Ethyl 4-{1-[(2,4-dinitro­phen­yl)hydrazono]eth­yl}-5-(2-naphthyl­methoxy­meth­yl)isoxazole-3-carboxyl­ate

The title compound, C26H23N5O8, was prepared and its structure investigated to further develop a working hypothesis for the essential binding pharmacophore for ligands of the System Xc- transporter [Patel et al. (2004 ▶). Neuropharmacology, 46, 273–284]. The hydrazone group displays an E geometry and the isoxazole double bond and C=N group of the hydrazone are in an s-cis relationship. The secondary amino NH group forms an intra­molecular N—H⋯O hydrogen bond to a ring nitro group. There is a dihedral angle of 44.27 (5)° between the isoxazole plane and the hydrazone group plane

BIOISOSTERES OF AMPA: CONFORMATIONAL ANALYSIS AND STRUCTURE ACTIVITY RELATIONSHIP

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Concentrations of L-glutamate in the CNS are regulated by a family of excitatory amino acid transporters (EAATs) that rapidly sequester and concentrate glutamate in glia and neurons, and thereby influence transmitter access to EAA receptors. In contrast to the EAAT-mediated uptake of L-Glu, the system Xc- (SXc-) transporter (an obligate exchanger of L-glutamate and L-cystine) has been implicated in the export of L-Glu from CNS cells in such a manner that it can access and activate EAA receptors. The significance of SXc- actions is reflected in the range of CNS processes including: drug addiction, brain tumor growth and oxidative protection. Recent work has focused on the synthesis of analogs and bioisosteres of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), including lipophilic analogs using lateral metalation and electrophilic quenching and their evaluations at the system xc- transporter. Bioisosteres which are not limited to amino acids were synthesized from a common intermediate. During the synthesis of hydrazone bioisosteres, most electron rich hydrazines undergo ring closer to form fused bicyclic systems, the isoxazolo[3,4-d]pyridazinones. Several hydrazone acids synthesized, bind to the SXc- with affinities comparable to those of the endogenous substrates. In contrast, the isoxazolo [3,4-d]pyridazinone analogs exhibit little or no binding. These novel isoxazole-based analogues are used in combination with SAR data from other structurally diverse inhibitors to begin constructing a pharmacophore model of the SXc- substrate binding site

Competitive Pseudopericyclic [3,3]- and [3,5]-Sigmatropic Rearrangements of Trichloroacetimidates

The Woodward–Hoffmann rules predict whether concerted pericyclic reactions are allowed or forbidden based on the number of electrons involved and whether the cyclic orbital overlap involves suprafacial or antarafacial orbital overlap. Pseudopericyclic reactions constitute a third class of reactions in which orthogonal orbitals make them orbital symmetry allowed, regardless of the number of electrons involved in the reaction. Based on the recent report of eight-centered ester rearrangements, it is predicted that the isoelectronic eight-centered rearrangements of imidates would also be allowed. We now report that these rearrangements occur, and indeed, an eight-centered rearrangement is slightly favored in at least one case over the well-known six-centered Overman rearrangements, in a trichloroacetimidoylcyclohexadienone, a molecular system where both rearrangements are possible

Competitive Pseudopericyclic [3,3]- and [3,5]-Sigmatropic Rearrangements of Trichloroacetimidates

The Woodward–Hoffmann rules predict whether concerted pericyclic reactions are allowed or forbidden based on the number of electrons involved and whether the cyclic orbital overlap involves suprafacial or antarafacial orbital overlap. Pseudopericyclic reactions constitute a third class of reactions in which orthogonal orbitals make them orbital symmetry allowed, regardless of the number of electrons involved in the reaction. Based on the recent report of eight-centered ester rearrangements, it is predicted that the isoelectronic eight-centered rearrangements of imidates would also be allowed. We now report that these rearrangements occur, and indeed, an eight-centered rearrangement is slightly favored in at least one case over the well-known six-centered Overman rearrangements, in a trichloroacetimidoylcyclohexadienone, a molecular system where both rearrangements are possible

Experimental and Computational Studies on the [3,3]- and [3,5]-Sigmatropic Rearrangements of Acetoxycyclohexadienones: A Non-ionic Mechanism for Acyl Migration

Flash vacuum pyrolysis studies of substituted 6-acetoxy-2,4-cyclohexadienones (<b>3</b> and <b>10</b>) from 300 to 500 °C provide strong experimental evidence that direct [3,5]-sigmatropic rearrangements in these molecules are favored over the more familiar [3,3]-sigmatropic rearrangements. The preference holds when the results are extrapolated to 0.0% conversion, indicating that this is a concerted process. Pyrolysis of 6,6-diacetoxy-2-methyl-2,4-cyclohexadienone (<b>9</b>) at 350 °C gives a modest yield of the initial [3,5]-sigmatropic rearrangement product, 2,6-diacetoxy-6-methyl-2,4-cyclohexadienone (<b>11</b>). Qualitative arguments and electronic structure theory calculations are in agreement that the lowest energy pathway for each [3,5]-sigmatropic rearrangement is via an allowed, concerted pseudopericyclic transition state. The crystal structures of compounds <b>3</b>, <b>9</b>, and <b>10</b> prefigure these transition states. The selectivity for the [3,5] products increases with an increasing temperature. This unexpected selectivity is explained by a concerted, intramolecular, and pseudopericyclic transition state (<b>TS-5</b>) that forms a tetrahedral interemediate (<i>ortho</i>-acid ester <b>4′</b>), followed by similar ring openings to isomeric phenols, which shifts the equilibrium toward the phenols from the [3,5] (but not the [3,3]) products

Experimental and Computational Studies on the [3,3]- and [3,5]-Sigmatropic Rearrangements of Acetoxycyclohexadienones: A Non-ionic Mechanism for Acyl Migration

Flash vacuum pyrolysis studies of substituted 6-acetoxy-2,4-cyclohexadienones (<b>3</b> and <b>10</b>) from 300 to 500 °C provide strong experimental evidence that direct [3,5]-sigmatropic rearrangements in these molecules are favored over the more familiar [3,3]-sigmatropic rearrangements. The preference holds when the results are extrapolated to 0.0% conversion, indicating that this is a concerted process. Pyrolysis of 6,6-diacetoxy-2-methyl-2,4-cyclohexadienone (<b>9</b>) at 350 °C gives a modest yield of the initial [3,5]-sigmatropic rearrangement product, 2,6-diacetoxy-6-methyl-2,4-cyclohexadienone (<b>11</b>). Qualitative arguments and electronic structure theory calculations are in agreement that the lowest energy pathway for each [3,5]-sigmatropic rearrangement is via an allowed, concerted pseudopericyclic transition state. The crystal structures of compounds <b>3</b>, <b>9</b>, and <b>10</b> prefigure these transition states. The selectivity for the [3,5] products increases with an increasing temperature. This unexpected selectivity is explained by a concerted, intramolecular, and pseudopericyclic transition state (<b>TS-5</b>) that forms a tetrahedral interemediate (<i>ortho</i>-acid ester <b>4′</b>), followed by similar ring openings to isomeric phenols, which shifts the equilibrium toward the phenols from the [3,5] (but not the [3,3]) products

Influence of ethylene-Oxy spacer group on the activity of linezolid: synthesis of potent antibacterials possessing a thiocarbonyl group

The influence of an ethylene-oxy spacer element between the heterocycle and the aromatic ring in linezolid is reported. The introduction of such spacer group generated compounds with inferior antibacterial activity. However, the conversion of the acetamide group present in the linezolid analogues to either thiocarbamate or thioacetamide functionality restored the activity. The synthesis of linezolid analogues possessing the ethylene-oxy spacer group along with SAR studies with different heterocycles and preparation of some thiocarbonyl compounds possessing potent antibacterial property are presented