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1.
Eur J Med Chem ; 258: 115593, 2023 Oct 05.
Article in English | MEDLINE | ID: mdl-37390508

ABSTRACT

17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) is a multifunctional mitochondrial enzyme and putative drug target for the treatment of various pathologies including Alzheimer's disease or some types of hormone-dependent cancer. In this study, a series of new benzothiazolylurea-based inhibitors were developed based on the structure-activity relationship (SAR) study of previously published compounds and predictions of their physico-chemical properties. This led to the identification of several submicromolar inhibitors (IC50 ∼0.3 µM), the most potent compounds within the benzothiazolylurea class known to date. The positive interaction with 17ß-HSD10 was further confirmed by differential scanning fluorimetry and the best molecules were found to be cell penetrable. In addition, the best compounds weren't found to have additional effects for mitochondrial off-targets and cytotoxic or neurotoxic effects. The two most potent inhibitors 9 and 11 were selected for in vivo pharmacokinetic study after intravenous and peroral administration. Although the pharmacokinetic results were not fully conclusive, it seemed that compound 9 was bioavailable after peroral administration and could penetrate into the brain (brain-plasma ratio 0.56).


Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/drug therapy , Structure-Activity Relationship , 17-Hydroxysteroid Dehydrogenases , Brain/metabolism , Enzyme Inhibitors/chemistry
2.
Toxicol Lett ; 339: 12-19, 2021 Mar 15.
Article in English | MEDLINE | ID: mdl-33359020

ABSTRACT

Mitochondrial enzymes are targets of newly synthesized drugs being tested for the treatment of neurodegenerative disorders, such as Alzheimer's disease (AD). The enzyme 17ß-hydroxysteroid dehydrogenase type 10 (HSD10) is a multifunctional mitochondrial protein that is thought to play a role in the pathophysiology of AD and is one of the targets of new potential AD drugs. The in vitro effects of frentizole, riluzole, AG18051, and 42 novel modulators of HSD10 (potential AD drugs) on citrate synthase (CS) activity, monoamine oxidase (MAO) activity, complex I- or complex II-linked mitochondrial respiratory rate, and complex I activity were measured in isolated pig brain mitochondria. Based on their minimal inhibitory effects on the respiratory rate of mitochondria and CS and complex I activity, six novel compounds were selected for further testing. Assuming that inhibition of MAO-B could be a desirable effect of AD drugs, only AG18051 and one new compound met the criteria for MAO-B inhibition with minimal drug-induced effects on mitochondrial respiration. In conclusion, our in vitro screening of mitochondrial effect of novel potential AD drugs has enabled the selection of the most promising molecules for further testing that are relatively safe in terms of drug-induced mitochondrial toxicity.


Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 17-Hydroxysteroid Dehydrogenases/toxicity , Cell Respiration/drug effects , Enzyme Inhibitors/toxicity , Enzyme Inhibitors/therapeutic use , Mitochondria/drug effects , Neurodegenerative Diseases/drug therapy , Animals , Humans , Models, Animal , Swine
3.
Int J Mol Sci ; 21(6)2020 Mar 17.
Article in English | MEDLINE | ID: mdl-32192199

ABSTRACT

Human 17ß-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 17ß-hydroxysteroid dehydrogenase type 10 are promising compounds for potential drugs for neurodegenerative diseases that warrant further research and development.


Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/antagonists & inhibitors , Benzothiazoles/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Urea/chemistry , Urea/pharmacology , 3-Hydroxyacyl CoA Dehydrogenases/chemistry , Alzheimer Disease/drug therapy , Enzyme Activation , Humans , Kinetics , Molecular Structure , Recombinant Proteins , Structure-Activity Relationship
4.
Molecules ; 24(15)2019 Jul 29.
Article in English | MEDLINE | ID: mdl-31362457

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 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17ß-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 17ß-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.


Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , 17-Hydroxysteroid Dehydrogenases/chemistry , Benzothiazoles/chemistry , Urea/chemistry , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Cell Line , Dose-Response Relationship, Drug , Drug Design , Humans , Mitochondria/metabolism , Molecular Structure , Structure-Activity Relationship
5.
J Enzyme Inhib Med Chem ; 33(1): 665-670, 2018 Dec.
Article in English | MEDLINE | ID: mdl-29536773

ABSTRACT

Several neurodegenerative disorders including Alzheimer's disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease's progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.


Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/metabolism , Casein Kinase I/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Neurodegenerative Diseases/drug therapy , Phenylurea Compounds/pharmacology , Casein Kinase I/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Neurodegenerative Diseases/metabolism , Phenylurea Compounds/chemistry , Structure-Activity Relationship
6.
Eur J Med Chem ; 146: 38-46, 2018 Feb 25.
Article in English | MEDLINE | ID: mdl-29407964

ABSTRACT

The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2.


Subject(s)
Computer Simulation , Drug Design , Small Molecule Libraries/pharmacology , Toll-Like Receptor 4/antagonists & inhibitors , Cell Line , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Ligands , Molecular Docking Simulation , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship
7.
Biochemistry ; 56(13): 1879-1886, 2017 04 04.
Article in English | MEDLINE | ID: mdl-28319664

ABSTRACT

Mammalian dihydrofolate reductases (DHFRs) catalyze the reduction of folate more efficiently than the equivalent bacterial enzymes do, despite typically having similar efficiencies for the reduction of their natural substrate, dihydrofolate. In contrast, we show here that DHFR from the hyperthermophilic bacterium Thermotoga maritima can catalyze reduction of folate to tetrahydrofolate with an efficiency similar to that of reduction of dihydrofolate under saturating conditions. Nuclear magnetic resonance and mass spectrometry experiments showed no evidence of the production of free dihydrofolate during either the EcDHFR- or TmDHFR-catalyzed reductions of folate, suggesting that both enzymes perform the two reduction steps without release of the partially reduced substrate. Our results imply that the reaction proceeds more efficiently in TmDHFR than in EcDHFR because the more open active site of TmDHFR facilitates protonation of folate. Because T. maritima lives under extreme conditions where tetrahydrofolate is particularly prone to oxidation, this ability to salvage folate may impart an advantage to the bacterium by minimizing the squandering of a valuable cofactor.


Subject(s)
Bacterial Proteins/chemistry , Folic Acid/chemistry , Protons , Tetrahydrofolate Dehydrogenase/chemistry , Tetrahydrofolates/chemistry , Thermotoga maritima/enzymology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Catalytic Domain , Escherichia coli/chemistry , Escherichia coli/enzymology , Escherichia coli/genetics , Folic Acid/metabolism , Gene Expression , Hydrogen-Ion Concentration , Kinetics , NADP/chemistry , NADP/metabolism , Oxidation-Reduction , Protein Folding , Protein Structure, Secondary , Species Specificity , Temperature , Tetrahydrofolate Dehydrogenase/genetics , Tetrahydrofolate Dehydrogenase/metabolism , Tetrahydrofolates/metabolism , Thermodynamics , Thermotoga maritima/chemistry , Thermotoga maritima/genetics
8.
Bioorg Med Chem ; 25(3): 1143-1152, 2017 02 01.
Article in English | MEDLINE | ID: mdl-28082069

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aß). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34µM and 0.30µM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.


Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/antagonists & inhibitors , Alzheimer Disease/drug therapy , Benzothiazoles/pharmacology , Enzyme Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Phenylurea Compounds/pharmacology , Thiourea/pharmacology , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Alzheimer Disease/metabolism , Benzothiazoles/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Phenylurea Compounds/chemistry , Structure-Activity Relationship , Thiourea/chemical synthesis , Thiourea/chemistry
9.
Med Chem ; 2017 Jan 09.
Article in English | MEDLINE | ID: mdl-28067167

ABSTRACT

BACKGROUND: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) has been connected with the pathogenesis of Alzheimer's disease (AD). ABAD/ 17ß-HSD10 is a binding site for the amyloid-beta peptide (Aß) inside the mitochondrial matrix where it exacerbates Aß toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. METHODS: As ABAD's enzymatic activity is required for mediating Aß toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/ 17ß-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structure-activity relationship QSAR and pharmacophore studies have been performed. RESULTS AND CONCLUSIONS: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40µM) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.

