Benzothiazolyl ureas are low micromolar and uncompetitive inhibitors of 17β-HSD10 with implications to Alzheimer’s disease treatment
Abstract
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.
Citation
Schmidt , M , Benek , O , Vinklarova , L , Hrabinova , M , Zemanova , L , Chribek , M , Kralova , V , Hroch , L , Dolezal , R , Lycka , A , Prchal , L , Jun , D , Aitken , L , Gunn-Moore , F , Kuca , K & Musilek , K 2020 , ' Benzothiazolyl ureas are low micromolar and uncompetitive inhibitors of 17β-HSD10 with implications to Alzheimer’s disease treatment ' , International Journal of Molecular Sciences , vol. 21 , no. 6 , 2059 . https://doi.org/10.3390/ijms21062059
Publication
International Journal of Molecular Sciences
Status
Peer reviewed
ISSN
1422-0067Type
Journal article
Description
This research was funded by Ministry of Health of the Czech Republic (no. NV19-09-00578), Ministry of Education, Youth and Sports of the Czech Republic (project ESF no. CZ.02.1.01/0.0/0.0/18_069/0010054), University of Hradec Kralove (Faculty of Science, no. VT2019-2021, SV2115-2018, and Postdoctoral job positions at UHK), University Hospital Hradec Kralove (UHHK, 00179906), National Institute of Mental Health (NIMH-CZ) project no. LO1611 for financial support from MEYS under the program of NPU I, Wellcome Trust (204821/Z/16/Z), The Rosetrees Trust, and the RS MacDonald Charitable Trust.Collections
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.