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

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
et al (show 2 more authors) (2021) Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205. ACS MEDICINAL CHEMISTRY LETTERS, 12 (7). pp. 1077-1085.

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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 <b>14a</b> 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.

Item Type: Article
Uncontrolled Keywords: endoperoxide, antimalarial, Plasmodium falciparum, asymmetry, melting point, solubility
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Faculty of Science and Engineering > School of Physical Sciences
Depositing User: Symplectic Admin
Date Deposited: 06 Dec 2021 09:55
Last Modified: 18 Jan 2023 21:23
DOI: 10.1021/acsmedchemlett.1c00031
Open Access URL: https://archive.lstmed.ac.uk/18599/
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3144747