Severina H. Synthesis and physico-chemical properties of the CNS-agents among pyrimidin-4-one and pyrimidin-2(4)-tione derivatives

The thesis is devoted to theoretical substantiation of the modern methodology of the target-oriented search of the CNS-agents among pyrimidin-4-one and pyrimidin-2(4)-tione derivatives and its experimental confirmation. The main direction of the search for CNS-agents was antiepileptic activity, due to epilepsy is more than a neurological disease with a predisposition to spontaneous seizures, it’s also a complex systemic process associated with a range of different cognitive, behavioral, psychiatric disorders and concomitant comorbidity, e. g anxiety, psychosis, headache, etc. At the initial stage of research, a general design of target-oriented search of potential CNS-agents among pyrimidin-4(3H)-one and pyrimidin-2(4)-tione derivatives was developed. The choice of the main research scaffold - pyrimidin-4-one was substantiated, and on the basis of the principles of the modern pharmacophore concept of constructing innovative AEDs the directions of its functioning were determined, and the structures virtual base was formed. Candidate structures were ranked according to affinity indicators for GABAergic targets: to the active site of the positive allosteric modulator and benzodiazepine site of GABAА receptor and GABAAT inhibitor vigabatrin, and 14 groups of candidate structures for synthesis were formed. Methods of structural functionalization of 4-chloro-2-methyl/aryl-6-R-pyrimidine derivatives were developed, and a series of new 4-hydrazino-, 4-arylpiperazino-2-methyl/aryl-6-R-pyrimidines, as well as 2-(6-methyl-2-(4-trifluoromethyl)-pyrimidin-4-yl)aminoacetic and aminopropionic acids, were obtained. 2-arylamino-, 2-arylidenhydrazino- and N-acetyl/benzoyl hydrazides of 6-methyl-pyrimidin-4(3H)-one were synthesized. According to the results of a systematic study of the anticonvulsant activity of 150 synthesized pyrimidin-4-one and -2(4)-thione derivatives on the model of PTZ-induced seizures in comparison with phenobarbital and sodium valproate, a number of structural features of correlation «structure-anticonvulsant» were found