Bioisosteres of meta‐substituted benzenes

Swapping aromatic rings with small-ring hydrocarbon cages is a promising method for synthesising more effective drugs. Until recently, however, this tactic was restricted to the replacement of para-substituted phenyl groups. Now, two new methods describe reliable syntheses of a motif for exchanging meta-substituted benzene rings, ushering a new cage-motif into the mainstream and thus opening up opportunities for medicinal chemists.

Substituted benzene rings are frequently found in natural products and drug molecules. In the effort to develop more effective medicines, chemists have begun exploring the replacement of these aromatic rings with small-ringed hydrocarbon cages which can act as bioisosteres.¹⁾ In doing so, the fraction of sp³-hybridised carbon atoms (Fsp³) increases – embracing concepts highlighted in the well-known “Escape from Flatland“ article published by Humblet and co-workers in 2009²⁾ – which demonstrates a correlation between this property and an increased chance of clinical success. In particular, these modified molecules offer increased water solubility, membrane permeability and metabolic stability whilst maintainin

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