Norfloxacin-arylazopyrazole conjugates as potent light-active antibiotics: design, synthesis and light-assisted reversible control of antibiotic action

Abstract

Antibiotic resistance has become a threat to mankind in the 21st century. For suppressing the growth of multi-drug resistant bacteria via the photopharmacology approach, photoswitchable norfloxacin-arylazopyrazole conjugates were synthesized, and the photoswitching efficiencies and antimicrobial activities were tested before and after light irradiation. Most compounds exhibited very high to near quantitative isomerization yields with decent cis half-lives (7-28 h) and very high light fatigue resistance. The antimicrobial activity of these norfloxacin analogues was found to be selective to the Gram-positive bacteria. Notably, in comparison to the parent norfloxacin (MIC value 0.8 ug/mL), better efficiencies were displayed by conjugates having para-OMe-substituted arylazopyrazole (both trans and cis states) and para-SMe-substituted arylazopyrazole (cis state only). Some of our compounds in cis state displayed impressive bactericidal activity. Remarkably, a 20-times activity difference between cis and trans isomers was achieved by the visible-light responsive conjugate with para-SMe substitution, which is so far the highest activity difference from any reported photoswitchable antibiotic. Computational GOLD docking poses are in agreement with the experimental data.