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1.
BMC Chem ; 18(1): 70, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38600537

RESUMEN

In this article, we present the design and synthesis of amino-7,8-dihydro-4H-chromenone derivatives as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for the management of Alzheimer's disease (AD). The target compounds were evaluated against AChE and BChE in vitro, and 4k exhibited good potency against BChE (IC50 = 0.65 ± 0.13 µM) compared with donepezil used as a positive control. Kinetic studies revealed that compound 4k exhibited a competitive-type inhibition with a Ki value of 0.55 µM. Molecular docking and molecular dynamics simulations further supported the rationality of our design strategy, as 4k showed promising binding interactions with the active sites of BChE. Overall, our findings highlight the potential of amino-7,8-dihydro-4H-chromenone derivatives as promising candidates for developing novel therapeutics targeting cholinesterase in managing AD.

2.
Neurosci Lett ; 810: 137332, 2023 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-37302565

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disease, often characterized by progressive deficits in memory and cognitive functions. Cholinesterase inhibitors have been introduced as promising agents to enhance cognition and memory in both human patients and animal models of AD. In the current study, we assessed the effects of a synthetic phenoxyethyl piperidine derivative, compound 7c, as a novel dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), on learning and memory, as well as serum and hippocampal AChE levels in an animal model of AD. The model of dementia was induced by intracerebroventricular injection of streptozotocin (STZ, 2 mg/kg) to male Wistar rats. STZ-treated rats received compound 7c (3, 30, and 300 µg/kg) for five consecutive days. ​Passive avoidance (PA) learning and memory, as well as spatial learning and memory using Morris water maze, were evaluated. The level of AChE was measured in the serum and the left and right hippocampus. Findings demonstrated that compound 7c (300 µg/kg) was able to reverse STZ-induced impairments in PA memory, while also reduced the increased AChE level in the left hippocampus. Taken together, compound 7c appeared to act as a central AChE inhibitor, and its role in alleviating cognitive deficits in the AD animal model suggests that it may have therapeutic potential in AD dementia. Further research is required to assess the effectiveness of compound 7c in more reliable models of AD in light of these preliminary findings.


Asunto(s)
Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Ratas , Humanos , Masculino , Animales , Estreptozocina , Butirilcolinesterasa/efectos adversos , Acetilcolinesterasa , Ratas Wistar , Enfermedades Neurodegenerativas/tratamiento farmacológico , Trastornos de la Memoria/inducido químicamente , Aprendizaje por Laberinto , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Modelos Animales de Enfermedad
3.
BMC Chem ; 17(1): 56, 2023 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-37316931

RESUMEN

BACKGROUND: A new series of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide hybrids 11a-o was designed based on molecular hybridization of the active pharmacophores of the potent α-glucosidase inhibitors. These compounds were synthesized and evaluated against α-glucosidase. METHODS: The 15 various derivatives of indole-carbohydrazide-phenoxy-1,2,3-triazole-N-phenylacetamide scaffold were synthesized, purified, and fully characterized. These derivatives were evaluated against yeast α-glucosidase in vitro and in silico. ADMET properties of the most potent compounds were also predicted. RESULTS: All new derivatives 11a-o (IC50 values = 6.31 ± 0.03-49.89 ± 0.09 µM) are excellent α-glucosidase inhibitors in comparison to acarbose (IC50 value = 750.0 ± 10.0 µM) that was used as a positive control. Representatively, (E)-2-(4-((4-((2-(1H-indole-2-carbonyl)hydrazono)methyl) phenoxy)methyl)-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide 11d with IC50 = 6.31 µM against MCF-7 cells, was 118.8-times more potent than acarbose. This compound is an uncompetitive inhibitor against α-glucosidase and showed the lowest binding energy at the active site of this enzyme in comparison to other potent compounds. Furthermore, computational calculations predicted that compound 11d can be an orally active compound. CONCLUSION: According to obtained data, compound 11d can be a valuable lead compound for further structural development and assessments to obtain effective and potent new α-glucosidase inhibitors.

