RESUMEN
Drugs that act on α-adrenoceptors may contain morpholine and pyrimidinone heterocycles. The aim of this study was to synthesize a series of pyrimidinones (S6a-e and S8) and characterize their α-adrenoceptor activity. Cytotoxicity assays (MTT and LDH) were performed in A7r5 and HUVECs. Concentration-effect curves to phenylephrine (Phe) were performed in rat aortic rings in the presence of compounds S6a-e and S8 or vehicle. Nitric oxide (NO) production and NO stable metabolic products, nitrite and nitrate, expressed as total nitrogen oxides (NOx) were assessed in HUVECs by confocal microscopy with the DAF-2DA probe and by the Griess reaction, respectively. Molecular docking simulations were performed using the 6a compound and α2A-adrenoceptor. In the evaluated conditions, the percentage of viable cells and the release of LDH were similar between control cells and cells exposed to the tested pyrimidinones. S6d, S6e, S8, and the positive control prazosin (but not S6a, S6b, and S6c) decreased Phe-induced contractions in endothelium-denuded aortic rings. S6a, S6b, and S6c decreased Phe-induced contractions in endothelium-intact aortic rings. The effect of S6a was abolished by L-NAME. NO production and NOx levels were inhibited in the presence of the α2 receptor antagonist yohimbine and the NOS inhibitor L-NAME. The 6a docking simulation estimated that the mean binding free energy of the compound was lower than the estimated value for yohimbine. These data suggest that S6d, S6e, and S8 may be α1-adrenoceptor antagonists while S6a acts as an agonist of α2-adrenoceptors.
Asunto(s)
Células Endoteliales de la Vena Umbilical Humana , Simulación del Acoplamiento Molecular , Morfolinas , Pirimidinonas , Animales , Humanos , Ratas , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Pirimidinonas/farmacología , Pirimidinonas/química , Morfolinas/farmacología , Morfolinas/química , Óxido Nítrico/metabolismo , Masculino , Receptores Adrenérgicos alfa 2/metabolismo , Línea Celular , Aorta/efectos de los fármacos , Aorta/citología , Aorta/metabolismo , Ratas WistarRESUMEN
Dihydropyrimidinones (DHPMs) are heterocycles obtained by the multicomponent Biginelli reaction. Recently, new synthetic protocols have allowed us to explore functionalisation at less explored positions of DHPMs, such as the N1 position. In this context, a full literature survey of N1- substituted DHPMs was performed. We analysed 27 papers and identified 379 compounds with substituents at the N1 position, most of them with alkyl groups, and a total of 28% compounds with aromatic substituents attached at the N1 position. N1-substituted DHPMs were explored mainly due to their effects on cancer cell proliferation via numerous targets, such as kinesin Eg5, heat shock protein 70, heat shock protein 90, and the epidermal growth factor receptor. Similarity analyses were performed using the data of 379 DHPMs from different cheminformatic approaches, i.e., chemical property correlations, principal component analysis, similarity networks, and compound clustering.
Asunto(s)
Pirimidinonas , Proliferación Celular , Pirimidinonas/químicaRESUMEN
Dihydropyrimidinones are heterocycles with a pyrimidine moiety in the ring nucleus, which, in recent decades, have aroused interest in medicinal chemistry due to alleged versatile biological activity. In this systematic review, we describe the currently published activities of dihydropyrimidinone derivatives. Between 1990 and December 31st, 2016, 115 articles outlined biological activities or toxicity of DHPM derivatives, 12 of those involved in vivo experiments. The main activities associated with this class of compounds are antitumoral (43 articles), anti-inflammatory (12 articles), antibacterial (20 articles) and calcium channel antagonism/inhibition (14 articles). Antitumoral activity is the main biological property evaluated, since the main representative compound of this class (monastrol) is a known Eg5 kinesin inhibitor. This review depicts a variety of other pharmacological activities associated with DHPM derivatives, but the main findings are essentially in vitro characteristics of the substances. This review presents the current state of the art of DHPM biological activities and demonstrates that there is still a need for further in vivo studies to better delineate the pharmacological potential of this class of substances.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Antiparasitarios/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Pirimidinonas/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antiparasitarios/síntesis química , Antiparasitarios/química , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Humanos , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/químicaRESUMEN
Snakebites represent an important public health problem, with a great number of victims with permanent sequelae or fatal outcomes, particularly in rural, agriculturally active areas. The snake venom metalloproteases (SVMPs) are the principal proteins responsible for some clinically-relevant effects, such as local and systemic hemorrhage, dermonecrosis, and myonecrosis. Because of the difficulties in neutralizing them rapidly and locally by antivenoms, the search and design of small molecules as inhibitors of SVMPs are proposed. The Bothrops asper metalloprotease P1 (BaP1) is hereby used as a target protein and by High Throughput Virtual Screening (HTVS) approach, the free access virtual libraries: ZINC, PubChem and ChEMBL, were searched for potent small molecule inhibitors. Results from the aforementioned approaches provided strong evidences on the structural requirements for the efficient BaP1 inhibition such as the presence of the pyrimidine-2,4,6-trione moiety. The two proposed compounds have also shown excellent results in performed in vitro interaction studies against BaP1.
