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dc.creatorCvijetić, Ilija
dc.creatorVerbić, Tatjana
dc.creatorde Resende, Pedro Ernesto
dc.creatorStapleton, Paul
dc.creatorGibbons, Simon
dc.creatorJuranić, Ivan
dc.creatorDrakulić, Branko
dc.creatorZloh, Mire
dc.date.accessioned2019-04-25T09:50:30Z
dc.date.available2019-04-25T09:50:30Z
dc.date.issued2018
dc.identifier.issn0223-5234
dc.identifier.urihttp://cer.ihtm.bg.ac.rs/handle/123456789/2690
dc.description.abstractAntimicrobial 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.en
dc.publisherElsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172035/RS//
dc.relationUniversity of Hertfordshire
dc.rightsrestrictedAccess
dc.sourceEuropean Journal of Medicinal Chemistry
dc.subjectAryl diketo aciden
dc.subjectAntimicrobial activityen
dc.subjectMultidrug resistanceen
dc.subjectGram-positiveen
dc.subject3D QSARen
dc.subjectMolecular dockingen
dc.subjectDehydrosqualene synthaseen
dc.titleDesign, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strainsen
dc.typearticle
dc.rights.licenseARR
dcterms.abstractЗлох, Мире; Вербић, Татјана; де Ресенде, Педро Ернесто; Цвијетић, Илија; Стаплетон, Паул; Гиббонс, Симон; Дракулић, Бранко Ј.; Јуранић, Иван О.;
dc.citation.volume143
dc.citation.spage1474
dc.citation.epage1488
dc.citation.other143: 1474-1488
dc.citation.rankaM21
dc.description.otherThe peer-reviewed version: [http://cer.ihtm.bg.ac.rs/handle/123456789/2691]
dc.identifier.pmid29133041
dc.identifier.doi10.1016/j.ejmech.2017.10.045
dc.identifier.scopus2-s2.0-85033587333
dc.identifier.wos000423641400027
dc.type.versionpublishedVersionen


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