Design, synthesis, and evaluation of trisubstituted bicyclo[2.2.2]oct-2-enes as non-classical isosteres of trisubstituted benzenes

The limited availability of polycyclic hydrocarbon scaffolds that accurately mimic the torsional angles of polysubstituted benzenes poses a challenge in bioisostere design. To address this issue, we propose bicyclo[2.2.2]oct-2-enes as readily accessible structural isosteres of polysubstituted benzenes. To evaluate this hypothesis, a series of fungicide and antineoplastic analogs that incorporate the bicyclo[2.2.2]oct-2-ene core were synthesized. These patent-free compounds underwent structural characterization and biological validation, which confirmed their potential as isosteric replacements for the benzene ring.