ABSTRACT
BACKGROUND: Alzheimer's disease (AD) involves an irreversible and progressive neurodegeneration, with multifactorial pathophysiology, including the cholinergic deficit, amyloid plaques, neurofibrillary tangles, oxidative stress, and neurodegeneration. Despite the severity of the disease, the therapeutic arsenal is limited, arousing the interest of researchers to search for substances that can act on these markers. OBJECTIVE: In this review, we highlight some relevant points, such as the ability of chalcones to act on different targets related to the pathophysiology of Alzheimer's disease; cholinesterases, amyloid peptide, beta-secretase and other biomarkers. METHOD: This mini-review covered the literature concerning chalcones bioactivity from 2010 until now. In addition to the theoretical review, we included the prediction of physicochemical properties using SwissADME software. RESULTS: We found that the majority of the chalcones have been tested against cholinesterases, with moderate to good potencies, but in recent years, the number of publications related to targets of the amyloid hypothesis has been growing. Regarding the physicochemical properties, chalcones have a good profile, except for the water solubility, which is not favorable. CONCLUSION: The most important characteristic of these molecules is that many of the examples mentioned here act on more than one target, characterizing them as multi-target compounds. Regarding predicted properties, solubility stands out as the most problematic one; however, these structures can incorporate functional groups that circumvent this problem of solubility without interfering in the biological activity.
Subject(s)
Alzheimer Disease , Chalcones , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides , Chalcones/pharmacology , Chalcones/therapeutic use , Cholinesterases , HumansABSTRACT
Alzheimer's disease (AD) is a neurodegenerative process that compromises cognitive functions. The physiopathology of AD is multifactorial and is mainly supported by the cholinergic and amyloid hypotheses, which allows the identification the fundamental role of some markers, such as the enzymes acetylcholinesterase (AChE) and ß-secretase (BACE-1), and the ß-amyloid peptide (Aß). In this work, we prepared a series of chalcones and 2'-aminochalcones, which were tested against AChE and BACE-1 enzymes and on the aggregation of Aß. All compounds inhibited AChE activity with different potencies. We have found that the majority of chalcones having the amino group are able to inhibit BACE-1, which was not observed for chalcones without this group. The most active compound is the one derived from 2,3-dichlorobenzaldeyde, having an IC50 value of 2.71 µM. A molecular docking study supported this result, showing a good interaction of the amino group with aspartic acid residues of the catalytic diade of BACE-1. Thioflavin-T fluorescence emission is reduced in 30 - 40%, when Aß42 is incubated in the presence of some chalcones under aggregation conditions. In vitro cytotoxicity and in silico prediction of pharmacokinetic properties were also conducted in this study.
Subject(s)
Chalcones/pharmacology , Cholinesterase Inhibitors/pharmacology , Protease Inhibitors/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , Aspartic Acid Endopeptidases/metabolism , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/metabolism , Chalcones/pharmacokinetics , Chlorocebus aethiops , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacokinetics , Electrophorus , Humans , Mice , Molecular Docking Simulation , Peptide Fragments/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Protein Binding , Protein Multimerization/drug effects , Vero CellsABSTRACT
Alzheimer's disease (AD) is related to the anomalous binding that occurs between amyloid-ß peptide (Aß) and copper ion, through imidazole ring of histidine (His), as stated in the literature. It is also known that high-affinity metal ion chelators can be pharmacologically used as a possible therapeutic approach. In this work, we tested the ability "in vitro" of chitosan (Chi) to reduce Aß aggregation and Thioflavin T binding assay indicated that chitosan has affinity for Aß and interferes in its aggregation. We also tested the ability of Chi to uptake copper ions in the presence of Aß or His. Equilibrium data reveals that chitosan acted as an effective chelating agent competing with Aß and histidine for copper binding. The addition of histidine or Aß in the system promotes an unfolding of chitosan chains, as verified by small-angle X-ray scattering. Extended X-ray absorption fine structure and XPS spectra show that new copper interactions with groups containing nitrogen in the presence of histidine may occur. These results can help understanding fundamental chemical interactions among species detected in AD and biopolymers, opening up possibilities for new treatment approaches for this disease.
