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 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.