University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Int J Mol Sci. 2020 Mar 17;21(6):2059. doi: 10.3390/ijms21062059.
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 (, , and ). These compounds exhibited IC 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.
人 17β-羟甾类脱氢酶 10 型是一种多功能蛋白，参与线粒体中的许多酶和结构过程。该酶被认为与几种神经疾病有关，例如智力迟钝、帕金森病或阿尔茨海默病，其中它被证明与淀粉样β肽相互作用。我们基于苯并噻唑骨架制备了大约 60 种新化合物，并评估了它们的抑制能力和作用机制。最有效的抑制剂在苯环部分含有 3-氯和 4-羟基取代，苯并噻唑部分在 6 位有一个小取代基，两个部分通过脲连接子连接（，，和）。这些化合物的 IC 值为 1-2 μM，对乙酰乙酰辅酶 A 表现出底物的非竞争性作用机制。这些非竞争性苯并噻唑 17β-羟甾类脱氢酶 10 型抑制剂是治疗神经退行性疾病的潜在药物的有希望的化合物，值得进一步研究和开发。