10.
Bioorg Med Chem Lett ; 26(15): 3675-8, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27287370

ABSTRACT

Amyloid-beta peptide (Aß) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10). Altered enzyme function caused by the Aß-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.


Subject(s)
3-Hydroxyacyl CoA Dehydrogenases/antagonists & inhibitors , Alzheimer Disease/drug therapy , Benzothiazoles/pharmacology , Drug Design , Enzyme Inhibitors/pharmacology , Urea/pharmacology , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Animals , Benzothiazoles/chemistry , CHO Cells , Cell Survival/drug effects , Cricetulus , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Urea/analogs & derivatives , Urea/chemistry
11.
ChemMedChem ; 11(12): 1264-9, 2016 06 20.
Article in English | MEDLINE | ID: mdl-26427608

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.


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Drug Design , Indoles/chemical synthesis , Monoamine Oxidase Inhibitors/therapeutic use , Quinolines/chemical synthesis , Tacrine/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Blood-Brain Barrier/metabolism , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/toxicity , Hep G2 Cells , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/therapeutic use , Indoles/toxicity , Inhibitory Concentration 50 , Ligands , Monoamine Oxidase/chemistry , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/toxicity , Quinolines/chemistry , Quinolines/metabolism , Quinolines/therapeutic use , Quinolines/toxicity , Structure-Activity Relationship , Tacrine/metabolism , Tacrine/therapeutic use , Tacrine/toxicity
12.
Curr Med Chem ; 22(9): 1056 - 1085, 2015 02 26.
Article in English | MEDLINE | ID: mdl-25620098

ABSTRACT

The amyloid-ß peptide (Aß) has been associated with Alzheimer's disease (AD) for decades. The original amyloid cascade hypothesis declared that the insoluble extracellular plaques were responsible for Aß toxicity. Later, this hypothesis has been updated and soluble intracellular Aß forms and their effects within the cell have come into focus.Mitochondrial dysfunction plays an important role in the pathophysiology of AD. Aß was detected inside mitochondria and several mitochondrial proteins were found to interact directly with Aß. Such interactionscan affecta protein's function and cause damage to the mitochondria and finally to the whole cell.This review summarizes the current knowledge of mitochondrial proteins directly interacting with Aß and discusses their significance for the development of therapeutics in the treatment of AD.

13.
Curr Med Chem ; 22(6): 730-47, 2015.
Article in English | MEDLINE | ID: mdl-25515509

ABSTRACT

Benzothiazole compounds represent heterocyclic systems comprising a benzene ring fused with a thiazole ring containing nitrogen and sulphur in its structure. Besides the presence of a benzothiazole core in naturally occurring molecules, synthesized compounds containing a benzothiazole moiety in their structure proved to be a significant class of potential therapeutics, as they exhibit biological effects such as antitumor, antibacterial, antitubercular, antiviral, anthelmintic, antidiabetic and many others. Apart from the aforementioned peripheral or microbial active sites, benzothiazole analogues are also biologically active compounds in the central nervous system, where some approved drugs containing a benzothiazole moiety have already been identified and are used in the treatment of various neurological disorders. New benzothiazole molecules are currently under development and are being evaluated for several uses including diagnostics and as therapeutic drug candidates for the treatment of epilepsy and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis amongst others.


Subject(s)
Anticonvulsants/chemistry , Benzothiazoles/chemistry , Neuroprotective Agents/chemistry , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/drug therapy , Animals , Anticonvulsants/therapeutic use , Benzothiazoles/therapeutic use , Humans , Neuroprotective Agents/therapeutic use , Quantitative Structure-Activity Relationship , Radionuclide Imaging
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