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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| Veröffentlicht in: | Journal of medicinal chemistry 2020-10, Vol.63 (20), p.11585-11601 |
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| container_title | Journal of medicinal chemistry |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.0c00746 |
| format | Article |
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Paul ; Rendina, Louis M ; Hallyburton, Irene ; Anderson, Mark ; Sharma, Raman ; Walker, Gregory S ; Obach, R. Scott ; Todd, Matthew H</creator><creatorcontrib>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</creatorcontrib><description>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. 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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. 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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. 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| ispartof | Journal of medicinal chemistry, 2020-10, Vol.63 (20), p.11585-11601 |
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| source | MEDLINE; ACS Publications |
| 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 |
| title | Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials |
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