Abstract:Vinylogous Acyl Compounds. XXI. 1H‐N.M.R. Spectroscopic Investigations on 3‐Chloropropen‐iminium Salts
The 1H‐n.m.r. data of a series of 3‐aryl‐3‐chloropropeniminium salts 5 are reported. From the vicinal coupling constants 3J(H1, 2H) as well as from NOE difference spectra follows that salts of type 5 have throughout E(1,2)Z(2,3) configuration.
“…N , N -Dimethylamino-3,3-diphenylpropylamine hydrochlorides 18 and 19 were prepared by treatment of the appropriate acetophenone with phenylmagnesium bromide, subsequent Vilsmeier formylation of the 1,1-diphenylethanol, and catalytic hydrogenation of the resulting 3,3-diphenyl-2-propeniminium salt (Scheme ). 3 …”
Cationic amphiphilic drugs have a propensity to interact with biological interphases. This study was designed to gain more insight into the molecular properties of catamphiphilic drugs which govern this type of interaction. A series of phenylpropylamine model compounds were synthesized in which modifications were incorporated at the aromatic part of the molecule. The replacement of (45)Ca(2+) from phosphatidylserine monolayers served to monitor drug binding to the phospholipid. The influence on the phase-transition temperature of liposomes of dipalmitoylphosphatidic acid was measured to assess the perturbing action of the drugs on the structural organization of phospholipid assemblies. The antiarrhythmic activity of the compounds was determined in Langendorff preparations of guinea pig hearts to assess the membrane-stabilizing action. Quantitative structure-activity relationship (QSAR) models for these endpoints were developed using both intra- and intermolecular QSAR descriptors. Intermolecular membrane-interaction descriptors were derived from molecular dynamics simulations of the compounds in a model phospholipid monolayer. QSAR models were derived for all endpoints using partial least-squares regression (PLS) and a genetic algorithm tool, the genetic function approximation (GFA). Membrane-interaction descriptors appear to be of a particular importance in explaining the influence of the compounds on the phase-transition temperature of DPPA liposomes, while the other endpoints can be adequately modeled by intramolecular descriptors. The calcium-displacing activity at phosphatidylserine monolayers is governed by the electrostatic properties of the compounds. Measures of lipophilicity and molecular size are of particular importance for antiarrhythmic activity. Possible improvements to both the molecular modeling and the applied computational protocol of membrane-solute systems are identified and discussed.
“…N , N -Dimethylamino-3,3-diphenylpropylamine hydrochlorides 18 and 19 were prepared by treatment of the appropriate acetophenone with phenylmagnesium bromide, subsequent Vilsmeier formylation of the 1,1-diphenylethanol, and catalytic hydrogenation of the resulting 3,3-diphenyl-2-propeniminium salt (Scheme ). 3 …”
Cationic amphiphilic drugs have a propensity to interact with biological interphases. This study was designed to gain more insight into the molecular properties of catamphiphilic drugs which govern this type of interaction. A series of phenylpropylamine model compounds were synthesized in which modifications were incorporated at the aromatic part of the molecule. The replacement of (45)Ca(2+) from phosphatidylserine monolayers served to monitor drug binding to the phospholipid. The influence on the phase-transition temperature of liposomes of dipalmitoylphosphatidic acid was measured to assess the perturbing action of the drugs on the structural organization of phospholipid assemblies. The antiarrhythmic activity of the compounds was determined in Langendorff preparations of guinea pig hearts to assess the membrane-stabilizing action. Quantitative structure-activity relationship (QSAR) models for these endpoints were developed using both intra- and intermolecular QSAR descriptors. Intermolecular membrane-interaction descriptors were derived from molecular dynamics simulations of the compounds in a model phospholipid monolayer. QSAR models were derived for all endpoints using partial least-squares regression (PLS) and a genetic algorithm tool, the genetic function approximation (GFA). Membrane-interaction descriptors appear to be of a particular importance in explaining the influence of the compounds on the phase-transition temperature of DPPA liposomes, while the other endpoints can be adequately modeled by intramolecular descriptors. The calcium-displacing activity at phosphatidylserine monolayers is governed by the electrostatic properties of the compounds. Measures of lipophilicity and molecular size are of particular importance for antiarrhythmic activity. Possible improvements to both the molecular modeling and the applied computational protocol of membrane-solute systems are identified and discussed.
Tetrazole Compounds. 4. Alkylation of 1‐Aryl‐5‐(2‐dimethylamino‐vinyl)‐1 H‐tetrazoles
Alkylation of 1‐aryl‐5‐(2‐dimethylamino‐vinyl)‐1 H‐tetrazoles 1 with dialkyl sulfates or alkyl iodides yields mainly 4‐alkyl‐1‐aryl‐5‐(2‐dimethylamino‐vinyl)‐1 H‐tetrazolium salts which can be isolated free from isomers by separation as perchlorates 2. The reaction proceeds with retention of the E configuration of the vinyl group. In contrast to 1 the methyl groups of the dimethylamino substituent in 2 are magnetically non‐equivalent indicating restricted rotation of this residue. On heating 2 with aqueous mineral acids the dimethylaminovinyl moiety undergoes degradation to a methyl group affording 4‐alkyl‐1‐aryl‐5‐methyl‐1 H‐tetrazolium salts 4, the structure of which was confirmed by independent synthesis. With hot aqueous alkali hydroxide 2 reacts under ring cleavage to give aryl azide. — 1H n.m.r. and u.v. spectroscopic data of the tetrazolium salts 2 and 4 are reported.
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