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

• Published in: ACS medicinal chemistry letters 2021-07, Vol.12 (7), p.1077-1085
• Main Authors: Woodley, Christopher M, Nixon, Gemma L, Basilico, Nicoletta, Parapini, Silvia, Hong, Weiqian David, Ward, Stephen A, Biagini, Giancarlo A, Leung, Suet C, Taramelli, Donatella, Onuma, Keiko, Hasebe, Takashi, O’Neill, Paul M
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.1c00031

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-to-head 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.