4.
Drug Des Devel Ther ; 14: 3087-3097, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32801647

RESUMEN

PURPOSE: Genetic diseases can be the result of genetic dysfunctions that happen due to some inhibitory and/or environmental risk factors, which are mostly called mutations. One of the most promising treatments for these diseases is correcting the faulty gene. Gene delivery systems are an important issue in improving the gene therapy efficiency. Therefore, the main purpose of this study was modifying graphene oxide nanoparticles by spermine in order to optimize the gene delivery system. METHODS: Graphene oxide/APTES was modified by spermine (GOAS) and characterized by FT-IR, DLS, SEM and AFM techniques. Then pEGFP-p53 was loaded on GOAS, transfected into cells and evaluated by fluorescent microscopy and gene expression techniques. RESULTS: FT-IR data approved the GOAS sheet formation. Ninety percent of the particles were less than 56 nm based on DLS analysis. SEM analysis indicated that the sheets were dispersed with no aggregation. AFM results confirmed the dispersed structures with thickness of 1.25±0.87 nm. STA analysis showed that GOAS started to decompose from 400°C and was very unstable during the heating process. The first weight loss up to 200°C was due to the evaporation of absorbed water, the second one observed in the range of 200-550°C was assigned to the decomposition of labile oxygen- and nitrogen-containing functional groups, and the third one above 550°C was attributed to the removal of oxygen functionalities. In vitro release of DNA demonstrated the efficient activity of the new synthesized system. Ninety percent of the cells were transfected and showed the GFP under fluorescence microscopy, and TP53 gene was expressed 51-fold in BT-20 cells compared to ß-actin as the reference gene. Flow cytometry analysis confirmed the apoptosis of the cells rather than necrosis. CONCLUSION: It could be concluded that the new synthesized structure could transfer a high amount of the therapeutic agent into cells with best activity.


Asunto(s)
Neoplasias de la Mama/terapia , Técnicas de Transferencia de Gen , Terapia Genética , Grafito/química , Nanopartículas/química , Propilaminas/química , Silanos/química , Espermina/química , Neoplasias de la Mama/genética , Femenino , Proteínas Fluorescentes Verdes/genética , Humanos , Microscopía Fluorescente , Espectroscopía Infrarroja por Transformada de Fourier , Transfección , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética
5.
J Nanosci Nanotechnol ; 20(5): 3206-3216, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-31635666

RESUMEN

An adapted one-pot route to nanocatalyst-assisted synthesis of 4H-chromenes via three component condensation reaction between dimedone, malononitrile, and a broad range of aryl aldehydes by the use of magnetic nickel ferrite nanoparticles is described. By this achievement, not only a novel route to highly efficient synthesis of these series of heterocycles was introduced but also the scope of these medicinally important products was developed via preparation of some novel products. Above all, a new application of nickel ferrite nanoparticles (NiFe2O4 NPs) as highly efficient, green and magnetically recyclable catalyst has been introduced. Overall, obtaining good to excellent yields of products, environmentally and economic benign procedure, easy handling, availability of starting materials, use of non-toxic solvents, and high recyclability of nano-catalyst could be countered as most important advantages of this methodology.

6.
Sci Rep ; 9(1): 19855, 2019 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-31882733

RESUMEN

Acetylcholinesterase (AChE) catalyzes the conversion of Aß peptide to its aggregated form and the peripheral anionic site (PAS) of AChE is mainly involved in this phenomenon. Also catalytic active site (CAS) of donepezil stimulates the break-down of acetylcholine (ACh) and depletion of ACh in cholinergic synapses are well established in brains of patients with AD. In this study, a set of compounds bearing phenoxyethyl amines were synthesized and their inhibitory activity toward electric eel AChE (eeAChE) and equine butyrylcholinesterase (eqBuChE) were evaluated. Molecular dynamics (MD) was employed to record the binding interactions of best compounds against human cholinesterases (hAChE and hBuChE) as well as donepezil as reference drug. In vitro results revealed that compound 5c is capable of inhibiting eeAChE activity at IC50 of 0.50 µM while no inhibitory activity was found for eqBuChE for up to 100 µM concentrations. Compound 5c, also due to its facile synthesis, small structure and high selectivity for eeAChE would be very interesting candidate in forthcoming studies. The main interacting parts of compound 5c and compound 7c (most potent eeAChE and eqBuChE inhibitors respectively) with receptors which confer selectivity for AChE and BuChE inhibition were identified, discussed, and compared with donepezil's interactions. Also during MD simulation it was discovered for the first time that binding of substrates like donepezil to dual CAS and PAS or solely CAS region might have a suppressive impact on 4-α-helical bundles near the tryptophan amphiphilic tetramerization (WAT) domain of AChE and residues which are far away from AChE active site. The results proposed that residues involved in donepezil interactions (Trp86 and Phe295) which are located in CAS and mid-gorge are the mediator of conformational changes in whole protein structure.


