Диссертация на соискание ученой степени доктора химических наук по специальности 02.00.03 – органическая химия. – Харьковский государст-венный университет, Харьков, 1999.
Диссертация посвящена исследованию реакционной способности, количественных соотношений структура-биологическая активность и приме-нению производных N-фенилантраниловой кислоты и акридина, которые широко используются в современной медицине. Их реакционная способность оценивалась путем изучения кислотно-основных равновесий, кинетики реакций получения и метаболизма. С использованием многофакторного корреляционного анализа созданы адекватные математические модели зависимости биологической активности соединений от их структуры. Результаты работы закладывают теоретический фундамент и методическую базу молекулярного дизайна и оптимизации синтезов эффективных лекарственных препаратов этих классов.
Ключевые слова: реакционная способность, связь структура – биологическая активность, N-фенилантраниловая кислота, акридин, многофакторный корреляционный анализ.
Svechnikova E.N. The reactivity, structure-biological activity relationship and the use of N-phenylanthranilic acid and acridine derivatives. – Manuscript.
The thesis for Doctor's Degree of Chemical Science by speciality 02.00.03 – Organic Chemistry. – Kharkiv State University, Kharkiv, 1999.
The thesis is devoted to the investigations of the reactivity, quantitative ratios of structure-biological activity relationship and the use of N-phenylanthranilic acid (N-PhAA) and acridine derivatives, which are widely applied in modern medicine.
The research of acid-basic properties of N-PhAA substituents demonstrated an isolating effects of bridge NH-group, a combined effects of influence transfer of the substituents with rI"rR. The sensitivity of the reaction centre to the electronic effects transfer of the substituents in the molecule's anthranilic fragment was proved to be higher in ~2.3 times compared with non-anthranilic fragment. The common correlation equation of pKa relationship with substituents' s-constants in both molecules' fragments has been determined. It is used for a highly reliable forecasting of N-PhAA substituents' acidity.
Researching the electroconductivity of the solutions at various temperatures the thermodynamics of N-PhAA substituents ionization was studies, the process endothermicity with the prevailed influence of the entropic factor was established. A slight anion solvation was shown. The isoentropicity of the reaction series was revealed.
The lypophilic properties of N-PhAA substituents were investigated by studying their distribution in the water-octanol system. The distribution coefficients were determined, their additive properties were proved, and hydrophobic constants of the 21 molecular fragments were calculated.
The kinetics of the alkaline hydrolysis reaction for b-dialkylaminoethyl and methyl esters of N-PhAA substituents were studied and its order was determined. It was established that the more electrophilic the carbon atom of the reaction centre was, the greater was the reaction's speed. The direct proportionality between speed and the force of the corresponding acids was related. The application of the Hammett equation was shown not only to p- and m-, but o- substituents with the similarly low r decreasing with the temperature increase. The reaction series isoparametericity was demonstrated.
The acid-basic properties of N-PhAA substituents hydrazides were investigated. The isolating action of –CONH-group was shown. The common equation of pKBH+ relationship with Hammett s-constants of both molecular fragments gives the same low sensitivity of the reaction centre to the substituents' influence and allows forecasting their basecity with a high accuracy.
The systematic research of the kinetics for acylation reaction of N-PhAA substituents and with benzoylchloride has been carried out. Its second order was proved, the numerous kinetic and activation parameters were determined their subordination to the Hammett equation with low r due to a slight division of charges in transition state was determined. The direct proportionality between the nucleophile's reactivity and its basicity was revealed. The cycle condensation was shown to lead to decreasing of reaction centre sensitivity. The reaction isokineticity with enthalpy control type was revealed and its coordinated substitution mechanism was identified.
The acid-base properties for substituents of 9-chlor-, 9-amino-, 9-methyl-amino-, 9-hydrazinoacridine, 9-thioacridone, acridinyl-9-thioacetic acids were investigated. The cycle condensation was shown to increase basicity as well as the introduction of thio-group. 9-NH2- group increases acridine basicity in 5 orders in contrast to 9- NH-NH2- group since the cation of the first compound, unlike the second one, is stabilized by conjugation. The cycle condensation was proved to decrease reaction centre sensitivity to the structure transformations, s-constants were obtained for 5 substituents.
Using acridine derivatives as indicators as well as the inner standard the methods for differentiated determination of acetylsalicylic acid, its chloranhydride and hydrochloric acid in technological mixtures, amine mixtures in natural and wastewater were developed.
Using the physico-chemical and kinetic parameters determined, adequate mathematic models of various type of biological activity dependency from the structure for numerous N-PhAA and acridine derivatives were created by different methods (empiric additive, chemical topology and graphs theory, physico-chemical). This allows to synthesize purposefully active antiphlogistics, diuretics, analgesics, and anticeptics.
The investigation contributes to the development of the structure-activity relationship quantitative theory. The results of research creates the theoretic and methodic basis for molecular design and the optimization of syntheses for effective drugs of these classes.
Key words: reactivity, structure-biological activity relationship, N-phenyl-anthranilic acid, acridine, multifactorial correlation analysis.
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