chemicallytechFine Chemical TechnologiesТонкие химические технологии2410-65932686-7575MIREA – Russian Technological University (RTU MIREA).10.32362/2410-6593-2023-18-3-219-229chemicallytech-1971Research ArticleCHEMISTRY AND TECHNOLOGY OF MEDICINAL COMPOUNDS AND BIOLOGICALLY ACTIVE SUBSTANCESХИМИЯ И ТЕХНОЛОГИЯ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ И БИОЛОГИЧЕСКИ АКТИВНЫХ СОЕДИНЕНИЙDesign and synthesis of 4-nitroimidazole derivatives with potential antitubercular activityДизайн и синтез производных 4-нитроимидазола с потенциальной антитуберкулезной активностьюhttps://orcid.org/0000-0001-7356-397XВедёхинаТ. С.VedekhinaT. S.

Ведёхина Татьяна Сергеевна, к.х.н., старший научный сотрудник лаборатории структуры и функций биополимеров

119435, Москва, ул. Малая Пироговская, д. 1а

ResearcherID AAZ-5822-2021

Scopus Author ID 57190025747

Tatiana S. Vedekhina, Cand. Sci. (Chem.), Senior Researcher, Laboratory of Structure and Functions of Biopolymers

1a, Malaya Pirogovskaya ul., Moscow, 119435

ResearcherID AAZ-5822-2021

Scopus Author ID 57190025747 

taveda@gmail.comhttps://orcid.org/0000-0001-9735-9690ЧудиновМ. В.ChudinovM. V.

Чудинов Михаил Васильевич, к.х.н., доцент кафедры биотехнологии и промышленной фармации

119571, Москва, пр-т Вернадского, д. 86

ResearсherID L-5728-2016

Scopus Author ID 6602589900

Mikhail V. Chudinov, Cand. Sci. (Chem.), Associate Professor, Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571

ResearсherID L-5728-2016

Scopus Author ID 6602589900 

chudinov@mirea.ruЛукинА. Ю.LukinA. Yu.

Лукин Алексей Юрьевич, к.х.н., доцент кафедры биотехнологии и промышленной фармации

119571, Москва, пр-т Вернадского, д. 86

ResearсherID P-1019-2016

Scopus Author ID 7102949868

Alexey Yu. Lukin, Cand. Sci. (Chem.), Associate Professor, Department of Biotechnology and Industrial Pharmacy

86, Vernadskogo pr., Moscow, 119571

ResearсherID P-1019-2016

Scopus Author ID 7102949868 

lukin@mirea.ruФедеральный научно-клинический центр физико-химической медицины имени академика Ю.М. Лопухина Федерального медико-биологического агентстваРоссияLopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyRussian FederationМИРЭА – Российский технологический университет (Институт тонких химических технологий им. М.В. Ломоносова)РоссияMIREA – Russian Technological University (M.V. Lomonosov Institute of Fine Chemical Technologies)Russian Federation202302082023183219229Copyright © Vedekhina T.S., Chudinov M.V., Lukin A.Y., 20232023Ведёхина Т.С., Чудинов М.В., Лукин А.Ю.Vedekhina T.S., Chudinov M.V., Lukin A.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.finechem-mirea.ru/jour/article/view/1971Objectives

Objectives. To develop the procedures for synthesis of hybrid molecules with potential anti-tubercular activity containing heterocyclic cores of 4-nitroimidazole and 1,3,4-thiadiazole within the framework of a double-drug strategy and predict bioactivity of target structures and drug-likeness physicochemical parameters.

Methods

Methods. Target compounds were prepared by classical organic synthesis methods. The structure of the obtained compounds was characterized by melting points, 1H and 13C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The calculation of the physicochemical parameters of the target compounds and prediction of their biological activity were carried out using publicly available software for cheminformatics and molecular modeling.

Results

Results. Acylation of propargylamine with (2-methyl-4-nitro-1H-imidazol-1-yl)acetic and (4-nitro-1H-imidazol-1-yl)acetic acids provided the corresponding amides, which were cyclized with seven different benzylamines in the presence of zinc triflate. In this way, seven new compounds were obtained at 20–30% yields. Ten arylamines were acylated with chloroacetyl chloride and the resulting chloroacetamides were converted into corresponding thio-oxahydrazides by the Willgerodt–Kindler reaction. Following acylation by (4-nitro-1H-imidazol-1-yl)acetic acid, these compounds were converted into the target hybrid imidazolyl-thiadiazoles at 29–54% yields.

Conclusions

Conclusions. Two series of new heterocyclic compounds with a hybrid structure including a privileged 4-nitroimidazole moiety linked to the second heterocycle, imidazole, or thiadiazole, were obtained. The synthesis and characterization of compounds by physicochemical methods was aimed at searching for anti-tuberculosis activity. The bioactivity potential of target compounds was demonstrated by preliminary calculations performed using public prognostic programs.

Цели

Цели. Разработка синтеза гибридных молекул c потенциальной противотуберкулезной активностью, содержащих гетероциклические системы 4-нитроимидазола и 1,3,4-тиадиазола, в рамках стратегии «double drug». Анализ соответствия их расчетных физико-химических параметров интервалам значений для лекарственно-подобных («drug-likeness») соединений.

Методы

Методы. Целевые соединения были получены классическими методами органического синтеза. Структура полученных соединений была охарактеризована температурами плавления, спектроскопией ядерного магнитного резонанса 1H и 13C, масс-спектрометрией высокого разрешения. Расчет физико-химических параметров целевых соединений и прогнозирование их биологической активности проводили с использованием общедоступного программного обеспечения для хемоинформатитки и молекулярного моделирования.

Результаты

Результаты. Ацилированием пропаргиламина (2-метил-4-нитро-1Н-имидазол-1-ил)уксусной и (4-нитро-1Н-имидазол-1-ил)уксусной кислотами были получены пропаргиламиды, которые циклизовали с 7 различными бензиламинами в присутствии трифлата цинка. Таким способом с выходами 20–30% от теоретического была получена серия из 7 новых 2-[(4-нитро-1Н-имидазол-1-ил)метил]-1-бензил-5-метил-1Н-имидазолов. 10 ариламинов были ацилированы хлорацетилхлоридом. Полученные хлорацетамиды реакцией Вильгеродта–Киндлера превратили в соответствующие тиооксагидразиды. Эти соединения после ацилирования (4-нитро-1Н-имидазол-1-ил)уксусной кислотой были превращены циклодегидратацией в целевые гибридные имидазолил-тиадиазолы, с выходами 29–54%.

Выводы

Выводы. Получены две серии новых гетероциклических соединений с гибридной структурой, включающей привилегированный фрагмент 4-нитроимидазола, соединенный алкильным линкером со вторым гетероциклом – имидазолом или тиадиазолом. Соединения сконструированы с целью поиска противотуберкулезной активности, синтезированы и охарактеризованы физико-химическими методами. Предварительные расчеты, выполненные с помощью общедоступных прогностических программ, показали возможный потенциал биологической активности целевых структур.

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The authors declare that there are no conflicts of interest present.