L.N. Gumilyov Eurasian National University, a dissertation defense for the degree of Doctor of Philosophy (PhD) by Kanasheva Nurdana on the topic «Synthesis and research of macro- and supramolecular systems based on bicyclic bisureas» in the educational program «8D05306 – Chemistry».
The dissertation was carried out at the «Chemistry education department» of L.N. Gumilyov Eurasian National University.
The language of defense is kazakh
Official reviewers:
Zhumagaliyeva Shynar Nurlanovna – Professor of the Department of Chemistry and Technology of Organic Substances, Natural Compounds and Polymers of Al-Farabi Kazakh National University, Dr.Chem.Sci., Professor, (Almaty, Republic of Kazakhstan);
Mangazbayeva Rauash Amantayevna – Professor of the Department of Chemical and Biochemical Engineering at the Geology and Oil-gas Business Institute named after K. Turyssov, Cand.Chem.Sci., Assoc. Professor, (Almaty, Republic of Kazakhstan).
Temporary members of the Dissertation Council:
Bektenov Nesipkhan Abzhaparovich – Professor of the Department of Chemistry of the Abai Kazakh National Pedagogical University, Dr.Chem.Sci., Professor (Almaty, Republic of Kazakhstan);
Appazov Nurbol Orynbasaruly – Research Professor of the educational program «Engineering Technologies» of Korkyt Ata Kyzylorda University, Cand.Chem.Sci. (Kyzylorda, Republic of Kazakhstan);
Pavlovsky Viktor Ivanovich – Professor of N.M. Kizhner Research and Educational Center at the National Research Tomsk Polytechnic University, Dr.Chem.Sci. (Tomsk, Russian Federation).
Scientific consultants:
Yerkassov Rakhmetulla Sharapidenovich – Dr.Chem.Sci., Professor of the Department of Chemistry, L.N. Gumilyov Eurasian National University, (Astana, Republic of Kazakhstan);
Bakibaev Abdigali Abdimanapovich – Leading Researcher at the Laboratory of Organic Synthesis, Tomsk State University, Dr.Chem.Sci., Professor (Tomsk, Russian Federation).
The defense will take place on May 21, 2025, at 03:00 PM in the Dissertation Council for the training direction «8D053 – Physical and chemical sciences» in the educational program «8D05306 – Chemistry» of L.N. Gumilyov Eurasian National University. Conducting a meeting of the dissertation council in a mixed (offline and online) format.
Link: https://surl.li/lnbmki
Address: Astana, Kazhymukan str., 13, L.N. Gumilyov ENU, building №3, room 333.
Abstract (English): General description of the work. The dissertation focuses on investigating the conditions for obtaining macro- and supramolecular systems based on bicyclic bisureas (glycoluril) as precursors for polymer compounds, as well as assessing their practical properties to explore their potential in developing biocomposite materials for medical applications. The dissertation is presented as a series of two articles and one review, published by the doctoral student in accordance with paragraph 5-1 of the Rules for Awarding Degrees, approved by Order No. 127 of the Minister of Education and Science of the Republic of Kazakhstan, dated March 31, 2011 (registered in the Register of State Registration of Normative Legal Acts under No. 6951), as amended by Order No. 170 of the Minister of Education and Science of the Republic of Kazakhstan, dated April 30, 2020, and in accordance with the Order of the Minister of Education and Science of the Republic of Kazakhstan, dated March 9, 2021, No. 98, as amended by the Acting Minister of Science and Higher Education of the Republic of Kazakhstan, dated January 9, 2023, No. 7. The relevance of the work. Currently, glycoluril is used across various industries, including the production of pharmaceuticals, explosives, linking agents for the synthesis of special-purpose polymers, and other practically valuable compounds. In recent decades, an emerging and rapidly developing field of glycoluril chemistry has focused on the synthesis of macrocyclic compounds with unique, controllable properties, such as cucurbit[n]urils, bambus[n]urils, and tiara[n]urils, as well as the formation of supramolecular systems based on them. Supramolecular compounds derived from glycoluril have been explored as components of organic semiconductor materials, auxiliary compounds in pharmaceuticals (e.g., prolongators and molecular containers for controlled release), materials with “molecular recognition” properties, and molecular sensors for the rapid detection of amphiphilic components such as surfactants, bacterial endotoxins, and biogenic amines, where glycoluril serves as a structural building block. Despite considerable progress, the chemistry of glycoluril continues to evolve, remaining at the forefront of scientific research. In particular, the potential of macro- and supramolecular systems based on glycoluril opens up new opportunities to address modern challenges in various related fields, such as the development of biocomposite materials for medical applications, the creation of novel “smart materials”, and the design of targeted drug delivery systems. The convergence of these advancements in glycoluril chemistry underscores the relevance of this study, which focuses on the synthesis and investigation of novel macro- and supramolecular systems based on bicyclic bisureas. The purpose of the dissertation research. The purpose of this work is to develop methods for synthesizing novel glycoluril-based macrocyclic compounds and to investigate their physicochemical and biological properties. Tasks: 1. Analyze modern scientific literature on the synthesis methods of macrocyclic compounds based on glycoluril and their application as precursors for polymeric materials. 