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

Galina I Buravchenko,Dmitry A Maslov,Andrey E Shchekotikhin,Natalia E Grammatikova,Aleksey A Vatlin,Tianyu Zhang,Xirong Tian,Svetlana G Frolova,Olga B Bekker,Maxim A Kryakvin,Md Shah Alam,Valery N Danilenko,Ivan V Ivanov,Olga A Dontsova

doi:10.3390/ph15020155

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.

Highlights

Bacterial infections have represented one of the most serious dangers to human health and animal husbandry throughout time
We describe the synthesis and the profile of antimicrobial properties for the new series of 2-acyl-7-amino-3-trifluoromethylquinoxaline 1,4-dioxide derivatives
7-amino-3-trifluoromethylquinoxaline 1,4-dioxides was prepared by the nucleophilic substitution of halogen atoms which as in case of 6,7-dihalogeno-3-trifluoromethylquinoxaline

Summary

Introduction

Bacterial infections have represented one of the most serious dangers to human health and animal husbandry throughout time. There are over 12 classes of pathogenic bacteria, that cause various infectious diseases, which are considered as an increasing threat to human health due to their emerging resistance to most of antibacterial drugs, indicating the need for the development of novel agents for treating these drug-resistant bacteria [1]. A alarming tendency is the spread of multidrug- and totally drug-resistant bacteria (the so-called “superbugs”), which cause infections that cannot be treated with any of the existing antimicrobial drugs [3]. The plasmids were electroporated in M. smegmatis mc 155 cells as described earlier [65] and plated on M290 plates supplemented with kanamycin (50 μg/mL), hygromycin (50 μg/mL) and X-Gal (50 μg/mL), blue single-crossover colonies were selected.

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Results

Conclusion