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

Authorized Users Only
2018
Authors
Cvijetić, Ilija
Verbić, Tatjana
de Resende, Pedro Ernesto
Stapleton, Paul
Gibbons, Simon
Juranić, Ivan O.
Drakulić, Branko J.
Zloh, Mire
Article (Published version)
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Abstract
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. (C) 2017 Elsevier Masson SAS. All rights reserved.

Keywords:
Aryl diketo acid / Antimicrobial activity / Multidrug resistance / Gram-positive / 3D QSAR / Molecular docking / Dehydrosqualene synthase
Source:
European Journal of Medicinal Chemistry, 2018, 143, 1474-1488
Publisher:
  • Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
Funding / projects:
  • Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-172035)
  • University of Hertfordshire

DOI: 10.1016/j.ejmech.2017.10.045

ISSN: 0223-5234

PubMed: 29133041

WoS: 000423641400027

Scopus: 2-s2.0-85033587333
[ Google Scholar ]
6
6
URI
https://cherry.chem.bg.ac.rs/handle/123456789/2075
Collections
  • Publikacije
  • Publikacije
Institution/Community
Hemijski fakultet
TY  - JOUR
AU  - Cvijetić, Ilija
AU  - Verbić, Tatjana
AU  - de Resende, Pedro Ernesto
AU  - Stapleton, Paul
AU  - Gibbons, Simon
AU  - Juranić, Ivan O.
AU  - Drakulić, Branko J.
AU  - Zloh, Mire
PY  - 2018
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/2075
AB  - 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
PB  - Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
T2  - European Journal of Medicinal Chemistry
T1  - Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains
VL  - 143
SP  - 1474
EP  - 1488
DO  - 10.1016/j.ejmech.2017.10.045
UR  - Kon_3406
ER  - 
@article{
author = "Cvijetić, Ilija and Verbić, Tatjana and de Resende, Pedro Ernesto and Stapleton, Paul and Gibbons, Simon and Juranić, Ivan O. and Drakulić, Branko J. and Zloh, Mire",
year = "2018",
abstract = "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. (C) 2017 Elsevier Masson SAS. All rights reserved.",
publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux",
journal = "European Journal of Medicinal Chemistry",
title = "Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains",
volume = "143",
pages = "1474-1488",
doi = "10.1016/j.ejmech.2017.10.045",
url = "Kon_3406"
}
Cvijetić, I., Verbić, T., de Resende, P. E., Stapleton, P., Gibbons, S., Juranić, I. O., Drakulić, B. J.,& Zloh, M.. (2018). Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains. in European Journal of Medicinal Chemistry
Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux., 143, 1474-1488.
https://doi.org/10.1016/j.ejmech.2017.10.045
Kon_3406
Cvijetić I, Verbić T, de Resende PE, Stapleton P, Gibbons S, Juranić IO, Drakulić BJ, Zloh M. Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains. in European Journal of Medicinal Chemistry. 2018;143:1474-1488.
doi:10.1016/j.ejmech.2017.10.045
Kon_3406 .
Cvijetić, Ilija, Verbić, Tatjana, de Resende, Pedro Ernesto, Stapleton, Paul, Gibbons, Simon, Juranić, Ivan O., Drakulić, Branko J., Zloh, Mire, "Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains" in European Journal of Medicinal Chemistry, 143 (2018):1474-1488,
https://doi.org/10.1016/j.ejmech.2017.10.045 .,
Kon_3406 .

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