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

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

Volume: 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*Kamil Musilek*

Affiliation:

• University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF,United States Minor Outlying Islands

• University Hospital in Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove,Czech Republic

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.

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.

Cite this article as:

Benek Ondrej, Hroch Lukas, Aitken Laura, Dolezal Rafael, Guest Patrick, Benkova Marketa, Soukup Ondrej, Musil Karel, Kuca Kamil, Smith K. Terry, Gunn-Moore Frank*, Musilek Kamil*, 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 2017; 13 (4) . https://dx.doi.org/10.2174/1573406413666170109142725

DOI https://dx.doi.org/10.2174/1573406413666170109142725	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638