2. Investigate the synthesis conditions and biocompatibility of novel biocomposite materials based on glycoluril and sodium carboxymethylcellulose (Na-CMC) for the development of new anti-adhesive agents. 3. Synthesize a new glycoluril-melamine-formaldehyde (GUMEFA) polymer in the presence of hydroxyethylidene diphosphonic acid (HEDP) and examine the content of methylol groups and free formaldehyde in the resulting polymer. 4. Investigate the formation conditions of the GUMEFA polymer in the presence of a supramolecular complex (CB[6]@Pipa*2HCl) composed of cucurbit[6]uril (CB[6]) and 1,4-bis(2-hydroxyethyl)piperazine dihydrochloride (Pipa*2HCl). 5. Assess the hemocompatibility and antibacterial properties of the GUMEFA polymer synthesized with HEDP. The objects of research are glycoluril, composite film materials based on glycoluril and Na-CMC, glycoluril-melamine-formaldehyde polymer (GUMEFA), supramolecular complex based on cucurbit[6]uril and 1,4-bis(2-hydroxyethyl) piperazine dihydrochloride. The scientific novelty of the work. 1. A comprehensive review of the synthesis methods, properties, and applications of macrocyclic nitrogen-containing compounds based on glycoluril as precursors for polymeric materials has been conducted for the first time. 2. Novel composite film materials based on glycoluril and Na-CMC were synthesized, and their physicochemical and biological properties responsible for their anti-adhesion effect were identified. Experimental studies demonstrated that these composite films exhibit low macrophage adhesion to the surface (61±8 at 0.01% and 18±5 at 0.05%) and high antioxidant activity (10.02±0.86 µmol Trolox/g Film at 0.01% and 21.27±0.91 µmol Trolox/g Film at 0.05%), surpassing the commercial Seprafilm sample (macrophage adhesion: 128±16; antioxidant activity: 2.19±0.32 µmol Trolox/g Film). 3. A glycoluril-melamine complex (GU-ME) with a 1:5 ratio was synthesized and characterized for the first time, confirmed by IR and NMR spectroscopy. The possibility of its polycondensation into the GUMEFA polymer using HEDP as a "green" catalyst has been established. A mechanism for polymer formation has been proposed, along with an analysis of its composition, including free formaldehyde content (1.22–1.34 wt.%) and methylol group content (1.56–0.48 wt.%). For the first time, it was demonstrated that the supramolecular complex CB[6]@Pipa*2HCl serves as an efficient catalyst for the GUMEFA polymer synthesis, reducing plasticization time by 58% compared to hydrochloric acid and by 37.5% compared to HEDP. Additionally, its lower catalyst consumption enhances process efficiency and broadens potential applications in polymer chemistry. 4. For the first time, the hemolytic effect of the newly synthesized polymer GUMEFA was evaluated using the spectrophotometric method, and its antibacterial activity was assessed using the standard disk diffusion method in the author's modified approach. The polymer was synthesized using different catalysts: hydrochloric acid and HEDP. The main provisions of the dissertation submitted for defense. 1. The utilization of glycoluril derivatives in the synthesis of macrocyclic compounds, facilitated by the formation of reactive intermediates, enables the development of new structures with potentially enhanced functional properties. A literature review confirms the promising application of glycoluril in the synthesis of high-molecular-weight compounds (polymers), highlighting it as an underexplored field that offers new opportunities for the design of functional materials. 2. The established conditions for obtaining composite film materials (0.01% and 0.05% solutions; molar ratio of glycoluril to glyoxal – 1:2.5; pH – 2.7–4.0; biologically inert matrix: Na-CMC (M.W. 250000, DS = 0.9), Na-CMC (M.W. 250000, DS = 1.2), or hydroxypropylmethylcellulose; total weight – 10.0 g; t – 24 hours) ensure the biocompatibility of the material, comparable to the commercial medical product Seprafilm. 3. The influence of HEDP in the synthesis of the GUMEFA polymer results in a reduced content of free formaldehyde (determined by spectrophotometric and fluorometric methods) and methylol groups (analyzed using the reverse iodometric method) compared to the polymer synthesized in the presence of hydrochloric acid. 4. The application of HEDP as a catalyst in the synthesis of the GUMEFA polymer reduces its hemolytic effect (0.1889%) and enhances its antibacterial activity against Escherichia coli. The average diameter of bacterial growth inhibition zones was 47.8 mm, while for the polymer synthesized using hydrochloric acid, this indicator was lower (43.7 mm), with the differences being statistically significant (p < 0.05). The practical significance of the work. The findings from the studies on the synthesis conditions and biocompatibility of composite film materials based on glycoluril and Na-CMC provide a foundation for developing a prototype film material with anti-adhesion properties. These composite film compositions have potential applications in the creation of domestic barrier-type anti-adhesive agents for clinical surgery. The practical significance of the study is that using HEDP as a catalyst