Saturated bioisosteres of ortho-disubstituted benzenes (bicyclo[2.1.1]hexanes) were synthesized, characterized and validated. These cores were incorporated into the bioactive compounds Valsartan, Boskalid and Fluxapyroxad instead of the benzene ring. The saturated analogues showed as imilar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.

The ortho-substituted phenyl ring is a basic structural element in chemistry. It is found in more than three hundred drugs and agrochemicals. During the past decade, scientists have tried to replace the phenyl ring in bioactive compounds with saturated bioisosteres to obtain novel patentable structures. However, most of the research in this area has been devoted to the replacement of the para-substituted phenyl ring. Here we have developed saturated bioisosteres of the ortho-substituted phenyl ring with improved physicochemical properties: 2-oxabicyclo[2.1.1]hexanes. Crystallographic analysis revealed that these structures and the ortho-substituted phenyl ring indeed have similar geometric properties. Replacement of the phenyl ring in marketed agrochemicals fluxapyroxad (BASF) and boscalid (BASF) with 2-oxabicyclo[2.1.1]hexanes dramatically improved their water solubility, reduced lipophilicity and most importantly retained bioactivity. This work suggests an opportunity for chemists to replace the ortho-substituted phenyl ring in bioactive compounds with saturated bioisosteres in medicinal chemistry and agrochemistry.

Saturated bioisosteres of ortho-disubstituted benzenes (bicyclo[2.1.1]hexanes) were synthesized, characterized and validated. These cores were incorporated into the bioactive compounds Valsartan, Boskalid and Fluxapyroxad instead of the benzene ring. The saturated analogues showed as imilar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.

Water-soluble analogues of the ortho-substituted phenyl ring were developed. Replacement of the phenyl ring in bioactive compounds with 2 oxabicyclo[2.1.1]hexanes in many cases improved solubility, reduced lipophilicity, enhanced metabolic stability, and most importantly – retained bioactivity.

Water-soluble analogues of the ortho-substituted phenyl ring were developed. Replacement of the phenyl ring in bioactive compounds with 2 oxabicyclo[2.1.1]hexanes in many cases improved solubility, reduced lipophilicity, enhanced metabolic stability, and most importantly – retained bioactivity.