4.5 Article

Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205

Journal

ACS MEDICINAL CHEMISTRY LETTERS
Volume 12, Issue 7, Pages 1077-1085

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00031

Keywords

endoperoxide; antimalarial; Plasmodium falciparum; asymmetry; melting point; solubility

Funding

  1. Global Health and Innovative Technology (GHIT) Fund [G2015-120]

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Research has developed a method for synthesizing nonlinear analogues of second-generation antimalarials, showing up to 10-fold improvement in solubility compared to linear counterparts. Pharmacokinetic studies in rats revealed that a selected nonlinear analogue demonstrated significantly improved oral absorption and exposure in vivo, with more than double the AUC and increased oral bioavailability.
Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-tohead comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

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