Open AccessEnantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205
Author(s) -
Christopher M Woodley,
Gemma L. Nixon,
Nicoletta Basilico,
W. David Hong,
Stephen A. Ward,
Giancarlo A. Biagini,
Suet C. Leung,
Donatella Taramelli,
Keiko Onuma,
Takashi Hasebe,
Paul M. O’Neill
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00031
Subject(s) - in vivo , pharmacokinetics , bioavailability , pharmacology , chemistry , artemisinin , solubility , combinatorial chemistry , plasmodium falciparum , medicine , malaria , biology , organic chemistry , immunology , microbiology and biotechnology
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.