Novel Derivatives of Quinoxaline-2-carboxylic Acid 1,4-Dioxides as Antimycobacterial Agents: Mechanistic Studies and Therapeutic Potential

Frolova, S.G.; Vatlin, A.A.; Maslov, D.A.; Yusuf, B.; Buravchenko, G.I.; Bekker, O.B.; Klimina, K.M.; Smirnova, S.V.; Shnakhova, L.M.; Malyants, I.K.; Lashkin, A.I.; Tian, X.; Alam, M.S.; Zatonsky, G.V.; Zhang, T.; Shchekotikhin, A.E.; Danilenko, V.N.

Статья опубликована в высокорейтинговом журнале

Информация о цитировании статьи получена из Scopus
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 20 февраля 2024 г.

Авторы: Frolova Svetlana G., Vatlin Aleksey A., Maslov Dmitry A., Yusuf Buhari, Buravchenko Galina I., Bekker Olga B., Klimina Ksenia M., Smirnova Svetlana V., Shnakhova Lidia M., Malyants Irina K., Lashkin Arseniy I., Tian Xirong, Alam Md Shah, Zatonsky George V., Zhang Tianyu, Shchekotikhin Andrey E., Danilenko Valery N.
Журнал: Pharmaceuticals
Том: 16
Номер: 11
Год издания: 2023
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 1565
Последняя страница: 1565
DOI: 10.3390/ph16111565
Аннотация: The World Health Organization (WHO) reports that tuberculosis (TB) is one of the top 10 leading causes of global mortality. The increasing incidence of multidrug-resistant TB highlights the urgent need for an intensified quest to discover innovative anti-TB medications In this study, we investigated four new derivatives from the quinoxaline-2-carboxylic acid 1,4-dioxide class. New 3-methylquinoxaline 1,4-dioxides with a variation in substituents at positions 2 and 6(7) were synthesized via nucleophilic aromatic substitution with amines and assessed against a Mycobacteria spp. Compound 4 showed high antimycobacterial activity (1.25 μg/mL against M. tuberculosis) and low toxicity in vivo in mice. Selection and whole-genomic sequencing of spontaneous drug-resistant M. smegmatis mutants revealed a high number of single-nucleotide polymorphisms, confirming the predicted mode of action of the quinoxaline-2-carboxylic acid 1,4-dioxide 4 as a DNA-damaging agent. Subsequent reverse genetics methods confirmed that mutations in the genes MSMEG_4646, MSMEG_5122, and MSMEG_1380 mediate resistance to these compounds. Overall, the derivatives of quinoxaline-2-carboxylic acid 1,4-dioxide present a promising scaffold for the development of innovative antimycobacterial drugs.
Добавил в систему: Щекотихин Андрей Егорович

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Novel Derivatives of Quinoxaline-2-carboxylic Acid 1,4-Dioxides as Antimycobacterial Agents: Mechanistic Studies and Therapeutic Potentialстатья Исследовательская статья