Saturated bioisosteres of benzene: where to go next?

The replacement of para-substituted benzenes with saturated bi- and polycyclic bioisosteres - bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane and cubane, - often increases the potency, selectivity and metabolic stability of bioactive compounds. The currently remaining challenge for chemists, however, is to rationally design, synthesize and validate the saturated bioisosteres for ortho-and meta-substituted benzenes.