Woodley, Christopher M, Nixon, Gemma L 
ORCID: 0000-0002-9730-0960, Basilico, Nicoletta, Parapini, Silvia, Hong, Weiqian David, Ward, Stephen A, Biagini, Giancarlo A, Leung, Suet C ORCID: 0009-0009-3026-5521, 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.
ISSN 1948-5875, 1948-5875
Abstract
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: | 07 Dec 2024 22:01 |
| DOI: | 10.1021/acsmedchemlett.1c00031 |
| Open Access URL: | https://archive.lstmed.ac.uk/18599/ |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3144747 |
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