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

Abstract

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.

Quercetin Attenuates Quinocetone-Induced Cell Apoptosis In Vitro by Activating the P38/Nrf2/HO-1 Pathway and Inhibiting the ROS/Mitochondrial Apoptotic Pathway

“…Quinoxaline-1,4-dioxides (QdNOs), a class of quinoxaline derivatives, have been widely employed in agricultural and medicinal fields across the world due to their antibacterial, antitubercular, anticandidal, antiprotozoal, and anticancer activity [ 1 , 2 , 3 , 4 ]. Quinocetone (QCT) (i.e., 3- methyl-2-quinoxalin benzenevinylketo-1, 4-dioxide, Figure 1 A), a relatively new member of QdNOs family, was first approved as an antibacterial agent in China since 2003 [ 5 ].…”

Quinoxaline 1,4-Dioxides: Advances in Chemistry and Chemotherapeutic Drug Development

“…The reaction of aminobenzofuroxans 14j , k with benzoylacetonitrile in chloroform in the presence of Et 3 N also yields 7-amino-substituted quinoxaline-2-carbonitrile 1,4-dioxides 26a , b ( Scheme 7 ) [ 61 ]. This method of heterocyclization was later used to synthesize 7-(piperazin-1-yl)-3-trifluoromethylquinoxaline 1,4-dioxide 27a ( Scheme 7 ) [ 62 ]. The 7-amino derivatives of 26a , b have high aqueous solubility and downregulate the expression of HIF1α, BCL2, and ERα and induce apoptosis in MCF-7 cells at submicromolar concentrations.…”

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

“…A previously described 3-trifluoromethylquinoxaline 1,4-dioxide derivative 9 [12] was prepared in the same way, which involved two steps: a cyclization of benzofuroxan with ethyl 4,4,4-trifluoroacetoacetate in chloroform in the presence of triethylamine and a subsequent substitution of chlorine atom in position 7 of 3-trifluorimethylquinoxaline 1,4dioxide 8 with N-Boc-piperazine in THF (Scheme 2). The 13 C NMR spectra of derivatives 8 and 9 had two characteristic quadruplet signals that corresponded to their structures.…”

“…In prior research, we described a series of novel 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides with significant inhibitory properties against M. smegmatis. However, their activity against M. tuberculosis was limited [12]. In this study, we introduce a novel series of quinoxaline-2-carboxylic acid 1,4-dioxide derivatives with substituent variations at positions 3, 6, and 7.…”