| Abstract [eng] |
Master’s thesis of Linas Petrauskas “Synthesis of Substituted Benzimidazothiazines and Thiazoles for the Search of Amyloid Aggregation Modulators”. Supervisor dr. Rita Bukšnaitienė. Vilnius University, Faculty of Medicine, Institute of Biomedical Sciences, Pharmacy and Pharmacology Center. Vilnius, 2026. Aim of the research – to synthesize substituted benzimidazothiazines and the corresponding thiazoles for the search of amyloid aggregation modulators. Objectives of the research: 1. To synthesize the intermediate compounds – phenylpropargylmercaptobenzimidazoles – through 4 selected key reaction steps according to known methodologies. 2. To synthesize new target benzimidazothiazines from the developed alkynylmercaptobenzimidazoles via gold bromide-catalyzed intramolecular nucleophilic cyclization. 3. To synthesize new target benzimidazothiazoles from the developed alkynylmercaptobenzimidazoles using base or N-chlorosuccinimide-initiated intramolecular cyclizations. 4. To identify and confirm the structures of the target compounds using spectroscopic analysis methods. Object and methodology of research. The object of master’s thesis is the synthesis of novel compounds containing an imidazothiazine scaffold and exhibiting modulation of amyloid aggregation. The chemical reactions were carried out based on various methodologies, and their progress was monitored by thin-layer chromatography (TLC). For the identification and confirmation of the structures of the new compounds, 1H and 13C nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), and IR spectroscopy methods were applied, and melting points were determined. The target compounds were further prepared for amyloid aggregation studies according to laboratory protocols. Results and conclusions. Phenylpropargylmercaptobenzimidazoles (5a-c) were synthesized from the starting compounds (1a-c) in four steps, using Sonogashira coupling, Appel bromination, alkylation, and intramolecular cyclocondensation reactions. The most successful steps, giving the highest yields, were bromination and intramolecular cyclocondensation, whose products, 3a-c and 5a-c, were obtained in 94-97% and 82-94% yields, respectively. Meanwhile, the alkylation products (4a-c) were formed in moderate yields of 48-53%. The yields of the Sonogashira reaction products 2a-c ranged from 50% to 97%. In the final reaction step, 3 new target compounds – benzimidazothiazines with different substituents – were synthesized via gold bromide-catalyzed intramolecular nucleophilic cyclization (7a-c). The yields of these compounds were moderate, ranging from 47% to 53%. Using other synthetic methods, in which either a base or N-chlorosuccinimide was used to initiate intramolecular nucleophilic cyclization, 6 additional benzimidazothiazoles were synthesized, namely 6a-c and 8a-c, respectively. More consistent yields (36-57%) were obtained using the base-mediated reaction to afford compounds 6a-c, whereas greater yield variability (20-74%) was observed for compounds 8a-c, which contain a chloro substituent at the methylene bridge. In total, including intermediates, 23 compounds were synthesized, of which 19 are new and have not been described in the literature. Their structures were identified and confirmed by IR, 1H and 13C nuclear magnetic resonance spectroscopy, as well as by determination of melting points and high-resolution mass spectrometric analysis. Keywords. Imidazothiazines, amyloids, aggregation, gold catalyst. |
