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The stepwise, one-pot synthesis of heterobimetallic carbene gold(i) platinum(ii) complexes from readily available starting materials is presented. The protecting group free methodology is based on the graduated nucleophilicities of aliphatic and aromatic amines as linkers between both metal centers. This enables the selective, sequential installation of the metal fragments. In addition, the obtained complexes were tested as potential anticancer agents and directly compared to their gold(i) palladium(ii) counterparts.
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The reactivity of Zn2+ tetrahedral complexes with H2O2 was investigated in silico, as a first step in their disruption process. The substrates were chosen to represent the cores of three different zinc finger protein motifs, i. e., a Zn2+ ion coordinated to four cysteines (CCCC), to three cysteines and one histidine (CCCH), and to two cysteines and two histidines (CCHH). The cysteine and histidine ligands were further simplified to methyl thiolate and imidazole, respectively. H2O2 was chosen as an oxidizing agent due to its biological role as a metabolic product and species involved in signaling processes. The mechanism of oxidation of a coordinated cysteinate to sulfenate-κS and the trends for the different substrates were rationalized through activation strain analysis and energy decomposition analysis in the framework of scalar relativistic Density Functional Theory (DFT) calculations at ZORA-M06/TZ2P ae // ZORA-BLYP-D3(BJ)/TZ2P. CCCC is oxidized most easily, an outcome explained considering both electrostatic and orbital interactions. The isomerization to sulfenate-κO was attempted to assess whether this step may affect the ligand dissociation; however, it was found to introduce a kinetic barrier without improving the energetics of the dissociation. Lastly, ligand exchange with free thiolates and selenolates was investigated as a trigger for ligand dissociation, possibly leading to metal ejection; molecular docking simulations also support this hypothesis.
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In continuation of our previous works on the cytotoxic properties of organopalladium compounds, in this contribution we describe the first systematic study of the anticancer activity of Pd(II)-aryl complexes. To this end, we have prepared and thoroughly characterized a wide range of palladium derivatives bearing different diphosphine, aryl and halide ligands, developing, when necessary, specific synthetic protocols. Most of the synthesized compounds showed remarkable cytotoxicity towards ovarian and breast cancer cell lines, with IC50 values often comparable to or lower than that of cisplatin. The most promising complexes ([PdI(Ph)(dppe)] and [PdI(p-CH3-Ph)(dppe)]), characterized by a diphosphine ligand with a low bite angle, exhibited, in addition to excellent cytotoxicity towards cancer cells, low activity on normal cells (MRC5 human lung fibroblasts). Specific immunofluorescence tests (cytochrome c and H2AX assays), performed to clarify the possible mechanism of action of this class of organopalladium derivatives, seemed to indicate DNA as the primary cellular target, whereas caspase 3/7 assays proved that the complex [PdI(Ph)(dppe)] was able to promote intrinsic apoptotic cell death. A detailed molecular docking analysis confirmed the importance of a diphosphine ligand with a reduced bite angle to ensure a strong DNA-complex interaction. Finally, one of the most promising complexes was tested towards patient-derived organoids, showing promising ex vivo cytotoxicity.
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Antineoplásicos , Complejos de Coordinación , Simulación del Acoplamiento Molecular , Paladio , Fosfinas , Humanos , Paladio/química , Paladio/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Fosfinas/química , Fosfinas/farmacología , Ligandos , Relación Estructura-Actividad , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Estructura MolecularRESUMEN
An efficient [4 + 2] cyclization protocol to synthesize a series of twelve examples of 1,2,3-triazolo[4,5-b]aminoquinolines (5) as novel structurally modified tacrines was obtained by reacting readily accessible precursors (i.e., 3-alky(aryl)-5-amino-1,2,3-triazole-4-carbonitriles (3)) and selected cycloalkanones (4) of five-, six-, and seven-membered rings. We evaluated the AChE and BChE inhibitory activity of the novel modified tacrines 5, and the compound derivatives from cyclohexanone (4b) showed the best AChE and BChE inhibitory activities. Specifically, 1,2,3-triazolo[4,5-b]aminoquinolines 5bb obtained from 3-methyl-carbonitrile (3b) showed the highest AChE (IC50 = 12.01 µM), while 5ib from 3-sulfonamido-carbonitrile (3i) was the most significant inhibitor for BChE (IC50 = 1.78 µM). In general, the inhibitory potency of compound 5 was weaker than the pure tacrine reference, and our findings may help to design and develop novel anticholinesterase drugs based on modified tacrines.
