Geometry of lidocaine-like molecules: 2. Crystal structures of 2-benzyl-2-(1-piperidinyl)-N-(2,6-dimethylphenyl) acetamide and its hydrochloride hemihydrate

The title compounds both crystallize in the monoclinic space group P2₁ (Z = 4), with a = 12.574(1), b = 9.653(1) c = 16.483(1) Å, and = 91.84(1)° for the free base and a = 10.991(2), b = 16.864(3), c = 12.030(2) Å, = 99.35(3)° for the hydrochloride. The most important factors affecting conformation of the molecules are: ortho-substitution of the benzene ring in the acetanilide system and substitution of the C atom. Surprisingly, the conformation does not depend on the protonation state of the amine nitrogen atom, which greatly affects packing and hydrogen bonding patterns in the crystalline state. The conformation in which the H atom of the charged amine group is in a trans position to the main backbone of the molecule, is probably responsible for the antiarrhythmic activity, while a gauche conformation promotes local anaesthetic action. The separation of the lipophilic (xylidine) and amine groups, being two important pharmacophores, equals about 4.7 Å in the studied compounds and other structures comprising the amino-2,6-dimethyl-acetanilide system.     

Structure of 1,4-dihydro-1-ethyl-4-iminecinnoline-3-carboxylic acids, classical isosters of quinolone antibacterials: Crystal structures of hydrochlorides of 7-chloro and 7-methyl derivatives

Crystal structures of hydrochlorides of 7-chloro- and 7-methyl-4-iminecinnoline analogs of antibacterial quinolones have been determined by X-ray diffraction methods. The cell parameters for the 7-chloro (1) analog in the space group P2₁/c are a = 9.061(1), b = 19.062(1), c = 7.310(1)Å, = 104.92(1)°, Z = 4, and D _calc = 1.569 g/cm³ and for the 7-methyl (2) analog in the space group P are a = 7.277(5), b = 9.080(5), c = 10.058(5) Å, = 106.10(1), = 102.38(1), = 90.18(1)°, Z = 2, and D _calc = 1.429 g/cm³. Despite geometrical equivalency of methyl and chlorine and some resemblance of their packings, the crystal structures are not isostructural. Each compound forms a strong intramolecular hydrogen bond between protonated 4-imine (a donor) and 3-carboxylic (an acceptor) groups. Compounds with a similar bond, but with reversed functionality and orientation of the 3-carboxylic group, form common quinolones, being mostly 4-oxoquinoline-3-carboxylic acids. The difference should exclude chemical affinity of 4-imine analogs to the guanine base of a bacterial DNA in DNA-gyrase complex, as proposed by Shen et al. ² for 4-oxoquinoline-3-carboxylic acids showing antibacterial activity. Also the free acidic function of a carboxyl group may significantly lower permeability of 4-imine-3-carboxylic analogs of quinolones. Surprisingly, they have demonstrated antibacterial activity comparable with that of nalidixic acid.     

Absolute free energies of binding of peptide analogs to the HIV-1 protease from molecular dynamics simulations

The constants of binding of five peptide analogs to the active site of the HIV-1 aspartic-protease are calculated based on a novel sampling scheme that is efficient and does not introduce any approximations in addition to the energy function used to describe the system. The results agree with experiments. The squared correlation coefficient of the calculated vs. the measured values is 0.79. The sampling scheme consists of a series of molecular dynamics integrations with biases. The biases are selected based on an estimate of the probability density function of the system in a way to explore the conformational space and to reduce the statistical error in the calculated binding constants. The molecular dynamics integrations are done with a vacuum potential using a short cutoff scheme. To estimate the probability density of the simulated system, the results of the molecular dynamics integrations are combined using an extension of the weighted histogram analysis method (C. Bartels, Chem. Phys. Letters 331 (2000) 446-454). The probability density of the solvated ligand-protein system is obtained by applying a correction for the use of the short cutoffs in the simulations and by taking into account solvation with an electrostatic term and a hydrophobic term. The electrostatic part of the solvation is determined by finite difference Poisson-Boltzmann calculations; the hydrophobic part of the solvation is set proportional to the solvent accessible surface area. Setting the hydrophobic surface tension parameter equal to 8 mol(-1) K(-1) A(-2), absolute binding constants are in the muM to nM range. This is in agreement with experiments. The standard errors determined from eight repeated binding constant determinations are a factor of 14 to 411. A single determination of a binding constant is done with 499700 steps of molecular dynamics integration and 4500 finite difference Poisson-Boltzmann calculations. The simulations can be analyzed with respect to conformational changes of the active site of the HIV-1 protease or the ligands upon binding and provide information that complements experiments and can be used in the drug development process.     

