ABSTRACT
Six quinoline-piperonal hybrids were synthesized and evaluated as potential drugs against Alzheimer's disease (AD). Theoretical analysis of the pharmacokinetic and toxicological properties of the compounds suggest that they present good oral bio-availability and are also capable of penetrating the blood-brain barrier, qualifying as leads for new drugs against AD. Evaluation of their inhibitory capacity against acetyl- and butyrilcholinesterases (AChE and BChE) through Ellmann's test showed that three compounds present promising results with one of them being capable of inhibiting both enzymes. Further docking studies of the six compounds synthesized helped to elucidate the main interactions that may be responsible for the inhibitory activities observed.
Subject(s)
Benzaldehydes , Benzodioxoles , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Quinolines , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Benzaldehydes/chemistry , Benzodioxoles/chemistry , Chemistry Techniques, Synthetic , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacokinetics , Humans , Kinetics , Magnetic Resonance Spectroscopy , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Alzheimer's disease (AD) is a neurodegenerative, progressive, and fatal disorder characterized by marked atrophy of the cerebral cortex and loss of basal forebrain cholinergic neurons. The main pathological features of AD are related to neuronal degeneration and include extracellular deposition of amyloid beta plaques (Aß plaques), intracellular formation of neurofibrillary tangles (NFTs), and neuroinflammation. So far, drugs used to treat AD have symptomatic and palliative pharmacological effects, disappearing with continued use due to neuron degeneration and death. Therefore, there are still problems with an effective drug for treating AD. Few approaches evaluate the action of natural products other than alkaloids on the molecular targets of ß-amyloid protein (Aß protein) and/or tau protein, which are important targets for developing neuroprotective drugs that will effectively contribute to finding a prophylactic drug for AD. This review gathers and categorizes classes of natural products, excluding alkaloids, which in silico analysis (molecular docking) and in vitro and/or in vivo assays can inhibit the BACE1 and GSK-3ß enzymes involved in AD.
Subject(s)
Alzheimer Disease , Biological Products , Humans , Amyloid beta-Peptides/metabolism , Glycogen Synthase Kinase 3 beta , Molecular Docking Simulation , Amyloid Precursor Protein Secretases/metabolism , Biological Products/pharmacology , Biological Products/therapeutic use , Aspartic Acid Endopeptidases/therapeutic use , Alzheimer Disease/metabolism , tau Proteins/metabolism , tau Proteins/therapeutic useABSTRACT
Euterpe oleracea (açaí) fruit has approximately 15% pulp, which is partly edible and commercialized, and 85% seeds. Although açaí seeds are rich in catechins-polyphenolic compounds with antioxidant, anti-inflammatory, and antitumor effects-almost 935,000 tons/year of seeds are discarded as industrial waste. This work evaluated the antitumor properties of E. oleracea in vitro and in vivo in a solid Ehrlich tumor in mice. The seed extract presented 86.26 ± 0.189 mg of catechin/g of extract. The palm and pulp extracts did not exhibit in vitro antitumor activity, while the fruit and seed extracts showed cytotoxic effects on the LNCaP prostate cancer cell line, inducing mitochondrial and nuclear alterations. Oral treatments were performed daily at 100, 200, and 400 mg/kg of E. oleracea seed extract. The tumor development and histology were evaluated, along with immunological and toxicological parameters. Treatment at 400 mg/kg reduced the tumor size, nuclear pleomorphism, and mitosis figures, increasing tumor necrosis. Treated groups showed cellularity of lymphoid organs comparable to the untreated group, suggesting less infiltration in the lymph node and spleen and preservation of the bone marrow. The highest doses reduced IL-6 and induced IFN-γ, suggesting antitumor and immunomodulatory effects. Thus, açaí seeds can be an important source of compounds with antitumor and immunoprotective properties.
