RESUMEN
A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1â¯=â¯0.04 and COX-2â¯=â¯0.10⯵M, and naproxen: IC50 COX-1â¯=â¯11.3 and COX-2â¯=â¯3.36⯵M). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/farmacología , Dimetilsulfóxido/farmacología , Edema/tratamiento farmacológico , Úlcera Gástrica/tratamiento farmacológico , Sulfonas/farmacología , Ácido Acético , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiulcerosos/síntesis química , Antiulcerosos/química , Carragenina , Dimetilsulfóxido/síntesis química , Dimetilsulfóxido/química , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Humanos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/química , TermodinámicaRESUMEN
Amyloid beta (Aß) oligomerization is associated with the origin and progression of Alzheimer's disease (AD). While the A2V mutation enhances aggregation kinetics and toxicity, mixtures of wild-type (WT) and A2V, and also WT and A2T, peptides retard fibril formation and protect against AD. In this study, we simulate the equilibrium ensemble of WT:A2T Aß40 dimer by means of extensive atomistic replica exchange molecular dynamics and compare our results with previous equivalent simulations of A2V:A2V, WT:WT, and WT:A2V Aß40 dimers for a total time scale of nearly 0.1 ms. Qualitative comparison of the resulting thermodynamic properties, such as the relative binding free energies, with the reported experimental kinetic and thermodynamic data affords us important insight into the conversion from slow-pathway to fast-pathway dimer conformations. The crucial reaction coordinate or driving force of such transformation turns out to be related to hydrophobic interpeptide interactions. Analysis of the equilibrium ensembles shows that the fast-pathway conformations contain interpeptide out-of-register antiparallel ß-sheet structures at short interpeptide distances. In contrast, the slow-pathway conformations are formed by the association of peptides at large interpeptide distances and high intrapeptide compactness, such as conformations containing intramolecular three-stranded ß-sheets which sharply distinguish fast (A2V:A2V and WT:WT) and slow (WT:A2T and WT:A2V) amyloid-forming sequences. Also, this analysis leads us to predict that a molecule stabilizing the intramolecular three-stranded ß-sheet or inhibiting the formation of an interpeptide ß-sheet spanning residues 17-20 and 31-37 would further reduce fibril formation and probably the cytotoxicity of Aß species.
Asunto(s)
Péptidos beta-Amiloides/química , Amiloide/química , Simulación de Dinámica Molecular , Fragmentos de Péptidos/química , Péptidos beta-Amiloides/genética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Cinética , Mutación , Fragmentos de Péptidos/genética , Conformación Proteica en Lámina beta , Multimerización de Proteína , Soluciones , Relación Estructura-Actividad , TermodinámicaRESUMEN
Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where the recognition between ligand and receptor is affected by the ability of the interacting partners to adopt a favorable conformation for the binding. To explore the conformational space of flexible ligands and to obtain the relative free energy of the conformation wells, we have recently reported a multilevel computational strategy that relies on the predominant-state approximation-where the conformational space is partitioned into distinct conformational wells-and combines a low-level method for sampling the conformational minima and high-level ab initio calculations for estimating their relative stability. In this study, we assess the performance of the multilevel strategy for predicting the conformational preferences of a series of structurally related phenylethylamines and streptomycin in aqueous solution. The charged nature of these compounds and the chemical complexity of streptomycin make them a challenging test for the multilevel approach. Furthermore, we explore the suitability of using a molecular mechanics approach as a source of approximate ensembles in the first stage of the multilevel strategy. The results support the reliability of the multilevel approach for obtaining an accurate conformational ensemble of small (bio)organic molecules in aqueous solution.
Asunto(s)
Conformación Molecular , Simulación de Dinámica Molecular , Diseño de Fármacos , Ligandos , Fenetilaminas/química , Estreptomicina/químicaRESUMEN
The evolution of a ternary molecular system (imine, diene and nitrile) is analyzed to disclose the pathways leading to a divergent synthetic outcome. The Lewis acid catalyzed reaction between cyclohexadiene, 2-phenyl-indol-3-one and acetonitrile yields the imino-Diels-Alder adduct as the major product together with minor amounts of the Mannich-Ritter-amidine product. The experimental and computational data show that the relative orientation of the initial reactants dictates the synthetic outcome. The exo approach between imine and diene leads to the Diels-Alder adduct in a concerted process, whereas the endo mode leads to a polarized intermediate, which is trapped by acetonitrile to yield the multicomponent adduct.
