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dc.contributor.authorBenek, Ondrej
dc.contributor.authorHroch, Lukas
dc.contributor.authorAitken, Laura
dc.contributor.authorDolezal, Rafael
dc.contributor.authorGuest, Patrick
dc.contributor.authorBenkova, Marketa
dc.contributor.authorSoukup, Ondrej
dc.contributor.authorMusil, Karel
dc.contributor.authorHughes, Rebecca
dc.contributor.authorKuca, Kamil
dc.contributor.authorSmith, Terry K.
dc.contributor.authorGunn-Moore, Frank
dc.contributor.authorMusilek, Kamil
dc.date.accessioned2018-01-10T00:31:40Z
dc.date.available2018-01-10T00:31:40Z
dc.date.issued2017-06
dc.identifier.citationBenek , O , Hroch , L , Aitken , L , Dolezal , R , Guest , P , Benkova , M , Soukup , O , Musil , K , Hughes , R , Kuca , K , Smith , T K , Gunn-Moore , F & Musilek , K 2017 , ' 6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17β-HSD10 and potential drugs for Alzheimer's disease treatment : design, synthesis and in vitro evaluation ' , Medicinal Chemistry , vol. 13 , no. 4 , pp. 345-358 . https://doi.org/10.2174/1573406413666170109142725en
dc.identifier.issn1573-4064
dc.identifier.otherPURE: 248866050
dc.identifier.otherPURE UUID: ba669064-60f3-400e-aa79-ef0a25199a19
dc.identifier.otherPubMed: 28067167
dc.identifier.otherScopus: 85020833089
dc.identifier.otherORCID: /0000-0003-3422-3387/work/34730412
dc.identifier.otherORCID: /0000-0001-7259-4491/work/31318394
dc.identifier.otherWOS: 000402479000004
dc.identifier.urihttp://hdl.handle.net/10023/12448
dc.description.abstractBackground : The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer’s disease (AD). ABAD/ 17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβ toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods : As ABAD’s enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/ 17β-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structure-activity relationship QSAR and pharmacophore studies have been performed. Results and Conclusions : Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40µM) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.
dc.format.extent14
dc.language.isoeng
dc.relation.ispartofMedicinal Chemistryen
dc.rights© 2017, Bentham Science Publishers. This work has been made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at www.benthamscience.com / https://doi.org/10.2174/157340641366170109142725en
dc.subjectAlzheimer's diseaseen
dc.subjectAmyloid-beta binding alcohol dehydrogenase (ABAD)en
dc.subject17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10)en
dc.subjectChemical synthesisen
dc.subjectEnzyme inhibitionen
dc.subjectFrentizoleen
dc.subjectQSARen
dc.subjectPharmacophore modellingen
dc.subjectQD Chemistryen
dc.subjectRC0321 Neuroscience. Biological psychiatry. Neuropsychiatryen
dc.subjectNDASen
dc.subject.lccQDen
dc.subject.lccRC0321en
dc.title6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17β-HSD10 and potential drugs for Alzheimer's disease treatment : design, synthesis and in vitro evaluationen
dc.typeJournal articleen
dc.description.versionPostprinten
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.Institute of Behavioural and Neural Sciencesen
dc.identifier.doihttps://doi.org/10.2174/1573406413666170109142725
dc.description.statusPeer revieweden
dc.date.embargoedUntil2018-01-09


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