Free Radical Rearrangement Synthesis And Microbiological Evaluation Of Novel 2-sulfoether-4-quinolone Scaffolds As Potential Antibacterial Agents

Bacterial multidrug resistance is becoming a global problem that threatens human health,but new antimicrobials that target resistant bacteria could not keep pace with the development of resistant bacteria.In order to develop new antimicrobial agents,scientists are turning their attention to fluoroquinolones molecules because of their broad antibacterial spectrum,long half-life,few adverse reactions,wide distribution of tissues and high bioavailability.Quinolones have been extensively studied on their broad advantages and have been approved for clinically four generations.Quinolones with 3-carboxy-4-quinolones showed broad-spectrum antibacterial activity including gastrointestinal infections,respiratory and urological diseases.Moreover,heterocyclic compounds having nitrogen and sulfur atoms have been identified as having the most comprehensive bioactivity profile.Therefore,sulfur atom was introduced into4-quinolone motif to obtain a series of 2-methylthio-4-quinolone derivatives.Their antibacterial activity was evaluated and the structure-activity relationship（SAR）was analyzed.A series of 2-methylthioquinolin-2（1H）-ones 3a-3t were obtained by nucleophilic reaction,methylation reaction and thermal cyclization reaction from N-acetoacetanilide.Compound 3a was further oxidized and hydrolyzed to give compounds 4 and 5,respectively.Their structures were confirmed by X-ray single crystal diffraction,¹H-NMR,¹³C-NMR and HRMS.The results showed that 2-methylthio-4-quinolone derivatives only exhibited the potential antibacterial activity against Gram-positive bacteria,and the MICs of 3m,3n,3p and 3t for S.aureus and Bacillus cereus were relatively low（0.8μM and 1.61μM for both bacteria,respectively）.The SAR of2-methylthio-4-quinolones showed that:（i）4-SCH₃ is required for antibacterial activity;（ii）the CF₃ of the benzene ring increases the antibacterial activity;（iii）Activity and location of the substituent:8-position>7-position>6-position;（iv）disubstituents show better activity.Microscopic analysis of 3n against S.aureus showed that the 3n compound could damage the bacterial cell wall structure,which in turn facilitated drug entry into the bacteria and inhibited bacterial survival.