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Acetilcolinesterasa , Butirilcolinesterasa , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Tacrina/farmacología , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Inhibidores de la Colinesterasa/química , Estructura MolecularRESUMEN
The selenoxide elimination is a well-known reaction in organochalcogen chemistry, with wide synthetic, biological, and toxicological implications. In this work, we apply benchmarked density functional theory (DFT) calculations to investigate different aspects of the title reaction in three (bio)chemically relevant models, spanning minimal systems of theoretical interests as well as biological or synthetic organochalcogenides. The activation strain analysis (ASA) methodology is employed along a suitable reaction coordinate to obtain insight into the role of the chalcogen and of the oxidation state, to pinpoint the factors that tune the elimination reactivity of the investigated systems. Lastly, we computationally validate the hypothesis that telluroxides eliminate more slowly than selenoxides because of a detrimental hydration process that leads to unreactive hydrates.
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Oxidación-ReducciónRESUMEN
A convenient synthesis of a broad series of thirteen examples of alkyne-spacer derivatives 2 from the well-known Sonogashira cross-coupling reaction on diazenyl-pyrazolo[1,5-a]pyrimidin-2-amine compounds 1 is reported. The reactivity of heterocycles 1 due the presence of selected electron-donor (EDG) and electron-withdrawing (EWG) groups attached to different alkynes was evaluated. Also, the reactional versatility due the position variation of the bromo atom at the scaffolds 1 was also investigated. In general, derivatives presented strong absorption bands at the 250-500â nm optical window and UV to cyan emission properties. Also, the redox analysis was recorded by electrochemical cyclic voltammetry technique. For HSA biomacromolecule assays, spectroscopic studies by UV-Vis, steady-state and time-resolved emission fluorescence, and molecular docking calculations evidenced the ability of each compound to establish interactions with human serum albumin (HSA). Finally, the behavior presented for this new class of heterocycles makes them a promising tool as optical sensors for albumins.
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Aminas , Albúmina Sérica Humana , Alquinos/química , Humanos , Simulación del Acoplamiento Molecular , Espectrometría de FluorescenciaRESUMEN
Toxic metals, such as mercury (Hg), lead (Pb), cadmium (Cd), and copper (Cu), are widespread in the biosphere, and human activities have contributed to their continuous release into the ecosystems. Metal-induced toxicity has been extensively studied in mammals; however, the effects of these metals on insects' behavior have been explored to far lesser degree. As the main mechanism of toxicity, the cationic metals, explored in this review, have high affinity for thiol-containing molecules, disrupting the function of several proteins and low-molecular-weight thiol-containing molecules. Existing literature has corroborated that Hg, Pb, Cd, and Cu can disrupt locomotor and mating behaviors, but their effects on insects' memory and learning have yet to be fully characterized. Though field studies on metal-induced toxicity in insects are limited, results from Drosophila melanogaster as an experimental model suggest that insects living in contaminated environments can have behavioral foraging and reproductive deficits, which may cause population decline. In this review, we address the interaction between metals and endogenous thiol groups, with emphasis on alterations in insect behavior.
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Cadmio , Mercurio , Animales , Drosophila melanogaster , Ecosistema , Humanos , Plomo , Mamíferos , Compuestos de SulfhidriloRESUMEN
The present study reports a simple two-step method for the synthesis of arylselanyl hydrazide derivatives using hypophosphorous acid and polyethylene glycol (H3 PO2 /PEG-400) as an alternative reducing system and hydrazine hydrate (NH2 NH2 â xH2 O/50-60 %). This single-vessel procedure was employed with methyl acrylate 2a and methyl bromoacetate 2b using diaryl diselenides to generate the nucleophile species to produce, respectively, 3-(arylselanyl)propane-hydrazides 4a-e and 2-(arylselanyl)acetohydrazides 5a-e with good yields by accelerating the reduction of -Se-Se- bond, when compared to available methods. The synthesized molecules are structurally similar to the isoniazid (INH). Therefore, we perform inâ silico molecular docking studies, using the lactoperoxidase enzyme, in order to verify whether the INH Se derivatives could interact in a similar way to INH at the active site of the mammalian enzyme. The inâ silico results indicated a similar type of interaction of the arylselanyl hydrazide derivatives with that of INH. In view of the similar inâ silico interaction of the selenium derivatives of INH, the arylselanyl hydrazide derivatives reported here should be tested against Mycobacterium tuberculosis inâ vitro.
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Antituberculosos , Mycobacterium tuberculosis , Animales , Hidrazinas , Isoniazida/química , Isoniazida/farmacología , Mamíferos , Simulación del Acoplamiento MolecularRESUMEN
The synthesis, structural analysis, and evaluation of the photophysical properties of twelve novel 2-aryl(heteroaryl)-6-(4-alkyl(aryl)-1H-1,2,3-triazol-1-yl)-4-(trifluoromethyl)quinolines (6-8), where aryl(heteroaryl)=Ph, 4-Me-C6 H4 , 4-F-C6 H4 and 2- furyl; 4-alkyl(aryl)=-CH2 OH, -(CH2 )5 CH3 and Ph, are reported. Hybrid scaffolds 6-8 were synthesized at 77-95 % yields by regioselective copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction of unpublished 6-azido-4-(trifluoromethyl)quinolines (2) with selected terminal alkynes (3-5). Azido intermediates 2 were obtained from the reaction of 6-amino-4-(trifluoromethyl)quinolines (1) and sodium azide at good yields (78-87 %). Compounds 6-8 were structurally fully characterized by 1 H-, 13 C- and 19 F- and 1 H-13 C 2D-NMR (HSQC, HMBC) spectroscopy, X-ray diffraction (SC-XRD) and HRMS analysis. Moreover, the photophysical properties, DNA- and HSA-binding experiments (bio-interactions), and molecular docking studies for compounds 6-8 were performed. These are discussed and compared with similar compounds from recent research.
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ADN/química , Simulación del Acoplamiento Molecular , Albúmina Sérica Humana/química , Animales , Bovinos , Humanos , Procesos FotoquímicosRESUMEN
Methylmercury (CH3Hg+) binding to catalytically fundamental cysteine and selenocysteine of peroxide-reducing enzymes has long been postulated as the origin of its toxicological activity. Only very recently, CH3Hg+ binding to the selenocysteine of thioredoxin reductase has been directly observed [Pickering, I. J. Inorg. Chem., 2020, 59, 2711-2718], but the precise influence of the toxicant on the peroxide-reducing potential of such a residue has never been investigated. In this work, we employ state-of-the-art density functional theory calculations to study the reactivity of molecular models of the free and toxified enzymes. Trends in activation energies are discussed with attention to the biological consequences and are rationalized within the chemically intuitive framework provided by the activation strain model. With respect to the free, protonated amino acids, CH3Hg+ binding promotes oxidation of the S or Se nucleus, suggesting that chalcogenoxide formation might occur in the toxified enzyme, even if the actual rate of peroxide reduction is almost certainly lowered as suggested by comparison with fully deprotonated amino acids models.
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Cisteína/química , Compuestos de Metilmercurio/química , Peróxidos/química , Sitios de Unión , Cisteína/análogos & derivados , Teoría Funcional de la Densidad , Estructura Molecular , Oxidación-ReducciónRESUMEN
Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.