Asunto(s)
Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Morfolinas/química , Piperidinas/química , Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Modelos Moleculares , Simulación de Dinámica Molecular
7.
Heliyon ; 5(9): e02426, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31687546

RESUMEN

A novel, nano-sized, bis(3-(piperazine-1-yl)propyl)tungstate (BPPT) is introduced as an efficient and reusable organometallic catalyst which is considered as a heterogeneous Bronsted-Lowry base and applied successfully for one-pot synthesis of methyl 2-amino-4-aryl substituted-4H-chromene derivatives with good to excellent yields. BPPT has been prepared via a two-step route from natrium tungstate salt. At first, the oxygens of Na2WO4 react with 1-bromo-3-chloropropane via nucleophilic substitution to produce bis(3-choloro propyl)tungstate. Then nucleophilic substitution of piperazine with chlorines produced bis(3-(piperazine-1-yl)propyl) tungstate. Bis(3-(piperazine-1-yl)propyl) tungstate, which was called BPPT, characterized by fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermal gravimetric analysis (TGA), transmission electron microscopy (TEM) and scanning electron microscope (SEM). The catalyst is heterogeneous, green and recyclable. It is a thermally stable and its handling is easy. Its catalytic activity is very high and leads to the production of 4H-pyran derivatives with good to excellent yields in short reaction times. Furthermore, molecular modeling studies and ADMETox prediction revealed that not only it can inhibit acetylcholinesterase enzyme and act as an anti-Alzheimer agent but also has no variation from Lipinski's rule of five and can be a good candidate as anti-Alzheimer agents. These above-mentioned facts can be countered as advantages of the current protocol.

8.
Mini Rev Med Chem ; 19(19): 1577-1598, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31538893

RESUMEN

Alzheimer, a progressive disease, is a common term for memory loss which interferes with daily life through severe influence on cognitive abilities. Based on the cholinergic hypothesis, and Xray crystallographic determination of the structure of acetylcholinesterase (AChE) enzyme, the level of acetylcholine (ACh, an important neurotransmitter associated with memory) in the hippocampus and cortex area of the brain has a direct effect on Alzheimer. This fact encourages scientists to design and synthesize a wide range of acetylcholinesterase inhibitors (AChEIs) to control the level of ACh in the brain, keeping in view the crystallographic structure of AChE enzyme and drugs approved by the Food and Drug Administration (FDA). AChEIs have slightly diverse pharmacological properties, but all of them work by inhibiting the segregation of ACh by blocking AChE. We reviewed significant scaffolds introduced as AChEIs. In some studies, the activity against butyrylcholinesterase (BuChE) has been evaluated as well because BuChE is a similar enzyme to neuronal acetylcholinesterase and is capable of hydrolyzing ACh. In order to study AChEIs effectively, we divided them structurally into 12 classes and briefly explained effective AChEIs and compared their activities against AChE enzyme.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/química , Diseño de Fármacos , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Alcaloides/síntesis química , Alcaloides/química , Enfermedad de Alzheimer/patología , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/uso terapéutico , Donepezilo/síntesis química , Donepezilo/química , Humanos , Rivastigmina/síntesis química , Rivastigmina/química , Tacrina/síntesis química , Tacrina/química
9.
Arch Pharm (Weinheim) ; 352(7): e1800352, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31136018

