Multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a potential drug target for the treatment of various pathologies. The most discussed is the pathology associated with Alzheimer's disease (AD), where 17β-HSD10 overexpression and its interaction with amyloid-β peptide contribute to mitochondrial dysfunction and neuronal stress. In this work, a series of new benzothiazole-derived 17β-HSD10 inhibitors were designed based on the structure-activity relationship analysis of formerly published inhibitors. A set of enzyme-based and cell-based methods were used to evaluate the inhibitory potency of new compounds, their interaction with the enzyme, and their cytotoxicity. Most compounds exhibited significantly a higher inhibitory potential compared to published benzothiazolyl ureas and good target engagement in a cellular environment accompanied by low cytotoxicity. The best hits displayed mixed-type inhibition with half maximal inhibitory concentration (IC50) values in the nanomolar range for the purified enzyme (3-7, 15) and/or low micromolar IC50 values in the cell-based assay (6, 13-16).

• Publication type
• Journal Article MeSH

Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer's disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

• Keywords
• Alzheimer’s disease, amyloid beta, drug, mitochondria, tau protein,
• MeSH
• Alzheimer Disease * metabolism   MeSH
• Amyloid metabolism   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Amyloidogenic Proteins metabolism   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Amyloid MeSH
• Amyloid beta-Peptides MeSH
• Amyloidogenic Proteins MeSH

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.

• Keywords
• 17β-hydroxysteroid dehydrogenase type 10, ABAD, Alzheimer’s disease, benzothiazole, inhibitor, neurodegeneration,
• MeSH
• 3-Hydroxyacyl CoA Dehydrogenases antagonists & inhibitors   chemistry   MeSH
• Enzyme Activation MeSH
• Alzheimer Disease drug therapy   MeSH
• Benzothiazoles chemistry   MeSH
• Enzyme Inhibitors chemistry   pharmacology   MeSH
• Kinetics MeSH
• Humans MeSH
• Urea chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Recombinant Proteins MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 3-Hydroxyacyl CoA Dehydrogenases MeSH
• Benzothiazoles MeSH
• HSD17B10 protein, human MeSH Browser
• Enzyme Inhibitors MeSH
• Urea MeSH
• Recombinant Proteins MeSH

: It has long been established that mitochondrial dysfunction in Alzheimer's disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17β-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17β-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells.

• Keywords
• 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), amyloid binding alcohol dehydrogenase (ABAD), benzothiazole, Alzheimer’s disease (AD), amyloid-beta peptide (Aβ), mitochondria,
• MeSH
• 17-Hydroxysteroid Dehydrogenases antagonists & inhibitors   chemistry   MeSH
• Alzheimer Disease drug therapy   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• Benzothiazoles chemistry   MeSH
• Cell Line MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Urea chemistry   MeSH
• Molecular Structure MeSH
• Drug Design MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 17-Hydroxysteroid Dehydrogenases MeSH
• Amyloid beta-Peptides MeSH
• Benzothiazoles MeSH
• Urea MeSH