Asunto(s)
Ciclohexenos/química , Iminas/química , Nitrilos/química , Acetonitrilos/química , Ácidos de Lewis/química , EstereoisomerismoRESUMEN
A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 µM) and BuChE (IC50=0.46±0.06 µM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aß aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/síntesis química , Indanos/síntesis química , Indoles/síntesis química , Modelos Moleculares , Inhibidores de la Monoaminooxidasa/síntesis química , Piperidinas/síntesis química , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Péptidos beta-Amiloides/química , Animales , Sitios de Unión , Butirilcolinesterasa/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Donepezilo , Electrophorus , Caballos , Humanos , Indanos/química , Indanos/farmacología , Indoles/química , Indoles/farmacología , Isoenzimas/química , Cinética , Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Fragmentos de Péptidos/química , Piperidinas/química , Piperidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Following our previous research on anti-inflammatory drugs (NSAIDs), we report on the design and synthesis of 4-(aryloyl)phenyl methyl sulfones. These substances were characterized for their capacity to inhibit cyclooxygenase (COX-1 and COX-2) isoenzymes. Molecular modeling studies showed that the methylsulfone group of these compounds was inserted deep in the pocket of the human COX-2 binding site, in an orientation that precludes hydrogen bonding with Arg120, Ser353, and Tyr355 through their oxygen atoms. The N-arylindole 33 was the most potent inhibitor of COX-2 and also the most selective (COX-1/COX-2 IC(50) ratio was 262). The indole derivative 33 was further tested in vivo for its anti-inflammatory activity in rats. This compound showed greater inhibitory activity than ibuprofen. Other compounds (20, 26, 9, and 30) showed strong activity against carrageenan-induced inflammation. The latter compounds showed a weak capacity to inhibit the proliferation of human cell lines K562, NCI-H460, and HT-29 in vitro.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de la Ciclooxigenasa/síntesis química , Sulfonas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 1/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Modelos Moleculares , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacología , TermodinámicaRESUMEN
Carboxylesterases (CEs) are a family of ubiquitous enzymes with broad substrate specificity, and their inhibition may have important implications in pharmaceutical and agrochemical fields. One of the most potent inhibitors both for mammalian and insect CEs are trifluoromethyl ketones (TFMKs), but the mechanism of action of these chemicals is not completely understood. This study examines the balance between reactivity versus steric effects in modulating the activity against human carboxylesterase 1. The intrinsic reactivity of the ketone moiety is determined from quantum mechanical computations, which combine gas phase B3LYP calculations with hydration free energies estimated with the IEF/MST model. In addition, docking and molecular dynamics simulations are used to explore the binding mode of the inhibitors along the deep gorge that delineates the binding site. The results point out that the activity largely depends on the nature of the fluorinated ketone, since the activity is modulated by the balance between the intrinsic electrophilicity of the carbonyl carbon atom and the ratio between keto and hydrate forms. However, the results also suggest that the correct alignment of the alkyl chain in the binding site can exert a large influence on the inhibitory activity, as this effect seems to override the intrinsic reactivity features of the fluorinated ketone. Overall, the results sustain a subtle balance between reactivity and steric effects in modulating the inhibitory activity of TFMK inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Esterasas/antagonistas & inhibidores , Halogenación/efectos de los fármacos , Cetonas/química , Cetonas/farmacología , Simulación de Dinámica Molecular , Teoría Cuántica , Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Hidrolasas de Éster Carboxílico/metabolismo , Inhibidores Enzimáticos/química , Esterasas/metabolismo , Humanos , Enlace de Hidrógeno/efectos de los fármacos , Concentración 50 Inhibidora , TermodinámicaRESUMEN
Recent experiments with amyloid-beta (Abeta) peptides indicate that the formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depend on their structure, which is governed by assembly dynamics. However, a detailed knowledge of the structure of at the atomic level has not been achieved yet due to limitations of current experimental techniques. In this study, replica exchange molecular dynamics simulations are used to identify the expected diversity of dimer conformations of Abeta(10-35) monomers. The most representative dimer conformation has been used to track the dimer formation process between both monomers. The process has been characterized by means of the evolution of the decomposition of the binding free energy, which provides an energetic profile of the interaction. Dimers undergo a process of reorganization driven basically by inter-chain hydrophobic and hydrophilic interactions and also solvation/desolvation processes.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/química , Simulación de Dinámica Molecular , Fragmentos de Péptidos/química , Entropía , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Distribución de Poisson , Unión Proteica , Conformación Proteica , Multimerización de ProteínaRESUMEN
The dual or selective ability of 24 derived mono- and 2,6-di-tert-butylphenols (DTBP) to act as inhibitors of cyclooxygenase (COX) and/or 5-lipoxygenase (LOX) enzymes is investigated. Firstly, we explored the conformational variability of the compounds. It is found that dual inhibitors can adopt four minimum energy conformations: cis or trans, depending on the orientation of the carbonyl oxygen atom (localized in the para position) relative to the hydroxyl hydrogen, and alpha or beta, depending on whether the carbonyl oxygen is below or above the phenyl plane. The possible bioactive conformations are selected by molecular superimposition to the optimised structure of tebufelone, a dual inhibitor in the clinical trial phase. From this selected conformation, different molecular parameters were calculated and correlated with both COX/LOX inhibitory activities. The MEP and GRID maps for different probes (hydrogen bond donor/acceptor, hydrophobic and ferric/ferrous interaction areas) are represented and discussed. The results point out the importance of the hydrogen donation and the hydrophobic properties in the COX inhibition whereas, for LOX inhibition, a redox mechanism might be involved. Finally, the predictive ability of the proposed QSAR equations is tested analysing a set of selective COX or LOX inhibitors.