Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 20, Pages 11585-11601Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00746
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Funding
- Australian Research Council
- Medicines for Malaria Venture [LP150101226]
- Australian Research Council [LP150101226] Funding Source: Australian Research Council
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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 opensource 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.
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