Talita Odriane Custodio Leite
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Juliana Silva Novais
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Beatriz Lima Cosenza de Carvalho
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Vitor Francisco Ferreira
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Leonardo Alves Miceli
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...
Background:
According to the World Health Organization, antimicrobial resistance is one of
the most important public health threats of the 21st century. Therefore, there is an urgent need for the
development of antimicrobial agents with new mechanism of action, especially those capable of evading
known resistance mechanisms.
Objective:
We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series
of 1H-indole-4,7-dione derivatives.
Methods:
The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)-
mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached
to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular
docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds
was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C
– APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis.
Results:
Several indolequinone compounds showed effective antimicrobial profile against Grampositive
(MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials
current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an
important effect against different biofilm stages formed by a serious hospital life-threatening resistant
strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis
based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico
studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives,
reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising
indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological
activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole-
4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating
bacterial infections.
Conclusion:
The highly substituted indolequinones were obtained in moderate to good yields. The
pharmacological study indicated that these compounds should be exploited in the search for a leading
substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.