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Inhibidores de la Colinesterasa/farmacología , Colinesterasas/metabolismo , Cicloparafinas/farmacología , Quinolinas/farmacología , Animales , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Cicloparafinas/síntesis química , Cicloparafinas/química , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
Mercury is a hazardous substance that has unique neurodevelopmental toxic effects in humans. However, the precise sequence of molecular events that culminate in Hg-induced neuropathology is still unknown. Though the omics studies have been generating an enormous amount of new data about Hg toxicity, our ability to interpret such a large quantity of information is still limited. In this opinion article, we will reinforce the necessity of new high throughput and accurate analytical proteomic methodologies, especially, thiol and selenol-proteome. Overall, we posit that improvements in thiol- and selenol-proteomic analyses will be pivotal in identifying the primary cellular targets of Hg. However, a better understanding of the complex cascades and molecular pathways involved in its toxicity will require extensive complementary studies in more complex systems.
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Approximately 90% of bladder carcinomas are of the urothelial carcinoma type, which are characterized by high rates of recurrence and predisposition to progress to invasive tumors, representing one of the most costly neoplasms for health systems. Intravesical chemotherapy is a standard for the treatment of non-invasive bladder cancer. However, chemotherapy is usually aggressive and cytotoxic, which increases the death rates caused by cancer. Heterocyclic compounds which exhibit favorable pharmacokinetic and pharmacodynamic properties may enhance drug affinity for a target protein by targeting the treatment. Thus, this work presents the synthesis, characterization, and in vitro biological evaluation of new antioxidant (inhibition of lipid peroxidation, scavenging of free radical DPPH, and thiol peroxidase-like activity) and antiproliferative chalcogenobiotin derivatives and tests them against bladder carcinoma 5637 cells. A prominent response was obtained for the selected compounds, with tellurium biotin derivatives displaying effective antioxidant and antiproliferative activity. The effective compounds also demonstrated no toxicity in in vitro or in vivo studies.
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Antineoplásicos/farmacología , Antioxidantes/farmacología , Calcógenos/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Calcógenos/síntesis química , Calcógenos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Peroxidación de Lípido/efectos de los fármacos , Estructura Molecular , Picratos/antagonistas & inhibidores , Relación Estructura-Actividad , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Methylmercury (MeHg+) is a neurotoxicant abundantly present in the environment. The long-term effects of MeHg+ have been investigated in rodents, yet data on the long-term or persisted toxicity of MeHg+ in invertebrates is scanty. Here, we examined the acute, intermediate, and chronic effects upon dietary administration of MeHg+ in nymphs of Nauphoeta cinerea. Besides, the potential reversibility of the toxic effects of MeHg+ after a detoxification period was evaluated. Nymphs were exposed to diets containing 0 (control), 2.5, 25, and 100 µg MeHg+/g of diet for 10, 30, and 90 days. Additional groups of nymphs were fed with the same dose of MeHg+ for 30 days and then were subjected to a detoxification period for 60 days. The nymphs exposed to 100 µg MeHg+/g succumbed to a high mortality rate, along with multiple biochemical (increase of reactive oxygen species production and glutathione S-transferase activity, as well as decrease in the acetylcholinesterase activity) and behavioral alterations. We observed delayed mortality rate and behavioral alterations in nymphs exposed to 100 µg MeHg+/g for 30 days and subsequently subjected to 60 days of detoxification. However, the biochemical alterations did not persist throughout the detoxification period. In conclusion, our results established the persistent toxic effect of MeHg+ even after a prolonged detoxification period and evidenced the use of N. cinerea as an alternative model to study the toxicity of MeHg+.
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Cucarachas , Compuestos de Metilmercurio , Animales , Cucarachas/química , Dieta , Compuestos de Metilmercurio/química , Compuestos de Metilmercurio/metabolismoRESUMEN
The methylation of mercuric mercury (Hg2+) in the aquatic sediments produces methylmercury (CH3Hg+), which is biomagnified along the food chain. The ingestion of piscivorous fish or aquatic mammals by pregnant women is of concern because it can cause long-lasting neurobehavioral deficits in their offspring.
