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

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.

Figure 1

Artemisinin and first generation derivatives.

Figure 2

Conformational analysis of less polar alcohol 6a (I and II) and more polar alcohol 6b (III and IV) using ¹H NMR spectroscopy.

Figure 3

Displacement ellipsoid plot (50% probability level) of two-carbon linked dimer alcohol 6b given at 110(2) K.

Figure 4

Two-carbon-linked dimer carbamates 7.

Scheme 1

Two-carbon-linked dimer derivatives.

Scheme 2

Two-carbon-linked dimer alcohols 6. a) DIBALH, CH₂Cl₂, −78 °C; 98% b) 8b, BH₃·THF, 0 °C - rt, 99% overall yield for both diastereomers; c) 8a, BH₃·THF, 0 °C - rt, 92%