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

Edwin G. Tse, Sevan D. Houston, Craig M. Williams, G. Paul Savage, Louis M. Rendina, Irene Hallyburton, Mark Anderson, Raman Sharma, Gregory S. Walker, R. Scott Obach, Matthew H. Todd (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)
9 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)11585-11601
Number of pages17
JournalJournal of Medicinal Chemistry
Volume63
Issue number20
Early online date17 Jul 2020
DOIs
Publication statusPublished - 22 Oct 2020

Fingerprint

Dive into the research topics of 'Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials'. Together they form a unique fingerprint.

Cite this