Assessing the rigidity of cubanes and bicyclo(1.1.1)pentanes as benzene bioisosteres

Abstract

Aromatic rings are critical core substructures in the majority of pharmaceutical compounds. There is much recent interest in replacing aromatic structures with saturated bioisosteres of benzene, which are generally fused or bridged ring systems. These bioisosteres often show improved solubility properties compared to benzene, and may also undergo fewer unwanted metabolic processes. One key reason why aromatic rings have proven so successful in drug design is their rigidity. This paper uses molecular dynamics simulations supported by crystallographic data to assess the rigidity of bicyclopentane and cubane ring systems as two of the most common benzene bioisosteres and compares this to benzene. Whilst a benzene ring is shown to be more flexible than these two bioisosteres in terms of its dihedral ring flexibility, substituents around the ring tend to behave in a much more similar way in both benzene and the bioisosteric systems.