Subject(s)
Amyloid beta-Peptides/metabolism , Chitosan/metabolism , Copper/metabolism , Histidine/metabolism , Alzheimer Disease/metabolism , Benzothiazoles/chemistry , Biopolymers/metabolism , Fluorescence , HumansABSTRACT
BACKGROUND: The most important cause of dementia affecting elderly people is the Alzheimer's disease (AD). Patients affected by this progressive and neurodegenerative disease have severe memory and cognitive function impairments. Some medicines used for treating this disease in the early stages are based on inhibition of acetylcholinesterase. Population aging should contribute to increase the cases of patients suffering from Alzheimer's disease, thus requiring the development of new therapeutic entities for the treatment of this disease. METHODS: The objective of this work is to identify new substances that have spatial structural similarity with donepezil, an efficient commercial drug used for the treatment of Alzheimer's disease, and to evaluate the capacity of inhibition of these new substances against the enzyme acetylcholinesterase. RESULTS: Based on a previous results of our group, we prepared a set of 11 spirocyclohexadienones with different substitutions patterns in three steps and overall yield of up to 59%. These compounds were evaluated in vitro against acetylcholinesterase. We found that eight of them are able to inhibit the acetylcholinesterase activity, with IC50 values ranging from 0.12 to 12.67 µM. Molecular docking study indicated that the spirocyclohexadienone, 9e (IC50 = 0.12 µM), a mixedtype AChE inhibitor, showed a good interaction at active site of the enzyme, including the cationic (CAS) and the peripheral site (PAS). CONCLUSION: We described the first study aimed at investigating the biological properties of spirocyclohexadienones as acetylcholinesterase inhibitors. Thus, we have identified an inhibitor, which provided valuable insights for further studies aimed at the discovery of more potent acetylcholinesterase inhibitors.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Molecular Docking Simulation , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Acetylcholinesterase/chemistry , Animals , Catalytic Domain , Cholinesterase Inhibitors/metabolism , Electrophorus , Free Radical Scavengers/chemistry , Free Radical Scavengers/metabolism , Free Radical Scavengers/pharmacology , Kinetics , Spiro Compounds/metabolismABSTRACT
Alzheimer's disease (AD) is the most common type of dementia and related to the degeneration of hippocampal cholinergic neurons, which dramatically affects cognitive ability. Acetylcholinesterase (AChE) inhibitors are employed as drugs for AD therapy. Three series of sulfonylhydrazone compounds were designed, and their ability to inhibit AChE was evaluated. Fifteen compounds were synthesized and twelve of them had IC50 values of 0.64-51.09 µM. The preliminary structure-activity relationships indicated that the methylcatechol moiety and arylsulfonyl substituents generated better compounds than both the benzodioxole and alkylsulfonyl chains. Molecular dynamics studies of compound 6d showed that the interaction with the peripheral binding site of AChE was similar to donepezil, which may explain its low IC50 (0.64 µM). Furthermore, the drug-likeness of 6d suggests that the compound may have appropriate oral absorption and brain penetration. Compound 6d also presented antiradical activity and was not cytotoxic to LL24 cells, suggesting that this compound might be considered safe. Our findings indicate that arylsulfonylhydrazones may be a promising scaffold for the design of new drug candidates for the treatment of AD.
Subject(s)
Acetylcholinesterase/drug effects , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Hydrazones/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Binding Sites , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Donepezil , Drug Design , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Indans/pharmacology , Inhibitory Concentration 50 , Models, Molecular , Piperidines/pharmacology , Structure-Activity RelationshipABSTRACT
BACKGROUND: Acetylcholinesterase (AChE) is an important target in the development of drug to treat Alzheimer's disease (AD). In this work, we investigated the effect of twenty-two synthesized chalcones on AChE activity. OBJECTIVE: This work is aimed to synthesize and evaluate the effect of chalcones on the AChE activity, as well as anti-oxidant activity and predict their pharmacokinetic profile. METHOD: Chalcones were synthesized through a Claisen-Schmidt condensation and their inhibitory effect on the AChE was evaluated by the Elmann's colorimetric method. To determine the anti-oxidant activity the DPPH radical scavenging method was chosen. RESULTS: We found that all chalcones inhibit this activity, with IC50 values ranging from 0.008 to 4.8 µM. We selected the most active compound 19 with an IC50 value of 0.008 µM for a kinetic study demonstrating a competitive inhibition mode. Molecular docking simulations showed a good interaction between 19 and the active site of AChE. Considering the prediction of pharmacokinetic parameters being a useful tool for selecting potential drug candidates, our study results suggest that the majority of chalcones, including the most active one, have a promising pharmacokinetic profile and blood-brain barrier permeability. The involvement of reactive oxygen species (ROS) in AD-related events has encouraged us to evaluate these chalcones as radical scavengers. CONCLUSION: We have found that compound 19 is a potent AChE inhibitor, and based on kinetic studies, it acts as a competitive inhibitor.
