ABSTRACT
Bicyclo[2.1.1]hexanes have been synthesized, characterized, and biologically validated as saturated bioisosteres of the ortho-substituted benzene ring. The incorporation of the 1,2-disubstituted bicyclo[2.1.1]hexane core into the structure of fungicides boscalid (BASF), bixafen (Bayer CS), and fluxapyroxad (BASF) gave saturated patent-free analogs with high antifungal activity.
ABSTRACT
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.
ABSTRACT
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 a similar level of antifungal activity compared to that of Boskalid and Fluxapyroxad.
