The N-acylsulfonamide functional group is a feature of the pharmacophore of biologically active compounds in a variety of contexts, including as antiviral, antibacterial, and antiproliferative agents. Although the N-acylsulfonamide structural motif presents alternative points of attachment that provide opportunities for structural diversification and modulation of physicochemical properties, the replacement of this functional group itself with a suitable bioisostere may be desirable. A number of N-acylsulfonamide bioisosteres have been developed over the years that provide opportunities to modulate both structure and physicochemical properties. To enable an assessment of the relative impact on physicochemical properties that these replacements may have compared to the N-acylsulfonamide group, a structure-property relationship study was conducted based on matched molecular pairs, in which the N-acylsulfonamide moiety of common template reference structures is replaced with a series of bioisosteres. The study, which includes an assessment of relative changes in acidity, permeability, lipophilicity and intrinsic solubility, shows that surrogate structures employed could significantly expand the range of attainable physicochemical properties. The data presented provides a basis for informed decisions when deploying N-acylsulfonamides, or surrogates thereof, in analog design.

Structure property relationships of N-acylsulfonamides and related bioisosteres

ACS Spring Meeting 2021

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