Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains.

Autor: Cvijetić IN; Innovation Center of the Faculty of Chemistry, University of Belgrade, Studentski trg 16, Belgrade, Serbia. Electronic address: ilija@chem.bg.ac.rs., Verbić TŽ; Faculty of Chemistry, University of Belgrade, Studentski trg 16, Belgrade, Serbia., Ernesto de Resende P; UCL School of Pharmacy, University College London, London, UK., Stapleton P; UCL School of Pharmacy, University College London, London, UK., Gibbons S; UCL School of Pharmacy, University College London, London, UK., Juranić IO; Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, University of Belgrade, Njegoševa 12, Belgrade, Serbia., Drakulić BJ; Institute of Chemistry, Technology and Metallurgy, Department of Chemistry, University of Belgrade, Njegoševa 12, Belgrade, Serbia., Zloh M; University of Hertfordshire, College Lane, Hatfield, AL10 9AB, UK. Electronic address: zloh@live.co.uk.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2018 Jan 01; Vol. 143, pp. 1474-1488. Date of Electronic Publication: 2017 Nov 11.
DOI: 10.1016/j.ejmech.2017.10.045
Abstrakt: Antimicrobial resistance (AMR) is a major health problem worldwide, because of ability of bacteria, fungi and viruses to evade known therapeutic agents used in treatment of infections. Aryldiketo acids (ADK) have shown antimicrobial activity against several resistant strains including Gram-positive Staphylococcus aureus bacteria. Our previous studies revealed that ADK analogues having bulky alkyl group in ortho position on a phenyl ring have up to ten times better activity than norfloxacin against the same strains. Rational modifications of analogues by introduction of hydrophobic substituents on the aromatic ring has led to more than tenfold increase in antibacterial activity against multidrug resistant Gram positive strains. To elucidate a potential mechanism of action for this potentially novel class of antimicrobials, several bacterial enzymes were identified as putative targets according to literature data and pharmacophoric similarity searches for potent ADK analogues. Among the seven bacterial targets chosen, the strongest favorable binding interactions were observed between most active analogue and S. aureus dehydrosqualene synthase and DNA gyrase. Furthermore, the docking results in combination with literature data suggest that these novel molecules could also target several other bacterial enzymes, including prenyl-transferases and methionine aminopeptidase. These results and our statistically significant 3D QSAR model could be used to guide the further design of more potent derivatives as well as in virtual screening for novel antibacterial agents.
(Copyright © 2017 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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