RESUMEN

A series of novel chroman-4-one derivatives were designed and synthesized successfully with good to excellent yield (3a-l). In addition, the obtained products were evaluated for their cholinesterase (ChE) inhibitory activities. The results show that among the various synthesized compounds, analogs bearing the piperidinyl ethoxy side chain with 4-hydroxybenzylidene on the 3-positions of chroman-4-one (3l) showed the most potent activity with respect to acetylcholinesterase (anti-AChE activity; IC50 = 1.18 µM). In addition, the structure-activity relationship was studied and the results revealed that the electron-donating groups on the aryl ring of the 3-benzylidene fragment (3k, 3l) resulted in the designed compounds to be more potent ChE inhibitors in comparison with those having electron-withdrawing groups (3h). In this category, the strongest ChE inhibition was found for the compound containing piperidine as cyclic amine, and a hydroxyl group (for AChE, compound 3l) and fluoro group (for butyrylcholinesterase (BuChE, compound 3i) on the para-position of the aryl ring of the benzylidene group. The molecular docking and dynamics studies of the most potent compounds (3i and 3l against BuChE and AChE, respectively) demonstrated remarkable interactions with the binding pockets of the ChE enzymes and confirmed the results obtained through in vitro experiments.


Asunto(s)
Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Simulación de Dinámica Molecular , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/enzimología , Animales , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Electrophorus , Caballos , Cinética , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-Actividad
10.
J Nanosci Nanotechnol ; 19(9): 5965-5973, 2019 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-30961767

RESUMEN

This work reports an adapted route to the highly efficient synthesis of arylidene ethyl cyanoacetate derivatives in the presence of catalytic amounts of molybdenum oxide nanoparticles (MoO3 NPs) under green conditions at ambient temperature. From the reaction, a wide range of novel arylidene ethyl cyanoacetates was successfully synthesized with high yields from the Knoevenagel condensation reaction between various aryl aldehydes and ethyl cyanoacetate in the presence of MoO3 nanoparticles. The capability of catalyst to separate from the reaction mixture and then reuse is another advantage of this reaction. Furthermore, obtained products belong to analogous of organic compounds that have shown biological activity, and can be used pharmaceutics.

11.
Comput Biol Chem ; 80: 249-258, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31029750

RESUMEN

An efficient, borax-catalyzed protocol for the synthesis of novel 4-aryl-substituted-4H-pyran derivatives fused to α-pyrone ring in a one-pot is described. By this achievement, some novel 4-aryl substituted 4H-pyrans fused to the α-pyrone ring as potential acetylcholinesterase inhibitors (AChEIs) with good to excellent yields are obtained from a one-pot three-component reaction between various aryl aldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one and malononitrile. The method is a facile, inexpensive, practical and highly efficient one to obtain target compounds. The chemical structures of all compounds were characterized by FT-IR, FT-13CNMR and FT-1HNMR, MS spectroscopy and also elemental analyses data. Furthermore, the purity of all novel compounds was checked by HPLC. In addition, both molecular modelling studies and Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMETox) prediction nominated all compounds as good acetylcholinesterase inhibitors to the potential treatment of Alzheimer, Parkinson and Autism diseases that among them compound 4f showed the best activity against acetylcholinesterase enzyme.


Asunto(s)
Acetilcolinesterasa/química , Inhibidores de la Colinesterasa/química , Pironas/química , Acetilcolinesterasa/metabolismo , Boratos/química , Catálisis , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacocinética , Tecnología Química Verde/métodos , Humanos , Cinética , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Pironas/síntesis química , Pironas/metabolismo , Pironas/farmacocinética
12.
Toxicol Res (Camb) ; 7(5): 745-753, 2018 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-30310653

RESUMEN

Paraquat (PQ) poisoning is principally reported in developing countries. However, most fatalities occur elsewhere due to the induction of multi-organ failure. PQ poisoning can hardly be managed by clinical practice, and no specific antidote has come into existence yet. Here three cases, including 17-, 20-, and 23-year-old men, who were poisoned with PQ, have been reported. Furthermore, the literature regarding biological mechanisms, clinical manifestation, and treatment of PQ-induced toxicity was reviewed. Patients who, either intentionally or accidentally, ingested PQ earlier were initially found to be stable at the emergency department (ED). Therefore, they were discharged from the hospital under a follow-up. However, after several days, the patients were referred to the hospital for the second time and despite cardiovascular resuscitation (CPR) efforts, they suddenly expired. The delayed death following exposure to PQ was reported for inducing gradual progressive pulmonary fibrosis, metabolic acidosis, neurotoxicity, renal failure, and liver injury in poisoned patients. Therefore, PQ-intoxicated patients should be supervised for up to several weeks, and kept in the hospital for a longer period of time. Clinical manifestations and laboratory findings are beneficial markers that act as useful predictors of PQ poisoning.

