Article Details


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

[ Vol. 13 , Issue. 4 ]

Author(s):

Ondrej Benek, Lukas Hroch, Laura Aitken, Rafael Dolezal, Patrick Guest, Marketa Benkova, Ondrej Soukup, Karel Musil, Kamil Kuca, Terry K. Smith, Frank Gunn-Moore and Kamil Musilek   Pages 345 - 358 ( 14 )

Abstract:


Background: 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 Aβtoxicity. 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 structureactivity relationship QSAR and pharmacophore studies have been performed.

Results and Conclusion: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40 µ M) 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.

Keywords:

17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), alzheimer’s disease, amyloid-beta binding alcohol dehydrogenase (ABAD), chemical synthesis, enzyme inhibition, frentizole, pharmacophore modelling, QSAR.

Affiliation:

University Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, University Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, University of Hradec Kralove, Faculty of Science, Department of Chemistry and Faculty of Informatics and Management, Center for Basic and Applied Research, Rokitanskeho 62, 500 03 Hradec Kralove, University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Department of Epidemiology, Trebesska 1575, 500 01 Hradec Kralove, National Institute of Mental Health, Topolova 748, 250 67 Klecany, University of Hradec Kralove, Faculty of Science, Department of Chemistry and Faculty of Informatics and Management, Center for Basic and Applied Research, Rokitanskeho 62, 500 03 Hradec Kralove, University of Hradec Kralove, Faculty of Science, Department of Chemistry and Faculty of Informatics and Management, Center for Basic and Applied Research, Rokitanskeho 62, 500 03 Hradec Kralove, Biomedical Science Research Complex, University of St. Andrews, North Haugh, St. Andrews. KY16 9ST, University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, University Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove

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