Photosynthesis inhibition by phenylureas: a QSAR approach.

A series of 21 N'-phenyl-N,N-disubstituted ureas was studied for its effects on thylakoidal electron transfer, photophosphorylation, and photosynthetic O2 evolution in class A chloroplasts and leaf fragments. The concentrations of test compounds that produced 50% inhibition of PS II electron transfer and of photosynthesis in class A chloroplasts were highly correlated. Urea derivatives with a N-lipophilic substituent (three or four carbon chains) were uncouplers (i.e., neburon uncoupled by 50% at 7 microM). The efficiency of inhibition of PS II electron transfer was increased by the presence of a 3,4-disubstitution of the phenyl ring. The presence of N-lipophilic substituents was necessary for there to be an inhibitory effect, but an increase in the length of the chain lowered the activity. The best QSAR equations that described the inhibitory activity of the whole series were obtained when using 1 chi v or MR (probably representing dispersion forces) associated with parameters that described the steric hindrance at the p position of the phenyl ring (Verloop's B2(4), B4(4)) or in its neighborhood (such as the angular parameter A4). The inhibitory efficiency of the phenylurea series on wheat and spinach pieces led to the conclusion that some extrachloroplastic factors seemed to limit the accessibility of the D1-protein target.

[QSAR analysis of the toxicity of a series of pyridines related to the mushroom toxin orellanine: comparison of the results obtained with physico-chemical, steric and quantal parameters]. / Analyse QSAR de la toxicité d'une série pyridinique apparentée à la toxine fongique orellanine: comparaison des résultats obtenus à l'aide de paramètres physico-chimiques, stériques et quantiques.

To complete a preceding work, we have made a QSAR study of a series of mono- or bi-pyridines, aminoxidized or not, wearing diverse substituents and related to the mushroom toxin orellanine. For the description of these molecules, we tried several sterical parameters which we have recently defined (sigma D and sigma S) or which we define here (D3) as well as physical and quantal parameters calculated with the CNDO/2 method, besides the parameter of hydrophobicity log P. Among the regression equations obtained, three have a correlation coefficient greater than 0.96, which is very high, taking into account the nature of the biological response (LD50). The importance of the hydrophobicity and of the size of the molecules in the expression of their toxicity is confirmed, as well as the particularity of orellanine in the series studied.

[Polynuclear neutrophils and periodontal diseases]. / Les polynucléaires neutrophiles et les maladies parodontales.

Periodontal diseases are bacteria associated diseases. The host response to these bacteria is critical. Non specific defense mechanisms are mainly mediated by the polymorphonuclear neutrophil which out numbers the others crevicular leucocytes. This paper reviews the beneficial and possible detrimental aspect of the neutrophil functions.

Uncoupling properties of a chlorophenol series on Acer cell suspensions: a QSAR study.

A series of 22 chlorinated phenols was investigated for their uncoupling effect on Acer cell suspensions. All the studied molecules were able to enter the cell and had instantaneous uncoupling properties: pentachlorophenol was the best uncoupler of the series (the concentration required to uncouple by 50% was 5 microM), being 200-fold more effective than 3-Cl or 2-Cl phenol, which were the molecules having the lowest activity. The QSAR (quantitative structure-activity relationship) study gave good equations for the uncoupling activity with the steric and electronic parameters taken together. The electronic parameter sigma was always present with a positive sign, whereas A, the angular parameter, was always negative. The general steric parameters (sigma D, 1 chi v, MR) represented the third component of the equations and each of them played practically an equivalent role. Equations of quality (r greater than 0.9), which were statistically significant, could be obtained after four compounds in F (2,5-diCl phenol; 2,4,5-triCl phenol; 2,4-diCl 6-NO2 phenol; and 2-Cl 4,6-diNO2 phenol) had been excluded and when quadratic terms were not present. The best equation (r = 0.940) was obtained with sigma D, A, and sigma 1. The comparison of the significant equations with those previously established with isolated mitochondria led us to suppose that there were no selective limiting steps during the transfer of the studied compounds from the reaction medium to mitochondria inside the cells. The major difference between the uncoupling results obtained with isolated mitochondria and with cells was that the concentrations needed to uncouple by 50% were always higher in cells.

Effects of chlorophenols on isolated class A chloroplasts and thylakoids: a QSAR study.

