title: 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.
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 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.
  
  
  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.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Benek
authors.forename: Lukas
authors.initials: L
authors.lastname: Hroch
authors.forename: Laura
authors.initials: L
authors.lastname: Aitken
authors.forename: Rafael
authors.initials: R
authors.lastname: Dolezal
authors.forename: Patrick
authors.initials: P
authors.lastname: Guest
authors.forename: Marketa
authors.initials: M
authors.lastname: Benkova
authors.forename: Ondrej
authors.initials: O
authors.lastname: Soukup
authors.forename: Karel
authors.initials: K
authors.lastname: Musil
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.affiliation: University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, United Kingdom.
authors.forename: Frank
authors.initials: F
authors.lastname: Gunn-Moore
authors.affiliation: University Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek