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Keywords = derivatives of quinoxaline-2-carboxylic acid 1,4-dioxide

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19 pages, 2974 KB  
Article
Novel Derivatives of Quinoxaline-2-carboxylic Acid 1,4-Dioxides as Antimycobacterial Agents: Mechanistic Studies and Therapeutic Potential
by Svetlana G. Frolova, Aleksey A. Vatlin, Dmitry A. Maslov, Buhari Yusuf, Galina I. Buravchenko, Olga B. Bekker, Ksenia M. Klimina, Svetlana V. Smirnova, Lidia M. Shnakhova, Irina K. Malyants, Arseniy I. Lashkin, Xirong Tian, Md Shah Alam, George V. Zatonsky, Tianyu Zhang, Andrey E. Shchekotikhin and Valery N. Danilenko
Pharmaceuticals 2023, 16(11), 1565; https://doi.org/10.3390/ph16111565 - 6 Nov 2023
Cited by 11 | Viewed by 3311
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Discovery and Development of New Antimycobacterial Agents)
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