ABSTRACT
BACKGROUND: Zika virus (ZIKV) is a flavivirus associated with microcephaly and other fetal anormalities. However, evidence of asymptomatic ZIKV infection in pregnant women is still scarce. This study investigated the prevalence of Zika infection in asymptomatic pregnant women attending two public maternities in Maranhão state, Northeast Brazil. METHODS: A total of 196 women were recruited at the time of delivery by convenience sampling from two maternity clinics in São Luís, Maranhão, Brazil, between April 2017 and June 2018. Venous blood, umbilical cord blood and placental fragments from maternal and fetal sides were collected from each subject. ZIKV infection was determined by reverse transcription polymerase chain reaction (RT-qPCR) for ZIKV and by serology (IgM and IgG). Nonspecific laboratory profiles (TORCH screen) were obtained from medical records. RESULTS: The participants were mostly from São Luís and were of 19-35 years of age. They had 10-15 years of schooling and they were of mixed race, married, and Catholic. ZIKV was identified in three umbilical cord samples and in nine placental fragments. Mothers with positive ZIKV RT-qPCR were in the age group older than 19 years. Of the 196 women tested by ZIKV rapid test, 6 and 117 women were positive for anti-ZIKV IgM and anti-ZIKV IgG antibodies, respectively. Placental Immunohistochemistry study detected ZIKV in all samples positive by RT-PCR. The newborns did not show any morphological and/or psychomotor abnormalities at birth. CONCLUSIONS: Asymptomatic ZIKV infection is frequent, but it was not associated to morphological and/or psychomotor abnormalities in the newborns up to 6 months post-birth. Although pathological abnormalities were not observed at birth, we cannot rule out the long term impact of apparent asymptomatic congenital ZIKV infection.
Subject(s)
Asymptomatic Infections/epidemiology , Pregnancy Complications, Infectious/epidemiology , Zika Virus Infection/epidemiology , Zika Virus/isolation & purification , Adolescent , Adult , Antibodies, Viral , Brazil/epidemiology , Chikungunya virus , Dengue Virus , Female , Humans , Immunohistochemistry , Placenta/virology , Pregnancy , Pregnancy Complications, Infectious/virology , Young Adult , Zika Virus Infection/virologyABSTRACT
Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.e., conformation and orientation) of this indole-indoline alkaloid into the AChE active site is unknown. Therefore, in order to propose a plausible binding mode between GSP and AChE, which might explain the observed experimental inhibitory activity, we performed comparative automatic molecular docking simulations using the AutoDock and Molegro Virtual Docker (MVD) programs. A sample of ten crystal structures of the Pacific electric ray (Torpedo californica) TcAChE, in complex with ten diverse active site ligands, was selected as a robust re-docking validation test, and also for GSP docking. The MVD results indicate a preferential binding mode between GSP and AChE, in which GSP functional groups may perform specific interactions with residues in the enzyme active site, according to the ligand-protein contacts detected by the LPC/CSU server. Four hydrogen bonds were detected between GSP and Tyr121, Ser122, Ser200, and His440, in which the last two residues belong to the catalytic triad (Ser200···His440···Glu327). Hydrophobic and π-π stacking interactions were also detected between GSP and Phe330 and Trp84, respectively; these are involved in substrate stabilization at the active site. This study provides the basis to propose structural changes to the GSP structure, such as molecular simplification and isosteric replacement, in order to aid the design of new potential AChE inhibitors that are relevant to the treatment of Alzheimer's disease.
Subject(s)
Acetylcholinesterase/chemistry , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemistry , Indole Alkaloids/chemistry , Binding Sites , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Ligands , Models, Molecular , Molecular Conformation , Protein Binding , Protein ConformationABSTRACT
As part of our study on bioactive agents from Brazilian rainforest plants, two new glucoalkaloids, 3,4-dehydro-strictosidine (1) and 3,4-dehydro-strictosidinic acid (2), were isolated from Chimarrhis turbinata, along with seven known glucoalkaloids, cordifoline (3), strictosidinic acid (4), strictosidine (5), 5 alpha-carboxystrictosidine (6), turbinatine (7), desoxycordifoline (8), and harman-3-carboxylic acid (9). The structures of the new alkaloids were established on the basis of comprehensive spectral analysis, mainly 1D and 2D NMR experiments, as well as high-resolution HRESIMS. Alkaloid 3 showed strong free-radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) as well as pronounced antioxidant activity evidenced by redox properties measured by ElCD-HPLC. Additionally, alkaloids 1-9 were submitted to TLC screening for acetylcholinesterase inhibitors. Both 7 and 8 were shown to be moderate acetylcholinesterase inhibitors at a concentration of 0.1 and 1.0 microM, respectively. In an in vitro rat brain assay, 7 showed moderate activity (IC(50) 1.86 microM), compared to the standard compound, galanthamine (IC(50) 0.92 microM).