RESUMO
Alzheimer's disease (AD) is characterized by a cholinergic deficit, prompting conventional therapies to elevate acetylcholine levels as a compensatory measure. Two main strategies involve the inhibition of acetylcholinesterase (AChE) and/or the stimulation of acetylcholine receptors (AChR). Caffeine (CFF), known as a partial agonist of nAChR and an AChE inhibitor, acts as a cholinergic enhancer. Additionally, it is suggested that CFF may exhibit neuroprotective capabilities through the inhibition of the human adenosine receptor type 2A (hA2AR) in the brain's striatum, potentially preventing cellular apoptosis. This study explores on the design and prediction of the bioactivity of CFF analogues with the aim of enhancing cholinergic signaling and providing neuroprotection to improve their therapeutic potential. We employed tools to predict pharmacokinetic and bioactivity properties, molecular docking, molecular dynamics, and target prediction to identify potential candidates among the designed CFF analogues capable of enhancing neurotransmission and providing cellular protection. In a novel approach, a normalized index is proposed for the combined analysis of the pharmacokinetic parameters and molecular docking binding affinities, which facilitates the systematic evaluation and comparison of the synthesized analogues and minimizes subjectivity in the selection of promising candidates. Results indicated that some analogues show promise in improving cholinergic activity and providing neuroprotection. These findings instill optimism, encouraging further research to corroborate their effects, while also representing a significant step towards the development of new therapeutic agents for AD.
Assuntos
Cafeína , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores , Cafeína/farmacologia , Cafeína/química , Cafeína/análogos & derivados , Cafeína/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Humanos , Simulação de Dinâmica Molecular , Simulação por Computador , Receptor A2A de Adenosina/metabolismo , Receptor A2A de Adenosina/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Neuroproteção/efeitos dos fármacos , Colinérgicos/farmacologia , Colinérgicos/químicaRESUMO
Aromatic plants are rich sources of essential oils (EOs), recognized for their therapeutic properties due to their diversity of phytochemicals. This study investigated the anxiolytic and antidepressant effects of Myrcia sylvatica essential oil (MsEO) through inhalation in an animal model and its in vitro anticholinesterase (AChE) activity. The EO was obtained by hydrodistillation, and its volatile constituents were analyzed by GC-MS. Swiss mice were exposed to doses of 0.1%, 1%, and 2% of the EO via an inhalation apparatus. The anxiolytic activity was assessed using the elevated plus maze and light-dark box tests, while antidepressant activity was evaluated using the tail suspension and forced swimming tests. To examine potential side effects, the animals were subjected to rotarod, Y-maze, and Morris water maze tests to assess motor coordination, memory, and learning. Anticholinesterase activity was determined by direct bioautography and colorimetry based on the Ellman method. The results demonstrated that inhalation of MsEO at doses of 0.1% and 1% significantly reduced anxiety and depressive-like behaviors without impairing memory, learning, or motor coordination in the animals. Moreover, MsEO inhibited acetylcholinesterase with an IC50 of 0.47 µg/mL. These findings suggest that MsEO has potential therapeutic applications for anxiety and depression disorders, with additional anticholinesterase activity warranting further investigation in cognitive-related conditions.
Assuntos
Ansiolíticos , Antidepressivos , Inibidores da Colinesterase , Óleos Voláteis , Animais , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Camundongos , Ansiolíticos/farmacologia , Ansiolíticos/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Antidepressivos/farmacologia , Antidepressivos/química , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológicoRESUMO
The current treatment of leishmaniasis is confronted with significant challenges, including limited efficacy, adverse effects, and parasite resistance to drugs. The search for alternative therapeutic options, including the utilisation of natural products, has demonstrated considerable promise. In this study, the antileishmanial activity of the flavonoid hesperetin against Leishmania donovani, the causative agent of visceral leishmaniasis, was reported for the first time. Hesperetin was obtained through the hydrolysis of hesperidin and subsequently subjected to chemical characterisation via Infrared and NMR spectroscopy. The antileishmanial activity and cytotoxicity against RAW 264.7 macrophages were evaluated using the MTT colorimetric assay. In order to investigate the potential mechanisms of action, in vitro acetylcholinesterase inhibition assays and molecular docking analyses were conducted. Hesperetin showed an antipromastigote effect (IC50: 62.89 µM) with no evidence of cytotoxicity (CC50: 612.8 µM), with a selectivity index (SI) of 9.74, being 5.4 times more effective than trivalent antimony. In comparison, antimony showed an IC50 of 80.16 µM, a CC50 of 145.04 µM and a SI of 1.8, indicating a limited safety margin. The compound was observed to inhibit acetylcholinesterase (IC50 of 18.44 µg/mL), present in mitochondrial and plasma membrane of the parasite. Molecular docking and dynamic simulations indicated that hesperetin inhibit sterol C-24 reductase, essential for ergosterol biosynthesis and membrane integrity of L. donovani and shows activity against N-myristoyl transferase, responsible for parasite proliferation cycle. These findings open promising avenues for the development of effective antileishmanial therapies.
Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Hesperidina , Concentração Inibidora 50 , Leishmania donovani , Simulação de Acoplamento Molecular , Hesperidina/farmacologia , Hesperidina/química , Animais , Camundongos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/enzimologia , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Antiprotozoários/farmacologia , Antiprotozoários/química , Células RAW 264.7 , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Antimônio/farmacologia , Antimônio/química , Simulação por ComputadorRESUMO
Sanionia uncinata, or Sickle-leaved-Hook-moss, is a cosmopolitan pleurocarpous moss composing the Antarctic Peninsulae biodiversity, primordially forming dense mats over rocks. The species was collected in 24 different spots located at King George Island and was processed to obtain 24 ethanolic extracts (ADS#) by a serial-24h-maceration, which were prospected for antimicrobial, cytotoxic, antioxidant, and acetylcholinesterase (AChE) inhibition activities by using in vitro tests. Alien material was removed from the non-sterilized plant samples before being submitted for extraction. It was observed that extracts collected in different spots showed different biological activities. Extracts ADS04(10.66±0,17mm) and ADS14(11.37±0,11mm) were active against Staphylococcus aureus, according to the diffusion in bioautography assay. They showed significant antioxidant activity and inhibited AChE; the cytotoxicity observed to the human breast cancer cells MCF-7 and MDA-MB-231 were higher than in normal cell line MCF-10A. ADS04 was 7.62 times more cytotoxic to MCF-7, and ADS14 was 2.03 times more cytotoxic to MDA-MB-231 than to MCF-10A. The extracts showed similar cytotoxicity between PC-3, a human prostate cancer cell line, and MCF-10A. Sanionia uncinata extracts are a vital potential source of biologically active compounds, particularly ADS04 and ADS14, including further prospection on eventual bryophyte's endophytic fungi.
Assuntos
Anti-Infecciosos , Antioxidantes , Inibidores da Colinesterase , Extratos Vegetais , Antioxidantes/farmacologia , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Anti-Infecciosos/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Regiões Antárticas , Briófitas/química , Linhagem Celular Tumoral , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacosRESUMO
Acetylcholinesterase (AChE) plays a pivotal role in the cholinergic system, and its inhibition is sought after in a wide range of applications, from insect control to Alzheimer's disease treatment. While the primary physiological isoforms of AChE are membrane-bound proteins, most assays for discovering new, safer, and potent inhibitors are conducted using commercially available soluble isoforms, such as the electric eel AChE (eeAChE). In this study, we conducted a comparative analysis of the activity and selectivity to phenolic inhibitors of recombinant human AChE, eeAChE and a mutant variant of human AChE known as dAChE4. Despite numerous mutations, dAChE4 closely resembles its parental protein and serves as a suitable model for monomeric human AChE. We also established an in vitro system of membrane-bound AChE to create a model that closely mimics the physiological isoforms. This system ensures the proper work of the enzyme and allowed us to control the exact concentration of enzyme and lipids per assay.
Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Humanos , Animais , Fenóis/farmacologia , Fenóis/química , Electrophorus , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Nanoestruturas/químicaRESUMO
Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer's disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified-some are involved with amyloid beta (Aß) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aß. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π-π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC50 value in the µM range. Also, benzimidazoles and benzothiazoles can inhibit Aß aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles' activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Inibidores da Colinesterase , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Humanos , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Agregados Proteicos/efeitos dos fármacos , Benzimidazóis/química , Benzimidazóis/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , AnimaisRESUMO
Systemic arterial hypertension is accompanied by autonomic impairments that, if not contained, promotes cardiac functional and morphological damages. Pyridostigmine bromide (PYR) treatment results in positive effects on autonomic control and beneficial cardiac remodeling. These findings were also observed after aerobic physical training (APT). However, little is known about PYR effects on left ventricular contractility, mainly when it is combined with APT. We aimed to investigate the effects of chronic acetylcholinesterase inhibition on cardiac autonomic tone balance, coronary bed reactivity, and left ventricular contractility in spontaneously hypertensive rats (SHR) submitted to APT. Male SHR (18 weeks) were divided into two groups (N = 16): untrained and submitted to APT for 14 weeks (18th to 32nd week). Half of each group was treated with PYR (15 mg/kg/day) for two weeks (31st to 32nd week). The experimental protocol consisted of recording hemodynamic parameters, double autonomic blockade with atropine and propranolol, and assessment of coronary bed reactivity and ventricular contractility in isolated hearts using the Langendorff technique. PYR and APT reduced blood pressure, heart rate, and sympathetic influence on the heart. The Langendorff technique showed that APT increased coronary perfusion pressure and left ventricle contractility in response to coronary flow and ß-agonist administration. However, treatment with PYR annulled the effects of APT. In conclusion, although chronic treatment with PYR reduces cardiac sympathetic tonic influence, it does not favor coronary bed reactivity and cardiac contractility gains. PYR treatment in the trained SHR group nullified the coronary vascular reactivity and cardiac contractility gains.
Assuntos
Inibidores da Colinesterase , Hipertensão , Contração Miocárdica , Condicionamento Físico Animal , Brometo de Piridostigmina , Ratos Endogâmicos SHR , Animais , Inibidores da Colinesterase/farmacologia , Masculino , Ratos , Contração Miocárdica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Brometo de Piridostigmina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Acetilcolinesterase/metabolismoRESUMO
Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.
Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Indolquinonas , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cinética , Indolquinonas/química , Simulação de Acoplamento Molecular , Ligantes , Termodinâmica , Modelos Moleculares , Humanos , Simulação de Dinâmica MolecularRESUMO
The Bauhinia ungulata, also known by its common name "pata de vaca", is one of the species used in Brazil for medicinal purposes, and is commonly used for the treatment of diabetes. In this study, the authors studied the interaction between the chemical constituents which are present in the essential oil of Bauhinia ungulata (EOBU), collected in Boa Vista-RR, Legal Amazon, and their effects on the enzyme acetylcholinesterase (AChE) in the essential oil. The analysis that we perform includes proton magnetic resonance ( 1H NMR), enzymatic inhibition, molecular docking, in silico toxicity prediction, enrichment analysis, and target prediction for biological interactions. According to the tests performed on the essential oil, it obtained 100% inhibition of the enzyme AChE. During 1H NMR experiments, it was found that α- Bisabolol, one of the main components, had a significant alteration in its chemical shift. A molecular docking analysis confirmed that this compound binds to the AChE enzyme, which confirms the 1H NMR analysis. The results of this work showed that the major component of EOBU acted as a possible inhibitor of AChE enzyme in vitro and in silico assays. These results show that EOBU could be potentially applied in Alzheimer's disease treatment.
Assuntos
Acetilcolinesterase , Bauhinia , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Óleos Voláteis , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Bauhinia/química , Brasil , Acetilcolinesterase/metabolismo , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Simulação por Computador , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/químicaRESUMO
Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system and particularly in the formation of amyloid plaques; therefore, the inhibition of AChE has become one of the most promising strategies for the treatment of AD, particularly concerning AChE inhibitors that interact with the peripheral anionic site (PAS). Ceanothic acid isolated from the Chilean Rhamnaceae plants is an inhibitor of AChE through its interaction with PAS. In this study, six ceanothic acid derivatives were prepared, and all showed inhibitory activity against AChE. The structural modifications were performed starting from ceanothic acid by application of simple synthetic routes: esterification, reduction, and oxidation. AChE activity was determined by the Ellmann method for all compounds. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compounds would be produced by interaction with the PAS of AChE. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the ceanothane derivatives were performed using the Swiss ADME tool.
