No abstract

No abstract

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget‐directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood–brain barrier (BBB) permeability properties. Indolotacrine 9 b (9‐methoxy‐2,3,4,6‐tetrahydro‐1H‐indolo[2,3‐b]quinolin‐11‐amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50: 1.5 μm), butyrylcholinesterase (BChE IC50: 2.4 μm) and MAO A (IC50: 0.49 μm), and it is also a weak inhibitor of MAO B (IC50: 53.9 μm). Although its cytotoxic (IC50: 5.5±0.4 μm) and hepatotoxic (IC50: 1.22±0.11 μm) profiles are not as good as those of the standard 7‐methoxytacrine (IC50: 63±4 and 11.50±0.77 μm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.

No abstract

: 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.

No 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.

17β-HSD10 is a mitochondrial enzyme involved in the metabolism of a wide range of substrates, including neurosteroids (He, Dobkin, & Yang, 2019) and sex steroids, maintaining their physiological level (Shafqat et al., 2003). However, it also plays an important role in tRNA processing as a structural component of RNase P (Holzmann et al., 2008). Its abnormal function including inherited mutations leads to disruption in mitochondrial physiology and is thought to be one of the underlying pathological causes for diseases such as Alzheimer's disease (He, Isaacs, & Yang, 2018) and some forms of cancer (Yang, He, & Schulz, 2005). This paper discusses the role of 17β-HSD10 in physiology, as well as its connections to various diseases. The first section gives an overview of 17β-HSD10 structure, localization and physiological functions. In the second section, the role of 17β-HSD10 in disease, specifically in neurodegenerative disorders and cancer are discussed, which together are attracting more and broader interest in this enzyme.