Asunto(s)
Antídotos/química , Antídotos/farmacología , Bothrops/metabolismo , Metaloendopeptidasas/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Venenos de Serpiente/antagonistas & inhibidores , Animales , Simulación por Computador , Descubrimiento de Drogas , Metaloendopeptidasas/metabolismo , Simulación del Acoplamiento Molecular , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
An efficient one-pot synthesis of 1,2,3-triazole derivatives of dihydropyrimidinones has been developed using two multicomponent reactions. The aldehyde-1,2,3-triazoles were obtained in good yields from in situ-generated organic azides and O-propargylbenzaldehyde. The target heterocycles were synthesized through the Biginelli reaction in which the aldehyde-1,2,3-triazoles reacted with ethyl acetoacetate and urea in the presence of Ce(OTf)3 as the catalyst. The corrosion inhibition of steel grade API 5 L X52 in 1 M HCl by the synthesized compounds was investigated using the electrochemical impedance spectroscopy technique. The measurements revealed that these heterocycles are promising candidates to inhibit acidic corrosion of steel.
Asunto(s)
Pirimidinonas/química , Acero/química , Triazoles/química , Azidas/química , Benzaldehídos/química , Catálisis , Corrosión , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Triazoles/síntesis química , Urea/químicaRESUMEN
The synthesis of a series of 14 new 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1H-pyrimidin-2-ones from the 1,3-dipolar cycloaddition reaction of 1-allyl-4-(trihalomethyl)pyrimidin-2(1H)-ones with aryl nitrile oxides is described. Also, the antiproliferative activity of the title compounds was tested against five human tumoral cell lines: MCF-7 breast cancer cell line, ER+ (estrogen receptor positive); HepG-2 (hepatoma); T-24 (bladder cancer); HCT-116 cell (colorectal carcinoma); and CACO-2. The preliminary results are promising, since three compounds presented IC50 values below 2 µM, as well as moderate to high selectivity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Isoxazoles/farmacología , Pirimidinonas/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Humanos , Isoxazoles/síntesis química , Isoxazoles/química , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
Acute lymphoblastic leukemia (ALL) is a malignant disorder caused by the proliferation of lymphoid progenitor cells and is the most common cancer in children. Cytotoxic nucleoside analogues are important chemotherapeutic agents, which are used in many cancers, including leukemias. In this study, we investigated the effects of the synthetic nucleoside analogue 1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethyl-pyrimidin-2(1H)-one, named compound 3 or C3, on leukemia cell lines. The compound stimulated cell death by apoptosis, evidenced by DNA fragmentation, phosphatidylserine externalization, and caspase-3 activation. Compound 3 seemed to trigger several cell death pathways. The mitochondrial pathway was evidenced through a disturbance of mitochondrial membrane potential, strong cytochrome c liberation, decrease of antiapoptotic Bcl-2 protein expression, and caspase-9 activation. The C3 also induced caspase-8 and -12 activation, an increase in the intracellular calcium level, and an overproduction of reactive oxygen species. Increased caspase 8 activity suggests that the extrinsic pathway was activated and that the ROS production and enzyme activity alteration (glutathione S-transferase, glutathione peroxidase, catalase, and glutathione reductase) might be related to oxidative stress. Finally, the increase in calcium release, CHOP expression, and caspase-12 activity might characterize endoplasmic reticulum stress. Compound 3 was likewise cytotoxic to leukemic and melanoma human cell lines. Taken together, the results contribute to further understanding the new pyrimidine analogue as a potential chemotherapeutic drug or lead molecule.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Pirimidinonas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células Jurkat , Ratones , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
