Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]­pentane (BCP) have been used as...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-10, Vol.63 (20), p.11585-11601
Main Authors: Tse, Edwin G, Houston, Sevan D, Williams, Craig M, Savage, G. Paul, Rendina, Louis M, Hallyburton, Irene, Anderson, Mark, Sharma, Raman, Walker, Gregory S, Obach, R. Scott, Todd, Matthew H
Format: Article
Language:English
Subjects:
Antimalarials - chemical synthesis
Antimalarials - chemistry
Antimalarials - pharmacology
Antimalarials - toxicity
Boron Compounds - chemistry
Bridged Bicyclo Compounds - chemical synthesis
Bridged Bicyclo Compounds - chemistry
Bridged Bicyclo Compounds - pharmacology
Bridged Bicyclo Compounds - toxicity
Cell Survival - drug effects
Chemistry, Pharmaceutical
Drug Design
Hep G2 Cells
Humans
Molecular Structure
Plasmodium falciparum - drug effects
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Summary:The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane and bicyclo[1.1.1]­pentane (BCP) have been used as highly effective phenyl mimics. Herein, we show the successful incorporation of a range of phenyl bioisosteres during the open-source optimization of an antimalarial series. Cubane (19) and closo-carborane (23) analogues exhibited improved in vitro potency against Plasmodium falciparum compared to the parent phenyl compound; however, these changes resulted in a reduction in metabolic stability; unusually, enzyme-mediated oxidation was found to take place on the cubane core. A BCP analogue (22) was found to be equipotent to its parent phenyl compound and showed significantly improved metabolic properties. While these results demonstrate the utility of these atypical bioisosteres when used in a medicinal chemistry program, the search to find a suitable bioisostere may well require the preparation of many candidates, in our case, 32 compounds.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00746