International Journal of Molecular Sciences (2020)
Update date:2022-07-30
Topics:
Aitken, Laura
Benek, Ondrej
Chribek, Matej
Dolezal, Rafael
Gunn-Moore, Frank
Hrabinova, Martina
Hroch, Lukas
Jun, Daniel
Kralova, Vendula
Kuca, Kamil
Lycka, Antonin
Musilek, Kamil
Prchal, Lukas
Schmidt, Monika
Vinklarova, Lucie
Zemanova, Lucie
Human 17β-hydroxysteroid dehydrogenase type 10 is a multifunctional protein involved in many enzymatic and structural processes within mitochondria. This enzyme was suggested to be involved in several neurological diseases, e.g., mental retardation, Parkinson’s disease, or Alzheimer’s disease, in which it was shown to interact with the amyloid-beta peptide. We prepared approximately 60 new compounds based on a benzothiazolyl scaffold and evaluated their inhibitory ability and mechanism of action. The most potent inhibitors contained 3-chloro and 4-hydroxy substitution on the phenyl ring moiety, a small substituent at position 6 on the benzothiazole moiety, and the two moieties were connected via a urea linker (4at, 4bb, and 4bg). These compounds exhibited IC50 values of 1–2 μM and showed an uncompetitive mechanism of action with respect to the substrate, acetoacetyl-CoA. These uncompetitive benzothiazolyl inhibitors of 17β-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.
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