Antimalarial Trioxolanes with Superior Drug-Like Properties and In Vivo Efficacy
The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogues with substitution patterns not previously ex...
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Published in | ACS infectious diseases Vol. 6; no. 7; pp. 1827 - 1835 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
10.07.2020
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Subjects | |
Online Access | Get full text |
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Summary: | The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogues with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogues bearing a trans-3″ carbamate side chain and find these to be superior, both in vitro and in vivo, to the previously reported amides. We identified multiple analogues that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like properties (logD, solubility, metabolic stability) similar or superior to next-generation clinical candidates like E209 and OZ609. While the preclinical assessment of new analogues is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author Contributions B.R.B., P.J.R., and A.R.R. conceived of experiments. B.R.B, P.T., and R.L.G. synthesized compounds. J.G. and J.L. determined EC50 values and performed the mouse infection model. A.R.R. and R.L.G. drafted the manuscript and all authors reviewed and edited the manuscript. |
ISSN: | 2373-8227 2373-8227 |
DOI: | 10.1021/acsinfecdis.0c00064 |