Subject(s)
Acetylcholinesterase/chemistry , Antioxidants/pharmacokinetics , Chalcones/pharmacokinetics , Cholinesterase Inhibitors/pharmacokinetics , Animals , Antioxidants/chemical synthesis , Antioxidants/chemistry , Antioxidants/metabolism , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Catalytic Domain , Chalcones/chemical synthesis , Chalcones/chemistry , Chalcones/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , Cytochrome P-450 CYP3A/metabolism , Gastrointestinal Absorption/drug effects , Kinetics , Molecular Docking Simulation , Tacrine/pharmacokinetics , TorpedoABSTRACT
2-Aminothiazolines share an isosteric relationship with imidazolines and oxazolines with antihypertensive activity mainly mediated by the imidazoline I1-receptor. In the present work, we have prepared five aminothiazolines, following a previously described synthetic pathway. Aminothiazolines derived from dicyclopropylmethylamine (ATZ1) and cyclohexylamine (3) are unprecedented in the literature. Competitive radioligand assay was carried out with all synthetic compounds, and the I1 receptor affinity in comparison to rilmenidine in PC12 cells was determined. Surprisingly, the rilmenidine isoster (ATZ1) showed no I1-receptor interaction. Diethyl (ATZ4) and 2-ethyl-hexylamine (ATZ5) derivatives bind to the receptor with 11.98 and 10.94nmol/l, respectively. These compounds were selected for in vivo experiments. Both compounds reduced the blood pressure of spontaneously hypertensive rats (SHR). The hypotensive effect of these compounds was abrogated in the presence of α2 adrenergic (yohimbine) and I1 (efaroxan) receptor antagonists suggesting that both aminothiazolines bind to the adrenergic and imidazoline receptors. Lipinski's descriptors of the synthesized aminothiazolines were calculated and are similar to the known imidazoline I1 receptor ligands. 3D-Similarity between ATZ5 and agmatine, the natural imidazoline receptor ligand, was also observed.
Subject(s)
Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Imidazoline Receptors/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Animals , Benzofurans/pharmacology , Imidazoles/pharmacology , Models, Molecular , Molecular Conformation , PC12 Cells , Rats , Rats, Inbred SHRABSTRACT
Acetylcholinesterase inhibitors and compounds that trigger Aß amyloid oligomerization and fibrillization represent an opportunity to discover new drug candidates to treat Alzheimer's disease. In this work, we synthesized nine new acylhydrazones and a known one, both employing 3-carboethoxy-4-quinolone derivatives as starting materials with chemical yields ranging from 63% to 90%. We evaluated the effect of these compounds on the acetylcholinesterase (AChE) activity and the fibrillization of Aß42 peptide. Except for one acylhydrazone, the compounds exhibited good inhibitory effect on AChE (1.2 µM < IC50 values < 17 µM). They also showed a significant decrease in the thioflavin-T fluorescence emission, suggesting an inhibitory effect on the Aß42 fibril formation.
Subject(s)
4-Quinolones/chemistry , Acetylcholinesterase/drug effects , Amyloid beta-Peptides/drug effects , Cholinesterase Inhibitors/pharmacology , Hydrazones/pharmacology , Peptide Fragments/drug effects , Amyloid beta-Peptides/chemistry , Hydrazones/chemistry , Peptide Fragments/chemistry , Spectrum Analysis/methodsABSTRACT
In this work we report our results concerning the study on the in vitro antiproliferative activity of 18 Baylis-Hillman adducts and some derivatives against a panel of humor tumor cell lines. A brief qualitative structure-activity relationship study indicated that carbon-carbon double bond and the presence of an electron-withdrawing substituent at the aromatic ring are essential for the activity. A quinoline-phthalide derivative has exhibited a potent effect on the proliferation of all cell lines. It is interesting to note their special cytotoxic activity against NCIADR cell line.