In this paper we report the design, synthesis and evaluation of a series of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease. The compounds show excellent results as acetylcholinesterase inhibitors, being as active as the standard drug. All these compounds also show very good antioxidant activity through different mechanisms of action.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Terapia Molecular Dirigida , Pirimidinonas/síntesis química , Pirimidinonas/uso terapéutico , Selenio/uso terapéutico , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Humanos , Pirimidinonas/química , Pirimidinonas/farmacocinéticaRESUMEN
The current manuscript describes the role and importance of catalysis and solvent effects for the Biginelli multicomponent reaction. The overwhelming number of new catalysts and conditions recently published for the Biginelli synthesis, including in some manuscripts entitled "catalyst-free" and/or "solvent-free" have incentivized controversies and hot debates regarding the importance of developing new catalysts and reaction conditions to perform this very important multicomponent reaction. These so-called "catalyst-free" reports have generated much confusion in the field, requiring urgent elucidations. In this manuscript, we exemplify, demystify, and discuss the crucial role of catalysis, solvent effects, mechanisms, kinetics, facts, presumptions, and myths associated with the Biginelli reaction aiming to avoid current and future confusion and to stimulate new approaches.
Asunto(s)
Pirimidinonas/química , Catálisis , Cinética , Estructura Molecular , SolventesRESUMEN
This report presents evidence that the following Solanum steroids: solasodine, diosgenin and solanine interact with human erythrocytes and molecular models of their membranes as follows: a) X-ray diffraction studies showed that the compounds at low molar ratios (0.1-10.0mol%) induced increasing structural perturbation to dimyristoylphosphatidylcholine bilayers and to a considerable lower extent to those of dimyristoylphosphatidylethanolamine; b) differential scanning calorimetry data showed that the compounds were able to alter the cooperativity of dimyristoylphosphatidylcholine, dimyristoylphosphatidylethanolamine and dimyristoylphosphatidylserine phase transitions in a concentration-dependent manner; c) in the presence of steroids, the fluorescence of Merocyanine 540 incorporated to the membranes decreased suggesting a fluidization of the lipid system; d) scanning electron microscopy observations showed that all steroids altered the normal shape of human erythrocytes inducing mainly echinocytosis, characterized by the formation of blebs in their surfaces, an indication that their molecules are located into the outer monolayer of the erythrocyte membrane.
Asunto(s)
Diosgenina/química , Membrana Eritrocítica/química , Membrana Dobles de Lípidos/química , Alcaloides Solanáceos/química , Solanina/química , Rastreo Diferencial de Calorimetría , Dimiristoilfosfatidilcolina/química , Diosgenina/farmacología , Membrana Eritrocítica/efectos de los fármacos , Colorantes Fluorescentes/química , Humanos , Microscopía Electrónica de Rastreo , Transición de Fase/efectos de los fármacos , Fosfatidiletanolaminas/química , Fosfatidilserinas/química , Pirimidinonas/química , Dispersión del Ángulo Pequeño , Alcaloides Solanáceos/farmacología , Solanina/farmacología , Difracción de Rayos XRESUMEN
The molecules of the title compound, C13H18N6O2S2, lie across twofold rotation axes in the space group C2/c. Although the pyrimidine ring is effectively planar, the bridging methylene C atom is displaced from the plane of the pyrimidine ring by 0.213â (2)â Å, while the C-C-C angle at the bridging C atom is 120.3â (2)°. The molecule contains two symmetry-related N-H···O hydrogen bonds, generating S(8) motifs, and intermoecular N-H···O hydrogen bonds link the molecules into a ribbon of edge-fused rings.