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Contaminación de Alimentos/análisis , Compuestos de Metilmercurio/análisis , Contaminantes Químicos del Agua/análisis , Animales , Monitoreo del Ambiente , Humanos , Compuestos de Metilmercurio/efectos adversos , Compuestos de Metilmercurio/toxicidad , Contaminantes Químicos del Agua/efectos adversos , Contaminantes Químicos del Agua/toxicidadRESUMEN
Methylmercury is a neurotoxicant that is found in fish and rice. MeHg's toxicity is mediated by blockage of -SH and -SeH groups of proteins. However, the identification of MeHg's targets is elusive. Here we focus on the chemistry of MeHg in the abiotic and biotic environment. The toxicological chemistry of MeHg is complex in metazoans, but at the atomic level it can be explained by exchange reactions of MeHg bound to -S(e)H with another free -S(e)H group (R1S(e)-HgMeâ¯+â¯R2-S(e)Hâ¯ââ¯R1S(e)Hâ¯+â¯R2-S(e)-HgMe). This reaction was first studied by professor Rabenstein and here it is referred as the "Rabenstein's Reaction". The absorption, distribution, and excretion of MeHg in the environment and in the body of animals will be dictated by Rabenstein's reactions. The affinity of MeHg by thiol and selenol groups and the exchange of MeHg by Rabenstein's Reaction (which is a diffusion controlled reaction) dictates MeHg's neurotoxicity. However, it is important to emphasize that the MeHg exchange reaction velocity with different types of thiol- and selenol-containing proteins will also depend on protein-specific structural and thermodynamical factors. New experimental approaches and detailed studies about the Rabenstein's reaction between MeHg with low molecular mass thiol (LMM-SH) molecules (cysteine, GSH, acetyl-CoA, lipoate, homocysteine) with abundant high molecular mass thiol (HMM-SH) molecules (albumin, hemoglobin) and HMM-SeH (GPxs, Selenoprotein P, TrxR1-3) are needed. The study of MeHg migration from -S(e)-Hg- bonds to free -S(e)H groups (Rabenstein's Reaction) in pure chemical systems and neural cells (with special emphasis to the LMM-SH and HMM-S(e)H molecules cited above) will be critical to developing realistic constants to be used in silico models that will predict the distribution of MeHg in humans.
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Encéfalo/metabolismo , Contaminantes Ambientales , Compuestos de Metilmercurio , Neuronas/metabolismo , Animales , Encéfalo/patología , Cisteína/metabolismo , Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Humanos , Compuestos de Metilmercurio/farmacocinética , Compuestos de Metilmercurio/toxicidad , Proteínas del Tejido Nervioso/metabolismo , Neuronas/patología , Selenoproteínas/metabolismoRESUMEN
Thimerosal (THIM) is a well-established antifungal and antiseptic agent widely used as a preservative in vaccines. Recent studies identified the neurotoxic effects of THIM, including malfunction of the monoaminergic system. However, the underlying cytotoxic mechanisms are not well understood. Here we used the fruit fly Drosophila melanogaster to investigate the mechanisms of THIM-induced neurotoxicity. We focused on the dopaminergic system, and the rate-limiting enzyme tyrosine hydroxylase (DmTyrH), to test the hypothesis that THIM can impair dopamine (DA) homeostasis and subsequently cause dysfunction. We studied the effect of THIM by feeding 1-2 day old flies (both sexes) food supplemented with 25 µM THIM for 4 days and determined THIM-induced effects on survival, oxidative stress, and metabolic activity based on MTT assay and acetylcholinesterase (AChE) activity. Our results demonstrate that D. melanogaster exposed to THIM present changes in DmTyrH expression and activity, together with altered DA levels that led to impaired motor behavior. These phenotypes were accompanied by an increase in oxidative stress, with a decrease in MTT reduction, in AChE activity, and also in survival rate. These findings suggest an initiating and primary role for THIM-mediated DmTyrH dysfunction that leads to impaired DA function and behavioral abnormalities, ultimately causing oxidative stress-related neurotoxicity.