Assuntos
Acetilcolinesterase , Domínio Catalítico , Inibidores da Colinesterase , Desenho de Fármacos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Humanos , Doença de Alzheimer/tratamento farmacológico , Cinética , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Ânions/química , AnimaisRESUMO
Depression and anxiety are recognized as the most common mental diseases worldwide. New approaches have considered different therapeutic targets, such as oxidative stress and the inflammation process, due to their close association with the establishment and progression of mental diseases. In the present study, we evaluated the antioxidant and anti-inflammatory activities of the methanolic extracts of the plant species Heteropterys brachiata and Heteropterys cotinifolia and their main compounds, chlorogenic acid and rutin, as potential complementary therapeutic tools for the treatment of anxiety and depression, since the antidepressant and anxiolytic activities of these methanolic extracts have been shown previously. Additionally, we also evaluated their inhibitory activity on the enzyme acetylcholinesterase (AChE). Our results revealed that both species exhibited potent antioxidant activity (>90%) through the TBARS assay, while by means of the DPPH assay, only H. cotinifolia exerted potent antioxidant activity (>90%); additionally, low metal chelating activity (<40%) was detected for all samples tested in the ferrozine assay. The methanolic extracts of H. brachiata and H. cotinifolia exhibited significant anti-inflammatory activities in the TPA-induced ear edema, while only H. cotinifolia exerted significant anti-inflammatory activities in the MPO assay (>45%) and also exhibited a higher percentage of inhibition on AChE of even twice (>80%) as high as the control in concentrations of 100 and 1000 µg/mL. Thus, the potent antioxidant and inflammatory properties and the inhibition of AChE may be involved in the antidepressant activities of the species H. cotinifolia, which would be positioned as a candidate for study in drug development as an alternative in the treatment of depression.
Assuntos
Anti-Inflamatórios , Antioxidantes , Extratos Vegetais , Antioxidantes/farmacologia , Antioxidantes/química , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Animais , Acetilcolinesterase/metabolismo , Antidepressivos/farmacologia , Antidepressivos/química , Antidepressivos/uso terapêutico , Camundongos , MéxicoRESUMO
CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.
Assuntos
Acetilcolinesterase , Alcaloides , Doença de Alzheimer , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Sesquiterpenos , Doença de Alzheimer/tratamento farmacológico , Alcaloides/química , Sesquiterpenos/química , Humanos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Barreira Hematoencefálica/metabolismo , Termodinâmica , Zinco/química , Modelos Moleculares , Ferro/química , Ferro/metabolismoRESUMO
Acetylcholinesterase (AChE) inhibitors are still an important option for managing symptoms of mild to moderate Alzheimer's disease. In this study, we aimed to evaluate the potential in vitro AChE inhibitory activity of two Argentinian endemic Solanaceae species, Jaborosa bergii and J. runcinata. UHPLC-DAD-HRMS metabolite profiling revealed the presence of withanolides in the active CH2Cl2 subextracts. Their fractionation led to the isolation and identification of two known spiranoid withanolides from J. runcinata and three new withanolides with a skeleton similar to that of trechonolide-type withanolides from J. bergii. The known compounds showed moderate AChE inhibitory activity, while the new ones were inactive.
Assuntos
Inibidores da Colinesterase , Solanaceae , Vitanolídeos , Vitanolídeos/farmacologia , Vitanolídeos/química , Vitanolídeos/isolamento & purificação , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Solanaceae/química , Argentina , Acetilcolinesterase/metabolismo , Acetilcolinesterase/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/químicaRESUMO
Rhipicephalus (Boophilus) microplus is a leading cause of significant economic losses in the livestock industry, and tick populations have developed multiple forms of resistance to acaricides; therefore, the potential of novel natural bioactive compounds that are effective for targeting ticks must be addressed. The aim of this study was to evaluate the acaricidal and anticholinesterase activities of R. aculeata seeds and to identify naturally occurring compounds that potentially inhibit anticholinesterase through in silico docking. The acaricidal activity of the extract of R. aculeata seeds against larval and adult R. microplus ticks was assessed through immersion tests. Inhibition of anticholinesterase activity was measured spectrophotometrically. Extracts of R. aculeata seeds showed activity against larvae and engorged females of R. microplus, and a reduction in the reproductive index were also observed. Rutin, chlorogenic acid, quercetin, and epicatechin exhibited noteworthy interactions with the active site residues of RmAChE. These findings could significantly contribute to the exploration of novel natural products that can potentially inhibit RmAChE and could be used in the development of new acaricides for tick control.