lowers the free formaldehyde content in the GUMEFA polymer, thereby broadening its potential applications and optimizing the plasticization process to reduce formaldehyde levels. Furthermore, the obtained samples, due to their high hemocompatibility and antibacterial properties, can be applied in various biomedical fields. Overall, the results pave the way for creating resins with diverse compositions and functions, advancing the development of new composite materials with tailored properties. The author's personal contribution to the dissertation research include the comprehensive search, analysis, and synthesis of established scientific data on the research topic, as well as the development of a detailed research plan. The author independently conducted all chemical experiments, including the isolation and purification of products, and interpreted the results obtained from physicochemical research methods. The applicant prepared materials for publication in scientific journals and presented the findings through reports at scientific conferences. Approbation of the work. The main provisions, conclusions and scientific results of the dissertation were reported and discussed at international conferences: the XII International Scientific and Practical Conference «Actual Problems of Natural Sciences» (Petropavlovsk, 2024), the ХХ International Conference of Students, Postgraduates and Young Scientists «Prospects for the Development of Fundamental Sciences» (Тomsk, 2023), 7th International Scientific Conference «Reviews of Modern Science» (Zurich, Switzerland, 2024), International Scientific Conference «Foundations and Trends in Research» (Copenhagen, Denmark, 2024), International Scientific Conference «European Research Materials» (Amsterdam, Netherlands, 2024). Publications. The main results of the dissertation research are reflected in 9 published works, including 2 articles and 1 review in scientific publications included in the first and second quartile of the impact factor according to the Journal Citation Reports of Clarivate Analytics; 1 publication in a foreign scientific publication, 5 works in the materials of the republican and international conferences. In the review Kabieva, S.K.; Zhumanazarova, G.M.; Kanasheva, N.; Bakibaev, A.A.; Panshina, S.Yu.; Malkov, V.S.; Mamaeva, E.A.; Knyazev, A.S. Methods of synthesizing glycoluril-based macrocyclic compounds as precursors for polymeric compounds. Journal of Saudi Chemical Society 2023, 27, 101768. the doctoral student contributed to the literature search on the research topic, conducted data analysis, and assisted in preparing the initial draft of the work. The journal “Journal of Saudi Chemical Society” has an Impact Factor for 2023 equal to 5.9, and has a quartile in chemistry, multidisciplinary – Q1. For 2023, CiteScore has an equal 8.9, the percentile in general chemistry is 83. In the article Kanasheva, N.; Fedorishin, D.A.; Lyapunova, M.V.; Bukterov, M.V.; Kaidash, O.A.; Bakibaev, A.A.; Yerkassov, R.; Mashan, T.; Nesmeyanova, R.; Ivanov, V.V.; et al. The Determination of the Biocompatibility of New Compositional Materials, including Carbamide-Containing Heterocycles of Anti-Adhesion Agents for Abdominal Surgery. Molecules 2024, 29, 851. the applicant is the first author. The journal “Molecules” for 2023 has an Impact Factor of 4.2, and the quartile for biochemistry and molecular biology, chemistry, multidisciplinary is Q2. The CiteScore for 2023 is 7.4, the percentile in chemistry (miscellaneous) is 83; the percentile in organic chemistry is 81; the percentile in physical and theoretical chemistry is 80; the percentile in analytical chemistry is 78; the percentile in pharmaceutical science is 81; the percentile in drug discovery is 73; the percentile in molecular medicine is 68. The doctoral student contributed to conducting experiments and analyzing data, generated graphs and tables, and edited the manuscript to enhance its structure, style, and clarity. Additionally, N.K. Kanasheva handled the article's formatting to meet the journal's requirements. The doctoral student is the first author in the article Kanasheva, N.; Ukhov, A.; Malkov, V.S.; Gubankov, A.; Sergazina, S.; Issabayeva, M.A.; Mashan, T.; Kolpek, A.; Ryskaliyeva, R.; Bakibaev, A.; et al. The Synthesis of a New Glycoluryl–Melamine–Formaldehyde Polymer under the Action of HEDP and the Investigation of the Content of Methylol Groups and Free Formaldehyde. Polymers 2024, 16, 2877 . The journal “Polymers” for 2023 has an Impact Factor of 4.7, and has a quartile in polymer science – Q1. It has a CiteScore of 8.0 for 2023, the percentile in general chemistry - 81; the percentile in polymers and plastics - 80. N.K. Kanasheva was directly involved in obtaining experimental data, processing and interpreting the results, preparing the initial manuscript, and writing the conclusions for the article. The applicant also participated in submitting the article to the journal and maintained communication with the editorial board throughout the review and publication process. The doctoral student was directly involved in obtaining experimental data, processing and interpreting the results for the preparation of materials and abstracts of 5 reports at national and international scientific conferences.
Conclusion of the Research Ethics Committee
Defense of the dissertation: https://youtu.be/rm4nIhQ1I4g