13.
Future Med Chem ; 9(7): 659-671, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28485614

RESUMEN

AIM: A series of 2-benzylidene-benzofuran-3-ones were designed from the structures of Ebselen analogs and aurone derivatives and synthesized in good yields. MATERIALS & METHODS: The target compounds were prepared by the condensation reaction between appropriate benzofuranones with amino alkoxy aldehydes and evaluated as cholinesterase inhibitors by Ellman's method. RESULTS: The in vitro anti-acetylcholinesterase (AChE)/butyrylcholinesterase activities of the synthesized compounds revealed that 7e (IC50 = 0.045 µM) is the most active compound against AChE. Furthermore, the docking study confirmed the results obtained through in vitro experiments and predicted the possible binding conformation. CONCLUSION: The anticholinesterase activities of benzylidene-benzofurane-3-ones as aurone analogs revealed that the compounds bearing piperidinylethoxy residue showed better activities against AChE, introducing these compounds for further drug discovery developments. [Formula: see text].


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Benzofuranos/síntesis química , Benzofuranos/farmacología , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Benzofuranos/química , Benzofuranos/metabolismo , Compuestos de Bencilideno/química , Sitios de Unión , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/metabolismo , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Cinética , Modelos Moleculares , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad
14.
Eur J Med Chem ; 97: 181-9, 2015 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-25969170

RESUMEN

A series of 3-(4-(aminoalkoxy)benzylidene)-chroman-4-ones 7a-r were designed and synthesized as analogs of homoisoflavonoids which are well known natural products with diverse pharmacological properties related to Alzheimer's disease. The in vitro anti-cholinesterase activity of designed compounds 7a-r against AChE and BuChE, revealed that compounds bearing piperidinylethoxy residue showed potent activity against AChE at sub-micromolar level (IC50 values = 0.122-0.207 µM), more potent than reference drug tacrine. The structure-activity relationships study of piperidinylethoxy series demonstrated that the selectivity and physicochemical properties of compounds could be optimized by selection of a proper substituent on the C-7 position of chroman ring, while the high potency of the molecule against AChE was reserved.


Asunto(s)
Aminas/síntesis química , Compuestos de Bencilideno/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Cromonas/síntesis química , Diseño de Fármacos , Aminas/química , Aminas/farmacología , Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacología , Dominio Catalítico , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Cromonas/química , Cromonas/farmacología , Ciclización , Concentración 50 Inhibidora , Modelos Moleculares
15.
Eur J Med Chem ; 86: 562-9, 2014 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-25216378

RESUMEN

A series of 2-aryl-3-nitro-2H-chromenes 4a-u were designed as hybrid analogs of flavanone, ß-nitrostyrene and nitrovinylstilbene scaffolds. They were synthesized from the reaction of appropriate ß-nitrostyrenes and salicylaldehydes in good yields. In vitro cytotoxic activities of compounds 4a-u were tested against breast cancer cell lines including MCF-7, T-47D and MDA-MB-231. Most compounds exhibited good cytotoxic activity against selected cell lines, being more potent than standard drug etoposide. Representatively, 8-methoxy-3-nitro-2-(4-chlorophenyl)-2H-chromene (4l) with IC50 = 0.2 µM against MCF-7 cells, was 36-times more potent than etoposide. Apoptosis as a mechanism of cell death for selected compounds 4h and 4l was confirmed morphologically by acridine orange/ethidium bromide double staining and TUNEL analysis, as well as caspase-3 activation assay.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Cromanos/química , Cromanos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad
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