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dc.contributor.authorPaulsen, Marianne Hagensen
dc.contributor.authorAusbacher, Dominik
dc.contributor.authorBayer, Annette
dc.contributor.authorEngqvist, Magnus
dc.contributor.authorHansen, Terkel
dc.contributor.authorHaug, Tor
dc.contributor.authorAnderssen, Trude
dc.contributor.authorAndersen, Jeanette Hammer
dc.contributor.authorSollid, Johanna U. Ericson
dc.contributor.authorStrøm, Morten B.
dc.date.accessioned2019-09-23T08:57:33Z
dc.date.available2019-09-23T08:57:33Z
dc.date.issued2019-09-06
dc.description.abstractThe rapid emergence and spread of multi-resistant bacteria have created an urgent need for new antimicrobial agents. We report here a series of amphipathic α,α-disubstituted β-amino amide derivatives with activity against 30 multi-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including isolates with extended spectrum β-lactamase – carbapenemase (ESBL-CARBA) production. A variety of halogenated aromatic side-chains were investigated to improve antimicrobial potency and minimize formation of Phase I metabolites. Net positive charge and cationic character of the derivatives had an important effect on toxicity against human cell lines. The most potent and selective derivative was the diguanidine derivative <b>4e</b> with 3,5-di-brominated benzylic side-chains. Derivative <b>4e</b> displayed minimum inhibitory concentrations (MIC) of 0.25–8 μg/mL against Gram-positive and Gram-negative reference strains, and 2–32 μg/mL against multi-resistant clinical isolates. Derivative <b>4e</b> showed also low toxicity against human red blood cells (EC50 > 200 μg/mL), human hepatocyte carcinoma cells (HepG2: EC50 > 64 μg/mL), and human lung fibroblast cells (MRC-5: EC50 > 64 μg/mL). The broad-spectrum antimicrobial activity and low toxicity of diguanylated derivatives such as <b>4e</b> make them attractive as lead compounds for development of novel antimicrobial drugs.en_US
dc.description.sponsorshipUiT the The Arctic University of Norwayen_US
dc.descriptionSource at <a href=https://doi.org/10.1016/j.ejmech.2019.111671>https://doi.org/10.1016/j.ejmech.2019.111671. </a>en_US
dc.identifier.citationPaulsen, M.H., Ausbacher, D., Bayer, A., Engqvist, M., Hansen, T., Haug, T. ... Strøm, M.B. (2019). Antimicrobial activity of amphipathic α,α-disubstituted β-amino amide derivatives against ESBL–CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic character. <i>European Journal of Medicinal Chemistry, 183</i>, 111671. https://doi.org/10.1016/j.ejmech.2019.111671en_US
dc.identifier.cristinIDFRIDAID 1724677
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.urihttps://hdl.handle.net/10037/16259
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalEuropean Journal of Medicinal Chemistry
dc.relation.projectIDMABIT: BS0068en_US
dc.relation.projectIDNorges forskningsråd: 214493en_US
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/FRINATEK/214493/Norway/HIT-TO-LEAD DEVELOPMENT OF NOVEL ANTIMICROBIAL AND ANTICANCER PEPTIDOMIMETICS//en_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Matematikk og naturvitenskap: 400::Kjemi: 440::Legemiddelkjemi: 448en_US
dc.subjectVDP::Mathematics and natural scienses: 400::Chemistry: 440::Pharmaceutical chemistry: 448en_US
dc.subjectAntibacterialen_US
dc.subjectAntimicrobial peptidesen_US
dc.subjectBeta-amino acidsen_US
dc.subjectESBLen_US
dc.subjectCARBAen_US
dc.subjectMulti-resistant bacteriaen_US
dc.subjectPeptidomimeticsen_US
dc.subjectSMAMPsen_US
dc.subjectSynthetic mimics of antimicrobial peptidesen_US
dc.titleAntimicrobial activity of amphipathic α,α-disubstituted β-amino amide derivatives against ESBL–CARBA producing multi-resistant bacteria; effect of halogenation, lipophilicity and cationic characteren_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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