Synthesis and evaluation of antibacterial and antibiofilm agents based on phenylamino-substituted 1,4-benzoquinones

Aim: This work describes the synthesis and antimicrobial evaluation of 6-aminated 1,4-benzoquinones (6-AQs) against seven resistant pathogens.
Materials & methods: The 6-AQs, synthesized via a Michael addition reaction between bromoquinone and p-substituted anilines, were assessed for their antimicrobial activity through both in vitro and in silico analyses.
Results: Bromoquinone and 6-AQs with electron-withdrawing groups demonstrated activity against Pseudomonas aeruginosa, with minimum inhibitory concentrations ranging from 16 to 128 μg/ml, comparable to standard antimicrobials. Two derivatives exhibited minimum inhibitory concentrations values against methicillin-resistant Staphylococcus aureus ranging from 64 to 128 μg/ml. These compounds demonstrated both bacteriostatic and bactericidal effects, and antibiofilm features.
Conclusion: The 6-AQs 19g and 19f showed a promising antimicrobial profile, indicating their potential as new therapeutic options.
In this work, the design, and development of phenylamino-substituted 1,4-benzoquinones with electron-donating or accepting groups for antimicrobial applications represents one approach in the ongoing battle against microbial infections.
The synthesis involved a sequential series of reactions, beginning with the bromination of vanillin to introduce a bromine atom into its aromatic ring. Subsequently, the brominated derivative was oxidized to generate 2-bromo-6-methoxy-1,4-benzoquinone, which was subjected to a Michael addition reaction with various aromatic amines to give the desired compounds.
Spectroscopic methods played a pivotal role in establishing the structures of the target compounds.
The phenylamino-substituted 1,4-benzoquinones showed antimicrobial activity against Gram-positive, and/or Gram-negative bacteria.
Selective activity of five analogs (19a, 19d, 19e, 19f and 22) detected against P. aeruginosa, with bacteriostatic profile similar to marketed antimicrobials.
Two derivatives (19g, 22) showed potential profile against MRSA, including reduction of biofilm formation, with no significant hemolytic effects, and good theoretical pharmacokinetic profiles.
The in-silico evaluation of the compounds indicated good gastrointestinal absorption, potential to cross the blood–brain barrier, and no carcinogenic risks, with potential for further clinical evaluations against serious microbial infections.