Implementation period: August 3, 2023 – December 31, 2025.
Scientific Supervisor of the Project: Doctor of Chemical Sciences, Full Professor Yu Valentina Konstantinovna
Objects of study: nanostructured inclusion complexes of β-cyclodextrin with aza- and diazacyclohexanes
The goal of the Research Project: To study the patterns of complexation of β-cyclodextrin with the functionally substituted aza- and/or diaza-cyclohexanes, as well as to develop an experimental technique, capable of determining the orientation and dynamics of the encapsulated and macrocyclic molecules by the physicochemical methods of analysis..
Relevance of the Project: Supramolecular chemistry transforms into applied chemistry, since on its basis many substances have been obtained and developed, which have found a practical application in various areas of modern technology in medicine and veterinary medicine, in agriculture, biotechnology and ecology, and other industries. The ability of cyclodextrins (CDs) to change the physical and chemical properties of the guests has been discovered, which makes it possible to improve the applied properties of the substances, forming the complex. Such positive effects are achieved as increasing the solubility of non-polar substances in water (10–100 times); reducing the volatility of easily evaporating organic liquids; increasing the stability of ingredients to the effects of oxygen, air, light, temperature; prolonging the action of the active principle, eliminating or reducing the side effects of the components, such as unpleasant odor or taste, and much more.
The practical implementation of encapsulation of biologically active molecules into an internal hydrophobic cavity requires the development of existing experimental techniques and the characterization of the complex guest-host systems. To correctly describe the dynamics of encapsulated biologically active molecules and their interaction with macrocyclic molecules, it is required: (a) the use of several complementary experimental methods; (b) complication of the structure of the guest molecules, studying their structural and chemical features of real encapsulated molecules.
The research work is devoted to one of the most promising and rapidly developing areas of modern supramolecular chemistry - the production of new nanostructured and microencapsulated dosage forms, convenient for use, of some biologically active functionally substituted aza- and/or diazacyclohexanes.
Beta-cyclodextrin (β-CD) is highly polar and has the lowest solubility in water among cyclodextrins, and is practically insoluble in acetone and hexane. Phenoxyalkyl derivatives of benzhydrylpiperazine are highly soluble in chloroform, hexane, benzene and when heated in ethanol. The use of organic solvents is undesirable for the preparation of the inclusion complexes if their use for medical purposes is planned. We used ethyl alcohol and distilled water to obtain β-CD CV with phenoxyalkyl derivatives of benzhydrylpiperazine. To obtain the complex, 0.00017 mol of β-CD is dissolved in 3 ml of distilled water at 50-60°C, and each phenoxyalkyl derivative of benzhydrylpiperazine is dissolved in 0.00017 mol in ethyl alcohol in 2.5 ml of ethanol upon heating. Then, in separate vials, 0.25 ml of the ethanol solution of a phenoxyalkyl derivative of benzhydrylpiperazine and an aqueous solution of β-CD are mixed at 50-60°C, resulting in a white cloudy solution, the turbidity is removed by adding heated ethanol until a clear solution is obtained.
A pharmacological study of conduction and terminal anesthesia and the acute toxicity of the MEP inclusion complex with β-cyclodextyrin has been carried out. A virtual screening and comparative analysis of the pharmacological activity of a number of obtained piperidine derivatives has been performed, identifying the relationship between the structure and properties of the previously studied compounds. m- and o- Isomers have been synthesized by fluorobenzoylation of 1-(2-ethoxyethyl-4-ethynylpiperidin-4-ol at the reagent ratio of 1:1 without a solvent and exposure of the mixture to ultrasound for 10 min with the yield of 81.6% and 87.8% respectively, while their yield when obtained in dioxane has been 47% and 56%. The structure of 1-(2-ethoxyethyl)-4-ethynyl-4-(m-fluorobenzoyloxy)piperidine and its hydrochloride has been determined by the X-ray diffraction study. The atomic coordinates and other parameters of LAS-286 base and LAS-286 structures are deposited in the Cambridge Structural Data Bank (CCDC 2297241 (LAS-286 base) and 2297243 (LAS-286),
The research is carried out in collaboration with the South Kazakhstan Medical Academy, Sh. Ualikhanov Kokshetau State University, S.D. Asfendiyarov Kazakh National Medical University, the Kuban State University (RF).
PUBLISHED:
Articles in peer-reviewed foreign and (or) domestic publications:
- Kemelbekov, U.; Volynkin, V.; Zhumakova, S.; Orynbassarova, K.; Papezhuk, M.; Yu, V. Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin.// 2024, 29, 1098. https://doi.org/10.3390/molecules29051098 (Scopus – Q 1, Percentile 73%)
- Khaiitova, Malika; Zhumakova, Symbat; Satbayeva, Elmira; Kemelbekov, Ulan; Tursunkhodzhaeva, Firuza; Azamatov, Azizbek; Tursymbek, Shynggys; Sabirov, Vahobjon; Nurgozhin, Talgat; Yu, Valentina. Experimental study of local anesthetic and antiarrhythmic activities of Fluorinated Ethynylpiperidine Derivatives // Brazilian Journal of Medical and Biological Research. – 2023 (accepted) (Scopus – Q 1, Percentile 84%).
Articles in peer-reviewed domestic publications recommended by the Committee for Quality Assurance in the Field of Science and Higher Education of the Ministry of Science and Higher Education of the Republic of Kazakhstan:
- Togyzbaeva N.A., Iskakova T.K., Sikhanova N.S., Kaldybayeva A.B., Malmakova A.E. 3,7-Диазабицикло[3.3.1]нонан-9-он О-бензоилоксимі β-циклодекстринмен комплексінің анальгетикалық белсенділігі// Қазақстанның химия журналы. - 2023. - № 4(84). - С. 5-16. DOI: https://doi.org/10.51580/2023-4.2710-1185.35
- Vasilyuk A. A., Kozlovsky V. I., Yu V. K. Screening of the analgesic activity of a number of new piperidine derivatives with substitutions in the 1st and 4th positions // Vestnik Pharmacii No. 3 (101), 2023. pp. 73-81.
Protection documents:
- Utility model patent No. 8793, dated January 19, 2024 β-cyclodextrin complex of dimethyl ((2,5-dimethoxyphenyl)(4-(pyrimidin-2-yl)piperazin-1-yl)methyl) phosphonate, which has a growth-stimulating activity /Ten A.Yu., Yu V.K., Zharkynbek T.E., Seilkhanov T.M., Mukhamadiyev N.S., Mendibayeva G.Zh., Bissenbai D.
Abstracts of the reports at the International Conferences
- Kaldybayeva A.B., Malmakova A.E., Neborak E.V.; Yu V:K: Potential of synthetic polyamines in the treatment of cancer cells // Materials of the Kazakh-Uzbek Symposium “Modern problems of polymer science” / Almaty, (October 12-13, 2023) - pp. 24-26.
- Ten A.Yu., Yu V.K., Kim Yu.Yu., Zharkynbek T.Y., Kystaubayeva N.U. Immobilization of oxyphosphonate on pectic substances // Materials of the Kazakh-Uzbek Symposium “Modern problems of polymer science” / Almaty, (October 12-13, 2023) - pp.36-37.
- Үдербаева Г.Д., Тоғызбаева Н.Ә., Отегулова К., Малмакова А.Е. Қаңқасында азагетероциклді фрагменті бар қосылыстардың жоғары фармакалогиялық әсерлілігі // Materials of the Kazakh-Uzbek Symposium “Modern problems of polymer science” / Almaty, (October 12-13, 2023) - pp.121-122.
