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

<b>Aim:</b> This work describes the synthesis and antimicrobial evaluation of 6-aminated 1,4-benzoquinones (6-AQs) against seven resistant pathogens. <b>Materials &amp; methods:</b> The 6-AQs, synthesized via a Michael addition reaction between bromoquinone and <i>p</i>-substituted anilines, were assessed for their antimicrobial activity through both <i>in vitro</i> and <i>in silico</i> analyses. <b>Results:</b> Bromoquinone and 6-AQs with electron-withdrawing groups demonstrated activity against <i>Pseudomonas aeruginosa</i>, 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 <i>Staphylococcus aureus</i> ranging from 64 to 128 μg/ml. These compounds demonstrated both bacteriostatic and bactericidal effects, and antibiofilm features. <b>Conclusion:</b> The 6-AQs <b>19g</b> and <b>19f</b> 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 (<b>19a</b>, <b>19d</b>, <b>19e</b>, <b>19f</b> and <b>22</b>) detected against <i>P. aeruginosa</i>, with bacteriostatic profile similar to marketed antimicrobials. Two derivatives (<b>19g</b>, <b>22</b>) showed potential profile against MRSA, including reduction of biofilm formation, with no significant hemolytic effects, and good theoretical pharmacokinetic profiles. The <i>in-silico</i> 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.