6-Benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17 beta-HSD10 and potential drugs for Alzheimer's disease treatment: Design, synthesis and in vitro evaluation
Abstrakt
Background: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) has been connected with the pathogenesis of Alzheimer's disease (AD). ABAD/17 beta-HSD10 is a binding site for the amyloid-beta peptide (A beta) inside the mitochondrial matrix where it exacerbates A beta 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 A beta 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/17 beta-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 Conclusion: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 +/- 0.40 mu 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.