Ural federal university: Chemists Create a New Way to Design Metalloenzyme Inhibitors

Scientists get highly reactive analogs of natural molecules (rapicons and funicons) in the laboratory. In turn, the molecules can become synthetic for new bioactive compounds. Scientists have proposed a new, ‘soft’ and convenient way to react with simple starting compounds. Based on these starting compounds, several complex (heterocyclic) systems can be created for effective and safe antiviral drugs. An important feature of the compounds is the ability to introduce a diketoacid fragment into various classes of compounds. This fragment is responsible for biological activity due to a system with metalloenzyme coenzymes (metal cations).

It is these organic compounds that can block the virus when the viral DNA is inserted into the DNA of the host cell. Modern medicines for HIV belong to the class of such drugs.

“One of the possibilities for searching for compounds with antiviral activity involves the preparation of polycarbonyl structures. This approach is used as one of the key steps in the methods of using the most advanced HIV inhibitors integrase, dolutegravir and bictegravir. Usually, this reaction is carried out using strong bases – harsh enolization. With the “hard” method, the range of products obtained is limited, side reactions are possible, ”says Dmitry Obydennov, Associate Professor of the Department of Organic Chemistry and High-Molecular Compounds of the Ural Federal University. “For the first time, we have presented that the acylation of enaminodions can be carried out under conditions of ‘mild’ enolization using acids as catalysts. Thanks to this, we have obtained the synthesis of a wide range of oxypyrones with a consistent structure. At the same time, it was possible to eliminate the side reaction.”

One of the effective methods of modern compounds is the use of chemically active and relatively simple molecules (‘building blocks’). These molecules provide access to a wide variety of related heterocyclic structures. Very often this role is played by polycarbonyl (diketones and triketones). It is to these classes of substrates that 4-pyrones. Such compounds are actively used in methods for the preparation and development of compounds such as dolutegravir and bictegravir. But despite the recognition of these “attractive-building blocks” for molecular design, they remain available substrates.

“The 3-hydroxy-4-pyrones we have obtained are chemically very active molecules, they have ample work opportunities, but they also provide the necessary pharmacophores. Therefore, on their basis, it is possible to construct molecules of various structures that are interesting from the point of their biological activity,” says Dmitry Obydennov.

Thus, scientists have developed a new convenient method for obtaining chemical compounds that are analogs of natural pyrons and synthetic for the design of new bioactive molecules. In the future, on the basis of these molecules and compounds, it is possible to obtain drugs for the therapy of the human immunodeficiency virus.