Recent Advances in Heterocyclic HIV Protease Inhibitors

Since the first cases of AIDS, reported in 1980, this disease has become chronic over the years, and researchers have been trying to keep it under control. Despite the development and spread of mutate viruses, HIV protease remains an important pharmacological target. In the development of new HIV protease inhibitors, heterocyclic fragments have proven to be of great importance, owing to their rigid core structure, which may fit better into the enzyme’s hydrophobic pockets, and the presence of a heteroatom, which may increase the number of H-bonding interactions at the active site. According to the concept of targeting the protein backbone, different aromatic or non-aromatic heterocyclic moieties have yielded inhibitors with sufficient activity against mutant viruses. This paper provides an overview of HIV protease inhibitors developed over the last fifteen years, with a focus on the presence of heterocycles in their structure, either in the core or on the side chains, which are crucial for their activity. The rationale behind the design of these new inhibitors, as well as the key synthetic steps involved in their preparation, is also described.