Asunto(s)
Pirimidinas/química , Pirimidinonas/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Estructura MolecularRESUMEN
BACKGROUND: Saflufenacil dissipation in soils under different moisture conditions is not available in the scientific literature. The objective of this study was to evaluate saflufenacil degradation and persistence in soils from rice regions under field capacity (non-flooded) and saturated (flooded) conditions. RESULTS: The accelerated solvent extraction (ASE) residue analytical method developed to conduct the study resulted in recovery greater than 80% for the combinations of soils and moisture conditions. Saflufenacil degradation was faster at field capacity for all soils, except for Morey soil. Herbicide half-life was 28.6, 15.0 and 23.1 days under field capacity treatments and 58.8, 36.9 and 79.7 under saturated conditions for Nada, Crowley and Gilbert soils respectively. A half-life no longer than 80 days was observed for the combination of soils and moisture treatments. CONCLUSION: An ASE method was developed and used to extract saflufenacil from soil samples. Half-life averaged among soils was 59 and 33 days for saturated and field capacity respectively. Saflufenacil persistence in the environment was 2-3 times longer under flooded conditions for most of the soils studied.
Asunto(s)
Herbicidas/química , Pirimidinonas/química , Suelo/química , Sulfonamidas/química , Semivida , Contaminantes del Suelo/química , Agua/análisisRESUMEN
The present work describes the synthesis, characterization, and application of a new ion-tagged iron catalyst. The catalyst was employed in the Biginelli reaction with impressive performance. High yields have been achieved when the reaction was carried out in imidazolium-based ionic liquids (BMIâ PF6, BMIâ NTf2, and BMIâ BF4), thus showing that the ionic-liquid effects play a role in the reaction. Moreover, the ion-tagged catalyst could be recovered and reused up to eight times without any noticeable loss in activity. Mechanistic studies performed by using high-resolution electrospray-ionization quadrupole-time-of-flight mass (HR-EI-QTOF) spectrometry and kinetic experiments indicate only one reaction pathway and rule out the other two possibilities under the development conditions. The theoretical calculations are in accordance with the proposed mechanism of action of the iron catalyst. Finally, the 37 dihydropyrimidinone derivatives, products of the Biginelli reaction, had their cytotoxicity evaluated in assays against MCF-7 cancer cell linages with encouraging results of some derivatives, which were virtually non-toxic against healthy cell linages (fibroblasts).
Asunto(s)
Antineoplásicos/síntesis química , Imidazoles/química , Hierro/química , Pirimidinonas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Catálisis , Técnicas Químicas Combinatorias , Ensayos de Selección de Medicamentos Antitumorales , Espectroscopía de Resonancia por Spin del Electrón , Femenino , Fibroblastos/efectos de los fármacos , Humanos , Cinética , Estructura Molecular , Pirimidinonas/química , Pirimidinonas/farmacologíaRESUMEN
The 6,7,8,9-tetrahydropyrimido[4,5-b][1,6]naphthyridin-4(3H,5H,10H)-ones 4,5a-g and their oxidized forms 6,7a-g were obtained from the catalyst-free reaction of 6-amino-2-methylthiopyrimidin-4(3H)-one 3 and (E)-3,5-bis(benzylidene)-1-alkyl-4-piperidones 1,2a-g under Microwave irradiation and their subsequent oxidation process with p-chloranil. Eighteen of the new compounds were evaluated in the US National Cancer Institute (NCI), where compound 4g presented a remarkable activity against 57 cancer cell lines, with the most important GI(50) values ranging from 1.48 to 9.92 µM from in vitro assays.
