only 20 day average survival). NH-aryl carbamate derivatives 7e, 7i, and 7j of 2-carbon-linked dimer alcohol 6b also significantly outperformed artemether (2) in prolonging the survival times (25-27 days) of malaria-infected mice.

Keywords: Antimalarial chemotherapy; Oral bioavailability; Single oral dose ACT; Trioxane dimer carbamates.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimalarials / chemical synthesis
Antimalarials / chemistry*
Antimalarials / pharmacology
Artemether
Artemisinins / chemistry*
Artemisinins / pharmacology
Artemisinins / therapeutic use
Carbamates / chemistry*
Carbamates / pharmacology
Carbamates / therapeutic use
Carbon / chemistry
Crystallography, X-Ray
Dimerization
Drug Therapy, Combination
Malaria / drug therapy
Malaria / mortality
Mefloquine / pharmacology
Mefloquine / therapeutic use
Mice
Molecular Conformation
Plasmodium berghei / drug effects
Structure-Activity Relationship
Survival Analysis

Substances

Antimalarials
Artemisinins
Carbamates
Carbon
artemisinin
Artemether
Mefloquine

Abstract

Publication types

MeSH terms

Substances

Grants and funding