Assuntos
Acaricidas , Inibidores da Colinesterase , Extratos Vegetais , Rhipicephalus , Sementes , Animais , Rhipicephalus/efeitos dos fármacos , Acaricidas/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Sementes/química , Inibidores da Colinesterase/farmacologia , Simulação por Computador , Feminino , Simulação de Acoplamento MolecularRESUMO
Amblyomma sculptum is a species of tick in the family Ixodidae, with equids and capybaras among its preferred hosts. In this study, the acaricidal activity of the essential oil (EO) from Piper aduncum and its main component, Dillapiole, were evaluated against larvae of A. sculptum to establish lethal concentration values and assess the effects of these compounds on tick enzymes. Dillapiole exhibited slightly greater activity (LC50 = 3.38 mg/mL; 95% CI = 3.24 to 3.54) than P. aduncum EO (LC50 = 3.49 mg/mL; 95% CI = 3.36 to 3.62) against ticks. The activities of α-esterase (α-EST), ß-esterase (ß-EST), and glutathione-S-transferase (GST) enzymes in A. sculptum larvae treated with Dillapiole showed a significant increase compared to the control at all concentrations (LC5, LC25, LC50 and LC75), similar results were obtained with P. aduncum EO, except for α-EST, which did not differ from the control at the highest concentration (LC75). The results of the acetylcholinesterase (AChE) activity show an increase in enzyme activity at the two lower concentrations (LC5 and LC25) and a reduction in activity at the two higher, lethal concentrations (LC50 and LC75) compared to the control. These results suggest potential mechanisms of action for these natural acaricides and can provide guidance for the future development of potential plant-derived formulations.
Assuntos
Acaricidas , Acetilcolinesterase , Amblyomma , Óleos Voláteis , Piper , Animais , Acaricidas/farmacologia , Acetilcolinesterase/metabolismo , Compostos Alílicos , Amblyomma/efeitos dos fármacos , Amblyomma/crescimento & desenvolvimento , Benzodioxóis/farmacologia , Inibidores da Colinesterase/farmacologia , Dioxóis , Esterases/metabolismo , Glutationa Transferase/metabolismo , Inativação Metabólica , Larva/efeitos dos fármacos , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Piper/químicaRESUMO
The olive oil sector is a fundamental food in the Mediterranean diet. It has been demonstrated that the consumption of extra virgin olive oil (EVOO) with a high content of phenolic compounds is beneficial in the prevention and/or treatment of many diseases. The main objective of this work was to study the relationship between the content of phenolic compounds and the in vitro neuroprotective and anti-inflammatory activity of EVOOs from two PDOs in the province of Granada. To this purpose, the amounts of phenolic compounds were determined by liquid chromatography coupled to mass spectrometry (HPLC-MS) and the inhibitory activity of acetylcholinesterase (AChE) and cyclooxygenase-2 (COX-2) enzymes by spectrophotometric and fluorimetric assays. The main families identified were phenolic alcohols, secoiridoids, lignans, flavonoids, and phenolic acids. The EVOO samples with the highest total concentration of compounds and the highest inhibitory activity belonged to the Picual and Manzanillo varieties. Statistical analysis showed a positive correlation between identified compounds and AChE and COX-2 inhibitory activity, except for lignans. These results confirm EVOO's compounds possess neuroprotective potential.
Assuntos
Fármacos Neuroprotetores , Azeite de Oliva , Fenóis , Azeite de Oliva/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/química , Fenóis/análise , Fenóis/química , Fenóis/farmacologia , Espanha , Ciclo-Oxigenase 2/metabolismo , Acetilcolinesterase/metabolismo , Cromatografia Líquida de Alta Pressão , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/química , Flavonoides/análise , Flavonoides/farmacologia , Flavonoides/químicaRESUMO
The repellent capacity against Sitophilus zeamais and the in vitro inhibition on AChE of 11 essential oils, isolated from six plants of the northern region of Colombia, were assessed using a modified tunnel-type device and the Ellman colorimetric method, respectively. The results were as follows: (i) the degree of repellency (DR) of the EOs against S. zeamais was 20-68% (2 h) and 28-74% (4 h); (ii) the IC50 values on AChE were 5-36 µg/mL; likewise, the %inh. on AChE (1 µg/cm3 per EO) did not show any effect in 91% of the EO tested; (iii) six EOs (Bursera graveolens-bark, B. graveolens-leaves, B. simaruba-bark, Peperomia pellucida-leaves, Piper holtonii (1b*)-leaves, and P. reticulatum-leaves) exhibited a DR (53-74%) ≥ C+ (chlorpyrifos-61%), while all EOs were less active (8-60-fold) on AChE compared to chlorpyrifos (IC50 of 0.59 µg/mL). Based on the ANOVA/linear regression and multivariate analysis of data, some differences/similarities could be established, as well as identifying the most active EOs (five: B. simaruba-bark, Pep. Pellucida-leaves, P. holtonii (1b*)-leaves, B. graveolens-bark, and B. graveolens-leaves). Finally, these EOs were constituted by spathulenol (24%)/ß-selinene (18%)/caryophyllene oxide (10%)-B. simaruba; carotol (44%)/dillapiole (21%)-Pep. pellucida; dillapiole (81% confirmed by 1H-/13C-NMR)-P. holtonii; mint furanone derivative (14%)/mint furanone (14%)-B. graveolens-bark; limonene (17%)/carvone (10%)-B. graveolens-leaves.
