Synthesis and Characterization of Novel 2-Acyl-3-trifluoromethylquinoxaline 1,4-Dioxides as Potential Antimicrobial Agents

The emergence of drug resistance in pathogens leads to a loss of effectiveness of antimicrobials and complicates the treatment of bacterial infections. Quinoxaline 1,4-dioxides represent a prospective scaffold for search of new compounds with improved chemotherapeutic characteristics. Novel 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides with alteration of substituents at position 2 and 6 were synthesized via nucleophilic substitution with piperazine moiety and evaluated against a broad panel of bacteria and fungi by measuring their minimal inhibitory concentrations. Their mode of action was assessed by whole-genomic sequencing of spontaneous drug-resistant Mycobacterium smegmatis mutants, followed by comparative genomic analysis, and on an original pDualrep2 system. Most of the 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides showed high antibacterial properties against Gram-positive strains, including mycobacteria, and the introduction of a halogen atom in the position 6 of the quinoxaline ring further increased their activity, with 13c being the most active compound. The mode of action studies confirmed the DNA-damaging nature of the obtained quinoxaline 1,4-dioxides, while drug-resistance may be provided by mutations in redox homeostasis genes, encoding enzymes potentially involved in the activation of the compounds. This study extends views about the antimicrobial and antifungal activities of the quinoxaline 1,4-dioxides and can potentially lead to the discovery of new antibacterial drugs. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Buravchenko G.I.1 , Maslov D.A.2 , Alam M.S. 3, 4, 5, 6 , Grammatikova N.E.1 , Frolova S.G.2, 7 , Vatlin A.A. 2, 8 , Tian X. 3, 4, 5, 6 , Ivanov I.V.1, 9 , Bekker O.B.2 , Kryakvin M.A.10 , Dontsova O.A.10, 11, 12 , Danilenko V.N. 2 , Zhang T.3, 4, 5, 6 , Shchekotikhin A.E.1
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  • 1 Gause Institute of New Antibiotics, Moscow, 119021, Russian Federation
  • 2 Laboratory of Bacterial Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, 119333, Russian Federation
  • 3 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
  • 4 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou, 510530, China
  • 5 Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
  • 6 University of Chinese Academy of Sciences, Beijing, 100049, China
  • 7 Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (State University), Dolgoprudny, 141701, Russian Federation
  • 8 Institute of Ecology, Peoples’ Friendship University of Russia (RUDN University), Moscow, 117198, Russian Federation
  • 9 Organic Chemistry Department, Faculty of Natural Sciences, Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow, 125190, Russian Federation
  • 10 Chemistry Department, Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119991, Russian Federation
  • 11 Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143028, Russian Federation
  • 12 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russian Federation
3-trifluoromethylquinoxaline 1,4-dioxides; Antimicrobial activity; DNA-damaging agents; M. smegmatis mutants; Structure–activity relationships
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