Synthesis of phosphinic and phosphoric analogs of aspartic acid

Approaches to the synthesis of 1-amino- and 2-amino-2-carboxyethylphosphinic and-phosphoric acids have been studied. A convenient method for the preparation of phosphinic acids is the reactions of ethyl diethoxymethylphosphonite with ethyl acetamidomethylenemalonate and ethyl 2-acetamidoacrylate.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 2066–2069, August, 1996.     

Exploring potential energy hypersurfaces for triple symmetric inversion in 3-azabicyclo[3.3.1]nonan-9-one and its N-methyl derivative

The potential energy hypersurfaces for the triple inversion, from chair to boat and α to β conformations, are explored theoretically in 3-azabicyclo[3.3.1]nonan-9-one and its N-methyl derivative, by using ab initio quantum-mechanical calculations. Both compounds are precursors of rigid analogs of the potential GABA_A and GABA_B receptor antagonists. In contrast to results from semiempirical calculations, the chair–chair β conformers are found to be, by far, the most stable structures for both the nonmethylated and N-methylated compounds. The inversion barriers are found to be relatively low, so that the conformers could be expected to exist in thermodynamic equilibrium at room temperature. A population analysis reveals, however, that, in the ab initio approach, the molecules seem to exist practically only in the chair–chair–β conformation. The theoretical results compare well with the available experimental data. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1567–1574, 1998     

新型血管紧张素转化酶抑制剂: 氮杂三肽类似物的合成及结构活性关系

设计与合成一系列氮杂三肽类似物, 测定了氮杂三肽类似物对血管紧张素转化酶的体外抑制活性, 探讨了它们的结构与抑制活性之间的关系, 结果表明氮杂丙氨酸是丙氨酸很好的替代物。     

Synthesis of optically active analogs of α-tocopherol based on (S)-(+)-dihydromyrcene

New optically active analogs of α-tocopherol (vitamin E) were synthesized starting from enantiomerically enriched (ee≈50%) (S)-(+)-dihydromyrcene. Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1631–1634, September, 2000.     

Synthesis of derivatives of 2-hydroxyimino- and 2-alkoxyimino-3-(acylhydrazono)butanoic acids

Esters andN-methylamides of 2-hydroxyimino- and 2-alkoxyimino-3-(acylhydrazono)-butanoic acids were synthesized by condensation of acyl hydrazines with the corresponding alkyl 2-hydroxyimino- and 2-alkoxyimino-3-oxobutanoates andN-methyl-2-methoxyimino-3-oxobutanamide. The compounds obtained are analogs of strobilurins, fungicidal antibiotics. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 499–504, March, 1999.     

Partialsynthetische Aristolochiasäuren und Analoge 4. Mitt.: 3,4,5,6-Tetramethoxy-1,8-dinitrophenanthren, 3,4,5,6-Tetramethoxy-8-nitro- und 3,4,5,6-Tetramethoxy-8,10-dinitrophenanthren-1-carbonsäuren

An aporphine alcaloid of the bulbocapnine-type (isocorydine) was used for the synthesis of aristolochic acid analogs. By degradation and nitration of the reaction product three new compounds, a dinitrophenanthrene, a nitro- and a dinitrophenanthrene acid were obtained and their structures were established.

     

HPLC enantioseparation of phenylalanine analogs by application of (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester as a new chiral derivatizing agent

Summary The indirect stereochemical resolution of the enantiomers of phenylalanine analogs was studied by high-performance liquid chromatographic methods. The resolution was performed by applying pre-column derivatization with (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester, (S)-NIFE, as a new chiral derivatizing agent. Its applicability is demonstrated by the derivatization and separation of a series of ring-and α-methyl-substituted phenylalanines and phenylalanine amides, and especially by the derivatization of sterically hindered, less reactive α-methyl-substituted phenylalanine analogs. The diastereomeric, derivatives produced were separated by reversed-phase high-performance liquid, chromatography. The conditions of both derivatization and separation were optimized. The method described offers good enantioselectivity for various chiral amino compounds derived from chemo-enzymatic processes.