Pharmacophore model for antiepileptic drugs acting on sodium channels

Fifteen antiepileptic drugs (AED), active against the maximal electroshock seizure test and able to block the neuronal voltage-dependent sodium channel, have been studied by means of a similarity analysis. Structural and electronic, quantum chemically derived characteristics are compared. Rigid analogs are included, because of the flexibility of some structures, in order to discern the conformational requirements associated with these ligands in the moment of the interaction. An inactive compound (ethosuximide) helps in the definition of the structural factors that are important for the activity. We propose a pharmacophore model that, giving an interpretation of the biological activity, allows the design of new AED with a well-defined mechanism of interaction.Facultad de Ciencias ExactasCentro de Química Inorgánic

A quantum chemistry approach to the electro-oxidation of CO adsorbed on Rh (111) cluster surfaces

A molecular-orbital interpretation of the electro-oxidation of CO adsorbed on Rh(111) single-crystal clusters in the presence of H2O is described. Calculations were based on the atom super-position and electron delocalization method. Different stabilization energies for ensembles of the type [Me]N(CO)n(OH)m for M = Rh or Pt are given. The stability of possible CO adsorbate configurations on Rh(111) surfaces depends on the applied electric potential in a way which is directly comparable with the one reported previously for CO adsorbates on Pt(111). Only linearly bonded CO adsorbates appear to be involved in the electrochemical CO oxidative interaction with H2O molecules on both Rh(111) and Pt(111).Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicada

Docking applied to the prediction of the affinity of compounds to p-glycoprotein

P-glycoprotein (P-gp) is involved in the transport of xenobiotic compounds and responsible for the decrease of the drug accumulation in multi-drug-resistant cells. In this investigation we compare several docking algorithms in order to find the conditions that are able to discriminate between P-gp binders and nonbinders. We built a comprehensive dataset of binders and nonbinders based on a careful analysis of the experimental data available in the literature, trying to overcome the discrepancy noticeable in the experimental results. We found that Autodock Vina flexible docking is the best choice for the tested options. The results will be useful to filter virtual screening results in the rational design of new drugs that are not expected to be expelled by P-gp.Facultad de Ciencias Exacta

Synthesis of anticonvulsant sulfamides: theoretical study of the related mechanism

A theoretical study of the mechanisms associated with the synthesis of anticonvulsant symmetric N,N’-substituted sulfamides is presented. Two possible synthetic routes are compared, which mainly differ in the use of pyridine as a nucleophilic agent in the reaction mechanism. Geometry optimization techniques and transition-state detection at the B3LYP/6-31G** level, modeling the solvent by means of an isodensity polarizable continuum approach, allow the most suitable method for the experimental process to be discerned.Facultad de Ciencias Exacta

Teorethical studies of the stability of 8a-alkyll-1,2,3,4,6,8a- hexahydronaphtalen-1-ones using semiempirical methods

The Birch alkylation products are very unstable. We are showing, in this communication, the results of a theoretical study that compares different decomposition reaction mechanisms. The conclusions are in agreement with our experimental results.Facultad de Ciencias Exacta

A quantum chemical approach to the influence of platinum surface structure on the oxygen electroreduction reaction

The O2 electroreduction reaction (OERR) on Pt behaves as a structure sensitive reaction whose peroxo intermediates are formed in a greater extent on Pt(100) than on Pt(111) surfaces. A semiempirical quantum chemistry interpretation of this behavior is attempted on the basis of the study of [Pt]N02OH systems, where N, the number of atoms in the Pt cluster, equals 18 and 25. Calculations indicate that dissociative O2 electroadsorption on Pt(111) and molecular O2 on Pt(100) are favored. As a result of the interactions of O2 and OH in adjacent positions, hydroperoxide intermediates are formed on Pt(100) leading to the possibility of having H2O2 as product from the OERR.Instituto de Investigaciones Fisicoquímicas Teóricas y AplicadasFacultad de Ciencias Exacta

Synthesis and anticonvulsant activity of amino acid-derived sulfamides

Sulfamides are promising functions for the design of new antiepileptic drugs (Bioorg. Med. Chem. 2007, 15, 1556-1567; 5604-5614). Following previous research in this line, a set of amino acid-derived sulfamides has been designed, synthesized, and tested as new anticonvulsant compounds. The experimental data confirmed the ability of some of the structures to suppress the convulsions originated by the electrical seizure (MES test) at low doses (100 mg/kg).Facultad de Ciencias Exacta

Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I, II, VII, XII and XIV

A set of sulfamides and sulfamates were synthesized and tested against several isoforms of carbonic anhydrase: CA I, CA II, CA VII, CA XII and CA XIV. The biological assays showed a broad range of inhibitory activity, and interesting results were found for several compounds in terms of activity (Ki <1μm) and selectivity: some aromatic sulfamides are active against CA I, CA II and/or CA VII; while they are less active in CA XII and CA XIV. On the other hand, bulky sulfamides are selective to CA VII. To understand the origin of the different inhibitory activity against each isozyme we used molecular modeling techniques such as docking and molecular dynamic simulations.Facultad de Ciencias Exacta

SAR Study of the anticonvulsant activity of amides and esters of the valproic acid

Las características conformacionales y electrónicas del acido valproico (vpa), valpramida (vpd), valproato de etilo (evp), valproato de propilo (pvp), valproato de butilo (bvp), valproato de isobutilo (ibvp) y valproato de valproilo (vvp), fueron analizadas por medio de la aplicación de métodos semiempíricos y evaluadas en comparación con las propiedades lipofílicas. El objetivo es comprender el origen del incremento de la actividad del vpa por amidación y la supresión de ésta por esterificación. Se discute la factibilidad de considerar a las amidas y ésteres como prodrogas del vpa, a partir de diferentes hipotesis que incluyen, entre otras: a) efectiva o no efectiva biotransformación de los ésteres a ácido y b) forma aniónica o neutra del vpa en el momento de interacción en el sitio de unión. La evaluacióii de los descriptores conformacionales, electrónicos y lipofílicos, muestran los requerimientos conformacionales como determinantes de la actividad anticonvulsivante, asociando la porción O-C-C-H a los requerimientos estructurales del farmacóforo.The conformational and electronic characteristics of valproic acid (vpa), valpromide (vpd), ethyl valproate (evp), propyl valproate (pvp), butyl valproate (bvp), isobutyl valproate (ibvp) and valproyl valproate (vvp), are analyzed at a semiempirical level, in comparison with their lipophilic properties. The goal is to understand the origin of the activity enhancement of vpa by amidation, and the suppression of its activity by esterification. The feasibility of considering the amide and the esters as prodrugs of vpa is discussed in the light of different hypothesis that include, among others: (a) effective or non effective biotransformation of the esters to the acid and (b) anionic or neutral form of the acid in the site of action. Among the conformational, electronic and lipophilic parameters, the conformational ones appear as determinant for the anticonvulsant activity, and point to the O-C-C-H portion, which might define a pharmacophore or is, at least, more closely related to the activity.Colegio de Farmacéuticos de la Provincia de Buenos Aire