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. 2024;16(21):2247-2261.
doi: 10.1080/17568919.2024.2400954. Epub 2024 Oct 14.

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

Talita O Custodio Leite  1 , Juliana S Novais  2 , Beatriz Lima C de Carvalho  1 , Flaviana Rodrigues F Dias  1   3 , Nathalia R C Martins  2 , Aldo Rodrigues da Silva  2 , Reinaldo Barros Geraldo  3 , Nayra Cordeiro da Conceição  3 , Norman Ratcliffe  3   4 , Vitor F Ferreira  5 , Helena C Castro  2   3 , Anna C Cunha  1
Affiliations

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

Talita O Custodio Leite et al. Future Med Chem. 2024.

Abstract

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.

Keywords: antibacterial agent; antibiofilm agent; biofilm; organic synthesis; phenylaminoquinones; quinones.

Plain language summary

[Box: see text].

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Conflict of interest statement

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
(A) Examples of some drugs 1–10 used in the treatment against major superbugs; (B) Examples of natural quinones with antitumor activity 11–13 and (C) Aminoquinone derivatives with antimicrobial activity 14–17.
Figure 2.
Figure 2.
Structural planning of benzoquinone derivatives 19a-h.
Figure 3.
Figure 3.
Synthesis of amino-benzoquinone derivatives 19a–h.
Figure 4.
Figure 4.
Effects of bromoquinone (22) and derivative 19g (1/8 MIC, 1/4 MIC and 1/2 MIC; MIC = Minimum inhibitory concentration) on methicillin-resistant Staphylococcus aureus (MRSA) biofilm development compared with vancomycin (4) (Van). (A) MRSA growth after 24 h of incubation with subinhibitory concentrations of 22 and 19g. (B) Biofilm formed on surfaces and stained with crystal violet after treatment with a subinhibitory concentration of 22. The data stand for the mean of the results of a total of nine samples (three independent experiments, each performed in triplicate). Bar is the standard deviation. Van vancomycin (1/4 MIC; 0.5 μg/ml). NS not significant; *p < 0.05; **p < 0.001; and ***p < 0.0001.
Figure 5.
Figure 5.
Comparison of the compounds molecular structure including: (A) 3D structure and MEP maps generated with MMFF/6-311**-G level electron density and (B) The stereo electronic properties HOMO and LUMO coefficients distribution. Electrostatic potentials mapped on the surface of the electron density are between -200 and 200 kJ/mol. The red and blue surfaces correspond to a negative and positive regions of the electrostatic potential (-200 and 200 kJ/mol) respectively. The atoms are colored in Corey-Pauling-Koltun (CPK) rules. HOMO: Highest occupied molecular orbital; LUMO: Lowest occupied molecular orbital; MEP: Molecular electrostatic potential.
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