Asunto(s)
Antineoplásicos/farmacología , Microondas , Naftiridinas/farmacología , Pirimidinonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Naftiridinas/síntesis química , Naftiridinas/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
Tuberculosis (TB) is an ancient human chronic infectious disease caused mainly by Mycobacterium tuberculosis. The emergence of strains resistant to first and second line anti-TB drugs, associated with the increasing number of TB cases among HIV positive subjects, and the large number of individuals infected with latent bacilli have urged the development of new strategies to treat TB. Enzymes of nucleotide metabolism pathways provide promising molecular targets for the development of drugs, aiming at both active and latent TB. The orotate phosphoribosyltransferase (OPRT) enzyme catalyzes the synthesis of orotidine 5'-monophosphate from 5'-phospho-α-d-ribose 1'-diphosphate and orotic acid, in the de novo pyrimidine synthesis pathway. Based on the kinetic mechanism and molecular properties, here we describe the design, selection and synthesis of substrate analogs with inhibitory activity of M. tuberculosis OPRT (MtOPRT) enzyme. Steady-state kinetic measurements were employed to determine the mode of inhibition of commercially available and chemically derived compounds. The 6-Hydroxy-2-oxo-1,2-dihydropyridine-4-carboxylic acid (6) chemical compound and its derivative, 3-Benzylidene-2,6-dioxo-1,2,3,6-tetrahydropyridine-4-carboxylic acid (13), showed enzyme inhibition constants in the submicromolar range. Isothermal titration calorimetry data indicated that binding of both compounds to MtOPRT have negative enthalpy and favorable Gibbs free energy probably due to their high complementarity to the enzyme's binding pocket. Improvement of compound 13 hydrophobic character by addition of an aromatic ring substituent resulted in entropic optimization, reflected on a thermodynamic discrimination profile characteristic of high affinity ligands. These inhibitors represent lead compounds for further development of MtOPRT inhibitors with increased potency, which may be tested as anti-TB agents.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Mycobacterium tuberculosis/enzimología , Orotato Fosforribosiltransferasa/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Antibacterianos/síntesis química , Antibacterianos/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Orotato Fosforribosiltransferasa/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/metabolismo , Factores de TiempoRESUMEN
The Biginelli reaction is a multicomponent reaction involving the condensation between an aldehyde, a ß-ketoester, and urea or thiourea, in the presence of an acid catalyst, producing dihydropyrimidinones (DHPMs). Owing to their important pharmacological properties, the DHPMs have been studied by many authors. However, most of the methodologies used for the synthesis of these compounds require drastic reaction conditions. In the current study, we report an efficient and clean procedure for preparing DHPMs by the use of citric acid or tartaric acid as a promoter of the Biginelli synthesis in ethanol as solvent. In addition, we have evaluated the antioxidant capacity of the compounds synthesized by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay and the thiobarbituric acid-reactive species test. Two compounds presented antioxidant activity and also reduced lipid peroxidation at concentrations of 200 and 300 µM. In summary, we report an environmentally friendly procedure for the preparation of DHPMs and demonstrate the antioxidant capacity of some of the compounds.
Asunto(s)
Antioxidantes/síntesis química , Ácido Cítrico/química , Pirimidinonas/síntesis química , Tartratos/química , Animales , Antioxidantes/química , Antioxidantes/farmacología , Etanol/química , Peroxidación de Lípido/efectos de los fármacos , Pirimidinonas/química , Pirimidinonas/farmacología , Ratas , Ratas Wistar , Solventes/químicaRESUMEN
2,6-Diphenyl-4-(2,4,6-triphenylpyridinium-1-yl)phenolate (1a) and 4-[(1-methyl-4(1H)-pyridinylidene)-ethylidene]-2,5-cyclohexadien-1-one (2a) were protonated in organic solvents (dichloromethane, acetonitrile, and DMSO) to form 1b and 2b, respectively. The appearance of the solvatochromic bands of 1a and 2a was studied UV-vis spectrophotometrically by deprotonation of 1b and 2b in solution in the presence of the following amines: aniline (AN), N-methylaniline (NMAN), N,N-dimethylaniline (NDAN), n-butylamine (BA), diethylamine (DEA), and triethylamine (TEA). Titrations of 1b and 2b with the amines were carried out and the binding constants were determined from the titration curves in each solvent, using a mathematical model adapted from the literature which considers the simultaneous participation of two dye: amine stoichiometries, 1:1 and 1:2. The data obtained showed the following base order for the two compounds in DMSO: BA>DEA>TEA, while aromatic amines did not cause any effect. In dichloromethane, the following base order for 1b was verified: TEA>DEA>BAâ«NDAN, while for 2b the order was: TEA>DEA>BA, suggesting that 1b is more acidic than 2b. The data in acetonitrile indicated for 1b and 2b the following order for the amines: DEA>TEA>BA. The diversity of the experimental data were explained based on a model that considers the level of interaction of the protonated dyes with the amines to be dependent on three aspects: (a) the basicity of the amine, which varies according to their molecular structure and the solvent in which it is dissolved, (b) the molecular structure of the dye, and (c) the solvent used to study the system.
