Synthesis and biological activity evaluation of new hybrid derivatives of tacrine and melatonin as potential cholinesterases inhibitors

1. Research project objectives/ Research hypothesis

The research project presented hereby applies only to basic research and aims to continue and extend the general method of the synthesis of new hybrid derivatives, combining in their structure the unit of melatonin or melatonin oxidation products and the unit of tetrahydroacridine. The compounds obtained by us so far are covered by a patent pending constitute the invention reported to the Patent Office of RP1.

The compounds obtained will be subjected to the biological activity tests, during which we hope to determine the structure-activity relationship and to identify new promising cholinesterase inhibitors.

2. Research project methodology

Our research group has been involved for several years in the synthesis and biological activity evaluation of melatonin derivatives and related compounds. Recently, we described construction of several phenserine analogues derived from a singlet oxygenpromoted cyclization of melatonin derivatives 4,5. The concept of substituting melatonin or its oxidation products through a carbamate bond linking to the oxygen atom of the phenol moiety lead to a new group of cholinesterases inhibitors, which is protected by a patent pending reported to the Patent Office RP1. These compounds posses a much higher biological activity than the previously studied derivatives of melatonin and its oxidation product. This fact strongly encourages us to continue our research.

The presented project is therefore a continuation and extension of the topics previously developed. We plan to obtain a series of new derivatives, including:

•  a combination of melatonin and tetrahydroacridine system;
•  a combination of oxidation products of melatonin and tetrahydroacridine system;

and

• modifications of the length of the chain linking the two fragments of hybrid compound;
• modifications of substituents in the ring of tetrahydroacridine.

For all the new derivatives a full analytical characterization using advanced spectroscopic and rentgenostructural techniques will be performed. The biological evaluation will be performed in cooperation with Medical Centre of Postgradual Education in Warsaw.

On the basis of the results obtained we will be able to determine the structure-activity relationship of this new structural class of cholinesterase inhibitors.

3. Expected impact of the research project on the development of science, civilization and society

The results obtained during the realization of this project will be summarized in the form of conference presentations and scientific publications. We expect to gather a great deal of valuable experimental data, interesting to other research groups looking for new compounds of importance in biological chemistry and pharmacology. The new cholinesterases inhibitors of the hybrid structure can be potentially used to alleviate and/or treatment of the Alzheimer’s disease and other neurodegenerative disorders. Alzheimer’s disease is the most common dementia in the elderly. In the last years of the twentieth century, about 15 million people suffered from Alzheimer’s disease2, and WHO estimates that if current trends persist, this number will double by 20203. An effective therapy withdrawing or at least halting the disease progress still remains unknown.

The currently used therapy focuses on the symptomatic treatment of memory and cognitive functions disorders. In this therapeutic strategy, cholinesterases inhibitors used in the early stages of the disease play an important role.

During the last ten years the search for new cholinesterases inhibitors expanded to include a group of so-called hybrid drugs, compounds which combine in their structure a known active compound unit and its copy or units of two different active compounds. The hybrid compounds, in which two active parts are linked together, often show a much higher activity compared to their non-hybrid precursors and the synergistic effect is frequently observed. The new cholinesterases inhibitors of the hybrid structure can be potentially used to alleviate and/or treatment of the Alzheimer’s disease and other neurodegenerative disorders.