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.

Charles University Prague Faculty of Pharmacy in Hradec Kralove Department of Pharmaceutical Chemistry and Drug Control Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

National Institute of Mental Health Topolova 748 250 67 Klecany Czech Republic

University Hospital Hradec Kralove Biomedical Research Centre Sokolska 581 500 05 Hradec Kralove Czech Republic

University of Defence Faculty of Military Health Sciences Department of Toxicology and Military Pharmacy Trebesska 1575 500 01 Hradec Kralove Czech Republic

University of Hradec Kralove Faculty of Science Department of Chemistry Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

University of St Andrews School of Biology Medical and Biological Science Building North Haugh St Andrews KY16 9TF UK

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C-3 Steroidal Hemiesters as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 10

Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity