This review aim to demonstrate the role of bioisosterism in rational drug design as well as in the molecular modification and optimization process aiming to improve pharmacodynamic and pharmacokinetic properties of lead compounds.

The indole scaffold probably represents one of the most important structural subunits for the discovery of new drug candidates. The demonstration that many alkaloids contain the indole nucleus, the recognition of the importance of essential amino acid tryptophan in human nutrition and the discovery of plant hormones served to bring about a massive search on indole chemistry, giving rise to a vast number of biologically active natural and synthetic products, with a wide range of therapeutic targets, such as anti-inflammatories, phosphodiesterase inhibitors, 5-hydroxytryptamine receptor agonists and antagonists, cannabinoid receptors agonists and HMG-CoA reductase inhibitors. Many of these target-receptors belong to the class of GPCRs (integral membrane G-protein coupled receptors) and possess a conserved binding pocket that is recognized by the indole scaffold in a “common” complementary binding domain, explaining the great number of drugs that contain the indole substructure, such as indomethacin, ergotamine, frovatriptan, ondansetron, tadalafil, among many others.

Privileged structures are defined as molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications. In the present work, we describe some examples and applications of the usefulness of the privileged structure concept for the structural design of new drug candidates, by discussing the eligibility of such motifs, including the identification of the N-acylhydrazone template as privileged structures.