Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains
Само за регистроване кориснике
2018
Аутори
Cvijetić, IlijaVerbić, Tatjana
de Resende, Pedro Ernesto
Stapleton, Paul
Gibbons, Simon
Juranić, Ivan
Drakulić, Branko
Zloh, Mire
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
Aryl diketo acid / Antimicrobial activity / Multidrug resistance / Gram-positive / 3D QSAR / Molecular docking / Dehydrosqualene synthaseИзвор:
European Journal of Medicinal Chemistry, 2018, 143, 1474-1488Издавач:
- Elsevier
Финансирање / пројекти:
- Рационални дизајн и синтеза биолошки активних и координационих једињења и функционалних материјала, релевантних у (био)нанотехнологији (RS-MESTD-Basic Research (BR or ON)-172035)
- University of Hertfordshire
Напомена:
- The peer-reviewed version: http://cer.ihtm.bg.ac.rs/handle/123456789/2691
DOI: 10.1016/j.ejmech.2017.10.045
ISSN: 0223-5234
PubMed: 29133041
WoS: 000423641400027
Scopus: 2-s2.0-85033587333
Институција/група
IHTMTY - JOUR AU - Cvijetić, Ilija AU - Verbić, Tatjana AU - de Resende, Pedro Ernesto AU - Stapleton, Paul AU - Gibbons, Simon AU - Juranić, Ivan AU - Drakulić, Branko AU - Zloh, Mire PY - 2018 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/2690 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 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 ER -
@article{ author = "Cvijetić, Ilija and Verbić, Tatjana and de Resende, Pedro Ernesto and Stapleton, Paul and Gibbons, Simon and Juranić, Ivan and Drakulić, Branko 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", 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" }
Cvijetić, I., Verbić, T., de Resende, P. E., Stapleton, P., Gibbons, S., Juranić, I., Drakulić, B.,& 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., 143, 1474-1488. https://doi.org/10.1016/j.ejmech.2017.10.045
Cvijetić I, Verbić T, de Resende PE, Stapleton P, Gibbons S, Juranić I, Drakulić B, 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 .
Cvijetić, Ilija, Verbić, Tatjana, de Resende, Pedro Ernesto, Stapleton, Paul, Gibbons, Simon, Juranić, Ivan, Drakulić, Branko, 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 . .