Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/76689
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dc.contributor.authorChan, KFen_US
dc.contributor.authorSun, Nen_US
dc.contributor.authorYan, SCen_US
dc.contributor.authorWong, ILKen_US
dc.contributor.authorLui, HKen_US
dc.contributor.authorCheung, KCen_US
dc.contributor.authorYuan, Jen_US
dc.contributor.authorChan, FYen_US
dc.contributor.authorZheng, Zen_US
dc.contributor.authorChan, EWCen_US
dc.contributor.authorChen, Sen_US
dc.contributor.authorLeung, YCen_US
dc.contributor.authorChan, THen_US
dc.contributor.authorWong, KYen_US
dc.date.accessioned2018-05-10T02:56:29Z-
dc.date.available2018-05-10T02:56:29Z-
dc.date.issued2017-
dc.identifier.citationACS omega, 2017, v. 2, no. 10, p. 7281-7292en_US
dc.identifier.issn2470-1343-
dc.identifier.urihttp://hdl.handle.net/10397/76689-
dc.description.abstractWe have recently identified a new class of filamenting temperature-sensitive mutant Z (FtsZ)-interacting compounds that possess a 2,4,6-trisubstituted pyrimidine-quinuclidine scaffold with moderate antibacterial activity. Employing this scaffold as a molecular template, a compound library of amine-linked 2,4,6-trisubstituted pyrimidines with 99 candidates was successfully established by employing an efficient convergent synthesis designed to explore their structure-activity relationship. The results of minimum inhibitory concentration (MIC) assay against Staphylococcus aureus strains and cytotoxicity assay against the mouse L929 cell line identified those compounds with potent antistaphylococcal properties (MIC ranges from 3 to 8 μg/mL) and some extent of cytotoxicity against normal cells (IC50 ranges from 6 to 27 μM). Importantly, three compounds also exhibited potent antibacterial activities against nine clinically isolated methicillin-resistant S. aureus (MRSA) strains. One of the compounds, 14av-amine16, exhibited low spontaneous frequency of resistance, low toxicity against Galleria mellonella larvae, and the ability to rescue G. mellonella larvae (20% survival rate at a dosage of 100 mg/kg) infected with a lethal dose of MRSA ATCC 43300 strain. Biological characterization of compound 14av-amine16 by saturation transfer difference NMR, light scattering assay, and guanosine triphosphatase hydrolysis assay with purified S. aureus FtsZ protein verified that it interacted with the FtsZ protein. Such a property of FtsZ inhibitors was further confirmed by observing iconic filamentous cell phenotype and mislocalization of the Z-ring formation of Bacillus subtilis. Taken together, these 2,4,6-trisubstituted pyrimidine derivatives represent a novel scaffold of S. aureus FtsZ inhibitors.en_US
dc.description.sponsorshipDepartment of Applied Biology and Chemical Technologyen_US
dc.language.isoenen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofACS omegaen_US
dc.titleEfficient synthesis of amine-linked 2,4,6-trisubstituted pyrimidines as a new class of bacterial FtsZ inhibitorsen_US
dc.typeJournal/Magazine Articleen_US
dc.identifier.spage7281-
dc.identifier.epage7292-
dc.identifier.volume2-
dc.identifier.issue10-
dc.identifier.doi10.1021/acsomega.7b00701-
dc.identifier.scopus2-s2.0-85032574341-
dc.description.validate201805 bcrc-
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