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.
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