Asunto(s)
Aminas/metabolismo , Pirimidinonas/metabolismo , Solventes/química , Aminas/química , Compuestos de Anilina/química , Compuestos de Anilina/metabolismo , Sitios de Unión , Butilaminas/química , Butilaminas/metabolismo , Interacciones Farmacológicas , Concentración de Iones de Hidrógeno , Modelos Biológicos , Conformación Molecular , Protones , Pirimidinonas/química , Soluciones , Solventes/metabolismo , Solventes/farmacología , Espectrofotometría , Estereoisomerismo , VolumetríaRESUMEN
The molecules of the title compound, C(26)H(25)N(3)OS, which was prepared by means of an acid-catalysed cyclocondensation reaction between a 6-aminopyrimidinone and 2,6-dibenzylidenecyclohexanone, exhibit a polarized electronic structure, namely (9E)-9-benzylidene-3-methyl-2-methylsulfanyl-5-phenyl-3,5,6,7,8,9-hexahydropyrimido[4,5-b]quinolin-10-ium-4-olate, involving charge separation in the vinylogous amide portion. Four hydrogen bonds, two each of the C-H...O and C-H...pi(arene) types, link the molecules into bilayers comprising inversion-related pairs of sheets, each containing a single type of R(4)(3)(36) ring.
Asunto(s)
Iones/química , Pirimidinonas/química , Quinolinas/química , Catálisis , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
(3Z)-3-{1-[(5-Phenyl-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuran-2(3H)-one, C(15)H(15)N(3)O(2), (I), and the stoichiometric adduct (3Z)-3-{1-[(5-methyl-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuran-2(3H)-one-6-(2-hydroxyethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7(4H)-one (1/1), C(10)H(13)N(3)O(2).C(10)H(13)N(3)O(2), (II), in which the two components have the same composition but different constitutions, are formed in the reactions of 2-acetyl-4-butyrolactone with 5-amino-3-phenyl-1H-pyrazole and 5-amino-3-methyl-1H-pyrazole, respectively. In each compound, the furanone component contains an intramolecular N-H...O hydrogen bond. The molecules of (I) are linked into a chain by a single intermolecular N-H...O hydrogen bond, while in (II), a combination of one O-H...N hydrogen bond, within the selected asymmetric unit, and two N-H...O hydrogen bonds link the molecular components into a ribbon containing alternating centrosymmetric R(4)(4)(20) and R(6)(6)(22) rings.
Asunto(s)
Furanos/química , Pirazoles/química , Pirimidinonas/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Estructura MolecularRESUMEN
Purine nucleoside phosphorylase (PNP) (EC.2.4.2.1) is an enzyme that catalyzes the cleavage of N-ribosidic bonds of the purine ribonucleosides and 2-deoxyribonucleosides in the presence of inorganic orthophosphate as a second substrate. This enzyme is involved in purine-salvage pathway and has been proposed as a promising target for design and development of antimalarial and antibacterial drugs. Recent elucidation of the three-dimensional structure of PNP by X-ray protein crystallography left open the possibility of structure-based virtual screening initiatives in combination with molecular dynamics simulations focused on identification of potential new antimalarial drugs. Most of the previously published molecular dynamics simulations of PNP were carried out on human PNP, a trimeric PNP. The present article describes for the first time molecular dynamics simulations of hexameric PNP from Plasmodium falciparum (PfPNP). Two systems were simulated in the present work, PfPNP in ligand free form, and in complex with immucillin and sulfate. Based on the dynamical behavior of both systems the main results related to structural stability and protein-drug interactions are discussed.