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

Journal of Medicinal Chemistry
Edwin TseMatthew H Todd

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 when 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, thirty-two compounds.

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Citations

May 4, 2021·RSC Medicinal Chemistry·Matthias R BauerBenjamin C Whitehurst
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Stefan SaretzEvamarie Hey-Hawkins
Jul 17, 2021·The Journal of Organic Chemistry·Thi Phuong LeJiří Kaleta
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Jun 22, 2021·Angewandte Chemie·Joseph M AndersonDarren L Poole
Oct 1, 2021·Journal of Medicinal Chemistry·Murugaiah A M Subbaiah, Nicholas A Meanwell

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