Assuntos
Inibidores da Colinesterase , Repelentes de Insetos , Óleos Voláteis , Sesquiterpenos Policíclicos , Animais , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Colômbia , Repelentes de Insetos/farmacologia , Repelentes de Insetos/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Piper/química , Óleos de Plantas/farmacologia , Óleos de Plantas/química , Sesquiterpenos Policíclicos/química , Sesquiterpenos Policíclicos/farmacologia , Gorgulhos/enzimologia , Gorgulhos/efeitos dos fármacos , Sesquiterpenos de Eudesmano/química , Sesquiterpenos de Eudesmano/farmacologia , Sesquiterpenos/química , Sesquiterpenos/farmacologiaRESUMO
This work evaluated the insecticidal, antifeedant and AChE inhibitory activity of compounds with eudesmane skeleton. The insecticidal activity was tested against larvae of Drosophila melanogaster and Cydia pomonella, the compounds 3 and 4 were the most active (LC50 of 104.2 and 106.7 µM; 82.0 and 84.4 µM, respectively). Likewise, the mentioned compounds were those that showed the highest acetylcholinesterase inhibitory activity, with IC50 of 0.26 ± 0.016 and 0.77 ± 0.016 µM, respectively. Enzyme kinetic studies, as well as molecular docking, show that the compounds would be non-competitive inhibitors of the enzyme. The antifeedant activity on Plodia interpunctella larvae showed an antifeedant index (AI) of 99% at 72 h for compounds 16, 27 and 20. The QSAR studies show that the properties associated with the polarity of the compounds would be responsible for the biological activities found.
Assuntos
Acetilcolinesterase , Inibidores da Colinesterase , Drosophila melanogaster , Inseticidas , Larva , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Sesquiterpenos de Eudesmano , Animais , Inseticidas/farmacologia , Inseticidas/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Larva/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Sesquiterpenos de Eudesmano/farmacologia , Sesquiterpenos de Eudesmano/química , Mariposas/efeitos dos fármacos , Sesquiterpenos/farmacologia , Sesquiterpenos/químicaRESUMO
Cholinergic deficit is a characteristic factor of several pathologies, such as myasthenia gravis, some types of congenital myasthenic syndromes, and Alzheimer's Disease. Two molecular targets for its treatment are acetylcholinesterase (AChE) and nicotinic acetylcholine receptor (nAChR). In previous studies, we found that caffeine behaves as a partial nAChR agonist and confirmed that it inhibits AChE. Here, we present new bifunctional caffeine derivatives consisting of a theophylline ring connected to amino groups by different linkers. All of them were more potent AChE inhibitors than caffeine. Furthermore, although some of them also activated muscle nAChR as partial agonists, not all of them stabilized nAChR in its desensitized conformation. To understand the molecular mechanism underlying these results, we performed docking studies on AChE and nAChR. The nAChR agonist behavior of the compounds depends on their accessory group, whereas their ability to stabilize the receptor in a desensitized state depends on the interactions of the linker at the binding site. Our results show that the new compounds can inhibit AChE and activate nAChR with greater potency than caffeine and provide further information on the modulation mechanisms of pharmacological targets for the design of novel therapeutic interventions in cholinergic deficit.
Assuntos
Cafeína , Receptores Nicotínicos , Cafeína/farmacologia , Acetilcolinesterase/metabolismo , Receptores Nicotínicos/metabolismo , Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologiaRESUMO
This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease.