Bioisosteric Replacements in Drug Design - New Developments in Medicinal Chemistry - page 218

intellectual property rights but also allows the exploration of new and potentially
much more interesting scaffolds that fulfill the same role of the reference active
molecules. Thus, scaffold hopping refers to the identification of different classes
of compounds having similar biological activity. In Medicinal Chemistry, the
search for different structural classes with similar biological activity is of high
interest in virtual screening methods [27].
One example of successful application of scaffold hopping is reported by Tung et
al [28], where the replacement of the indole ring of a potent anticancer agent,
targeting tubulin, by alternative 5,6-fused bicyclic heteroaromatics helped the
design of novel drug candidates with new intellectual property rights (Fig. 2 ).
Compounds A, B and C docked to the colchicine binding site in a similar way to
that of the indole scaffold, suggesting an antiproliferative mechanism similar with
the observed for the indole lead compound. Most interestingly, compound C, an
orally bioavailable anticancer agent, showed improved metabolic stability and
better aqueous solubility than the original indole lead compound.
Figure 2: Application of a scaffold hopping procedure, where the indolic scaffold of the original
reference molecule is substituted for new 5,6-fused bicyclic heteroaromatics [28].