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Dopamina/metabolismo , Timerosal/farmacología , Tirosina 3-Monooxigenasa/metabolismo , Animales , Drosophila melanogaster , Femenino , Glutatión Transferasa/metabolismo , Masculino , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
The toxicology of mercury (Hg) is of concern since this metal is ubiquitously distributed in the environment, and living organisms are routinely exposed to Hg at low to high levels. The toxic effects of Hg are well studied and it is known that they may differ depending on the Hg chemical species. In this chapter, we emphasize the neurotoxic effects of Hg during brain development. The immature brain is more susceptible to Hg exposure, since all the Hg chemical forms, not only the organic ones, can harm it. The possible consequences of Hg exposure during the early stages of development, the additive effects with other co-occurring neurotoxicants, and the known mechanisms of action and targets will be addressed in this chapter.
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Selenium is an essential trace element for animals and its role in the chemistry of life relies on a unique functional group: the selenol (-SeH) group. The selenol group participates in critical redox reactions. The antioxidant enzymes glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) exemplify important selenoproteins. The selenol group shares several chemical properties with the thiol group (-SH), but it is much more reactive than the sulfur analogue. The substitution of S by Se has been exploited in organic synthesis for a long time, but in the last 4 decades the re-discovery of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) and the demonstration that it has antioxidant and therapeutic properties has renovated interest in the field. The ability of ebselen to mimic the reaction catalyzed by GPx has been viewed as the most important molecular mechanism of action of this class of compound. The term GPx-like or thiol peroxidase-like reaction was previously coined in the field and it is now accepted as the most important chemical attribute of organoselenium compounds. Here, we will critically review the literature on the capacity of organoselenium compounds to mimic selenoproteins (particularly GPx) and discuss some of the bottlenecks in the field. Although the GPx-like activity of organoselenium compounds contributes to their pharmacological effects, the superestimation of the GPx-like activity has to be questioned. The ability of these compounds to oxidize the thiol groups of proteins (the thiol modifier effects of organoselenium compounds) and to spare selenoproteins from inactivation by soft-electrophiles (MeHg+, Hg2+, Cd2+, etc.) might be more relevant for the explanation of their pharmacological effects than their GPx-like activity. In our view, the exploitation of the thiol modifier properties of organoselenium compounds can be harnessed more rationally than the use of low mass molecular structures to mimic the activity of high mass macromolecules that have been shaped by millions to billions of years of evolution.
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Imitación Molecular , Compuestos de Organoselenio/farmacología , Selenoproteínas/química , Selenoproteínas/metabolismo , Compuestos de Sulfhidrilo/química , Animales , Catálisis , Humanos , Oxidación-ReducciónRESUMEN
A new series of 3,6-disubstituted 2-(methylthio)-4-(trifluoromethyl)-3,4-dihydropyrimidin-4-ols displaying methyl, phenyl, aryl, and heteroaryl groups at the 6-position; and methyl, ethyl, allyl, and phenyl groups at the 3-position of the dihydropyrimidine ring, were synthesized and evaluated in vitro for acetylcholinesterase inhibitory activity. Seven compounds showed activity with IC50 values in the lower micromolar range. The compound 4-trifluoromethyl-6-(4-fluorophenyl)-3-methyl-2-methylthio-3,4-dihydropyrimidin-4-ol (6e) had the best inhibitory activity (IC50 2.2 ± 0.9 µm) and this inhibition was characterized as competitive. The molecular docking study showed that the acetylcholinesterase enzyme accommodates compound 6e in its catalytic site. The enantiomers of compound 6e, present similar interactions: π-π stacking interactions between the aromatic ring of the ligand's 4-fluorophenyl moiety and the aromatic rings of the electron-rich Trp84; and H-bonds between the hydroxyl group of Tyr121 and the hydroxyl moiety from 6e. The antioxidant effect of the dihydropyrimidin-4-ols was also investigated.