A series of 22 chlorinated phenols was studied for their effects on photosynthesis of isolated chloroplasts. Each chlorophenol was an uncoupler, but the uncoupling activity depended upon substitution. The di-, tri-, or pentachloro substitution greatly enhanced the uncoupling activity. However, 2,6 substitution was not favorable to the uncoupling activity. Fifty percent uncoupling of photophosphorylations was obtained for concentrations between 4 mM for phenol itself, and 20 microM for pentachlorophenol. The quantitative structure-activity relationship (QSAR) study indicated a good relationship between, on the one hand, steric and electronic parameters, and, on the other hand, the uncoupling activity. In such equations, the A parameter describing ortho-substitution, always presented a negative sign. No good equation could be obtained with only log P and sigma. At concentrations which generally induced uncoupling, the chlorinated phenols inhibited the electron transfer in thylakoids. Di, tri, or penta substitution by chlorine enhanced the inhibition. A good relation appeared between this effect and the steric parameters MR and A. The study of isolated class A chloroplasts demonstrated that the uncoupling and the inhibition of the electron transfer in thylakoids could explain the effect of the chlorophenols on the whole photosynthetic mechanism. The effects of phenols on isolated chloroplasts were compared to those obtained with the same series on mitochondria. To explain the differences between QSAR equations, on the one hand for chloroplasts, and, on the other hand, for mitochondria, we suggested a selective binding of chlorinated phenols to proteins of the biological membranes.

Derivatives of 3-hydroxy acids: 4-oxo-1,3-dioxanes and 2-oxetanones.

Original 4-oxo-1,3-dioxanes and 2-oxetanones have been prepared from 3-hydroxy acids. Some pharmacological data and results from agricultural screenings are given.

Effect of chlorophenols on isolated plant mitochondria activities: a QSAR study.

Twenty-three chlorinated monophenols were investigated for their uncoupling and inhibitory properties on plant mitochondria. All the studied compounds had uncoupling properties but their activity was submitted to quantitative changes from 1- to 400-fold, according to the substitution. They also had inhibitory properties on the electron transfer at a level located upstream to the quinone pool. Three inhibitory types could be recognized: (a) chlorophenols inhibiting similarly the oxidation of every type of substrate (NADH, succinate, alpha-ketoglutarate, at pH 7.2; malate, at pH 7.5), (b) chlorophenols inhibiting first complex I, and (c) chlorophenols inhibiting first complex II. In this last case, the presence of substituents at the 2 and 6 positions increases selectively the inhibition of succinate oxidation. A quantitative structure activity relationship (QSAR) study was undertaken and showed that a good correlation appeared between the steric parameter, 1 chi v, and the inhibitory properties with NADH as substrate. This result could be explained by the binding of the chlorinated phenols with NADH dehydrogenase whose position, on the external surface of the mitochondrial membrane, is favorable to good accessibility of the xenobiotic. Equations for inhibitory properties with other substrates were clearly different. The relation between the uncoupling activity and the studied parameters was more complex but a good correlation occurred with the steric parameter (sigma D, A) and the electronic parameter sigma. Neither log P nor sigma alone gave equations of good quality. These results suggest a competition between the chlorophenol mobility in the inner membrane, necessary for uncoupling, and binding with different proteins in the same membrane on which the inhibitory activity is dependent.

A quantitative structure-activity relationship study on substituted pyridines as a contribution to the knowledge of the toxic effects of orellanine, a toxin from the mushroom Cortinarius orellanus.

Quantitative structure-activity relationships are established based upon the toxicity of 21 substituted pyridines. They are used as a predictive tool to calculate the toxicity of orellanine, a toxin from the mushroom Cortinarius orellanus (Fries). The actual toxicity of orellanine is quite different from the values calculated based upon the postulated bipyridine structure. The exact structure of orellanine may be questioned. However, our results show that even slight variations of the substituents of pyridines may cause dramatic changes of toxicity.

Toxicity and QSAR of chlorophenols on Lebistes reticulatus.

The 24-h toxicity of 20 substituted chlorophenols upon Lebistes reticulatus has been determined. The biological results have been tentatively connected with several of the following six parameters: logarithm of the octanol-water partition coefficient (log P); index of molecular connectivity (1 chi v); molecular refraction (RM); perimeter of the efficient section of the molecule (sigma D); constants of HAMMET (sigma); and melting point (F). A correlation is achieved using sigma D and sigma D2 with a correlation coefficient of 0.943.

[QSAR and aromatic series: proposals for steric parameters]. / QSAR et séries aromatiques: propositions de paramètres stériques.

A steric parameter, sigma D (the perimeter of the efficacious section of a molecule in the same plane as the aromatic ring) is proposed. A comparison between sigma D, RM and 1Xv in six different series of aromatic molecules was made. In most cases the new parameter is preferable.

[Application of Verloop parameters. Comparison with other steric parameters and problems of choice of parameter]. / Application des paramètres de Verloop. Comparaison avec les autres paramétres steriques, problemes de leur choix.

Verloop's steric parameters. L, B1, B2, B3, B4, were tested in five groups of molecules, generally successfully, These were compared with classical steric parameters: indices of molecular connectivity, Taft's Es parameter, Van der Waals radii and molecular refraction. Some rules have been developed to decide which parameters to use for various types of substituent.

GABA transaminase inhibitors.

In summary, several branched-chain fatty acids appeared to be competitive inhibitors of GABA-T and non-competitive inhibitors of SSADH. These compounds produce an increase in brain GABA level, and for two of these it was shown that the increase differs among various brain areas. An increase of GABA cannot be obtained by inhibition of SSADH. The increase in brain GABA seems to correlate with the anticonvulsant activity of branched-chain fatty acids.