Organocatalytic approaches towards easy synthesized, economical and high yielding Tamiflu derivatives
Despite widespread immunization, influenza still kills thousand of people, and costs to the US, Europe and Asia enormous amounts of money in terms of healthcare expenses and productivity losses. While immunization remains an important approach to prevent influenza, small-molecule antiviral agents represent a novel opportunity for an effective prevention and therapy of flu. Inhibitors of neuraminidase (NA), essential enzyme for viral replication in all three classes of influenza viruses, has been recently found. Two of these inhibitors have reached the market, namely zanamivir and oseltamivir phosphate. The recent health concerns related to the avian flu have increased the demand for stockpiles of neuraminidase inhibitors, both as a reasonable frontline therapy against a possible flu pandemic and as a preventive agent. However, natural sources of Shikimic acid are scarce, and the increasing demand have put further pressure to develop new routes that do not involve complex natural products. In addition, there is the need to simplify the synthetic processes and make them less expensive in order to find new drug candidates, cut the drug costs and improve availability as well as efficiency, new chemical synthesis are necessary. The project proposes a new domino reaction based on an organocatalytic approach to the synthesis of new Tamiflu derivatives. The chemistry involved in this project is easy to perform, and can be well adapted to the industrial context. Moreover, new chemical structures will be prepared and evaluated as potential drug against virulent and mutated flu viruses.[+] Read More
Influenza is a leading cause of morbidity, mortality, and economic loss throughout the world. The influenza pandemic in 1918 (the Spanish flu) is estimated to have killed more than 30 million people worldwide, more than the First World War. The avian H5N1 influenza, which originated in Hong Kong in 1997, has already infected over 100 humans and shows lethality of over 50%. The mounting fear is based on the concern that a mutated form of this virus may lead to a new pandemic. Despite widespread immunization, influenza still kills thousand of people, and results in enormous costs in US, Europe and Asia in terms of healthcare expenses and productivity losses. Prevention and treatment of influenza currently rely on inactivated vaccines and antiviral agents. Although vaccines are considered to be the best option for control of influenza, at least 6 months is needed to produce vaccines based on the surface glycoproteins of an epidemic virus strain. The efficacy of antiviral drugs such as Amantadine and Rimantadine is limited by their inapplicability to influenza B viruses and to the rapid emergence and transmission of drug-resistant variants. Synthesis of the neuraminidase inhibitors was a significant milestone in antiviral influenza therapy. Among all NA inhibitors Oseltamivir has emerged as a promising drug. The active centre among all influenza viruses makes it the potential target of Oseltamivir that would offer protection against any influenza virus that might emerge in humans. However, the Oseltamivir supply is a problem. In fact, the relative production processes are expensive, complicated, and not environmentally friendly. Although catalysis is sometimes a good way to solve difficult synthetic problems, Oseltamivir derivatives could not be prepared in a single metal catalytic reaction. In case of a pandemic episode, or dangerous mutation, Europe, China and the entire World will face the problem of preparing neuraminidase inhibitors in a relatively short amount of time.
The overall scientific and technical objective of the CATAFLU.OR project is to achieve new innovative, simple and straightforward synthetic routes for enhancing the availability and supply of neuraminidase inhibitors. The CATAFLU.OR project addresses this target, through the objective of preparing difficult and highly challenging neuraminidase inhibitors. Five main tasks characterize the work plan of the Cataflu.OR project: 1) Synthesis of modified catalysts for organocatalytic domino reaction. Scale up of the reaction. Test of the new catalyst in the established reaction domino reactions aiming the production of new cyclohexene derivatives. The manipulation of the derivatives will be used for a practical and rapid access to newly designed neuraminidase drug candidates. 2) Use of the catalysts in the design of new organocatalytic domino reactions. Synthesis of cyclic compounds via domino reactions. 3) Preparation of new neuraminidase inhibitor through the use of organocatalytic domino reactions. 4) Test of the new neuraminidase inhibitor with cell lines, animals and viruses. 5) Test in silico, in vitro, and in vivo of the newly prepared inhibitor against influenza viruses.
In particular, the project intends:
Furthermore, additional objectives of the project are:
The action may have a profound long-term effect in contributing to solve the problems related to Oseltamivir derivatives supply, experienced by European industries and European countries during the crisis of the Asian flu. In addition, this action will enforce the cooperation between China and Europe, opening the groups to further actions and cooperation, exchanging knowledge, ideas and science.