Number Of Organophosphorus Compounds Research Articles

New Enzymatic Targets for Organophosphorus Compounds

It is known that several decarboxylases (aromatic amino acid decarboxylase (AAD), histidine decarboxylase (HD) and glutamate decarboxylase (GD) with different molecular weights catalyze the most important reactions of neurotransmitter and neuromodulator biosynthesis. Pyridoxal phosphate, which serves as a cofactor for these enzymes, is one of organophosphorus compounds (OPC) having a structure similar to highly toxic substances such as warfare agents (WA) sarin, soman, Vx, a substance of type Vx, tabun and the so-called «Novichoks» (A230, A232, A234), as well as pesticides, widely used in agriculture (chlorpyrifos, malathion, glyphosate, mipafox, diazinon, paraoxon), based on their inhibitory effect on cholinesterases (ChE). The purpose of this work was to use computer modeling methods to evaluate the possible binding of various OPC to the catalytic centers of these enzymes instead of a cofactor, as well as similar interactions of decarboxylases (DC) with OPC when the active centers of DC already contain a built-in cofactor. Molecular docking has shown that a number of these OPC can compete with the cofactor for binding to the active centers of DC, and absolutely all the studied OPC (pesticides and WA) create obstacles to embedding the cofactor in the active center of AAD and HD. Such interactions will lead to a decrease in the level of formation of products of the corresponding catalytic reactions (dopamine, serotonin, phenylethylamine, serotonin, γ-aminobutyric acid) and the manifestation of their physiological functions. It was found that in the presence of a cofactor in the active center of the studied DC, the interaction of a number of OPC with the surface of these enzymes near the active center increases and exceeds the strength of the interaction of same enzymes with their typical substrates. At the same time, the maximum interaction that can lead to a significant inactivation of all the studied DC was revealed for the pesticides, while the effect of their presence was lower for WA. One of the highest levels of possible influence on the activity of DC was revealed for chlorpyrifos and diazinon. In total, for DC, the more dangerous substances with high potential neurotoxicity turned out to be not WA at all, including «Novichoks», namely pesticides, which, according to their known effect on ChE, are considered as low-toxic OPC. The conducted new theoretical studies indicate that, firstly, direct experimental studies are required that will confirm the bioinformatics calculations made; secondly, a revision of long-standing approaches to assessing the neurotoxicity of various OPC, based mainly on the use of ChE for these purposes, is necessary; thirdly, it may be necessary to formulate tasks for the development and the use of new systems for the determination of potentially neurotoxic substances, the effect of which will be based on the use of different DC; fourth, to study the possible using DC as a basis for the development of new catalytic enzymatic detoxifiers (antidotes) and CNS regenerators.

Quantum chemical calculations for understanding and predicting toxicity. I. Ab initioMODPOT/VRDDO calculations and electrostatic molecular potential contour maps of organophosphorus anticholinesterases

To demonstrate the feasibility of quantum chemical and other theoretical techniques in the understanding and correlation and then in the prediction of toxicity of a specific class of compounds, the organophosphorus acetylcholinesterase (AChE) inhibitors were chosen since these have relatively clear-cut one-dose acute lethal toxicity, both LD50, and ED50 for the triggering event inhibition of AChE, to serve as well-defined end points. It was possible to identify particular quantum chemical requisites which are related to and predictive of the toxic effects of these molecules. Ab initio calculations were carried out on a number of organophosphorus compounds using our own programs which incorporate a number of desirable options for ab initio calculations on large molecules, including ab initio effective core model potentials (MODPOT), which permit calculations of valence electrons only explicitly, yet accurately, and a charge-conserving integral prescreening evaluation (which we named VRDDO—variable retention of diatomic differential overlap) especially effective for spatially extended molecules. Ab initio calculations were carried out for the two optical isomers of GB: These isomers differ in their toxicities. From the wavefunctions of the optical isomers of GB (calculated relative to internal body-fixed coordinates) the electrostatic molecular potential contour maps (relative to the same absolute space-fixed reference coordinates) were generated in three dimensions around each molecule. These maps indicate vividly the differing stereoelectronic requisites for the different optical isomers and suggest the basis for the difference in their in vivo toxicities. These maps form three-dimensional stereoelectronic holograms and can even be used for reverse image holography to ascertain if new even hypothetical molecules fulfill the requisites. This is related to the first step in the inhibition of AChE, complex formation of the organophosphorus compound with AChE.

The biology and the control of [formula omitted], the tropical warble-fly of Latin America

Dermatobia hominis (Linnaeus, Jr., 1781), the tropical warble-fly, is one of the most important parasites of cattle in Latin America. In addition to cattle, D. hominis infests sheep, pigs, dogs and other mammals including man. D. hominis occurs from Southern Mexico to Northern Argentina. It is estimated that, worldwide, an annual loss of US $200,000,000 in milk, meat and hides is produced by D. hominis Over the centuries the farmers of Latin America have attempted to control the larvae of D. hominis through a variety of methods — manual extraction to the application of chemicals by means of several routes of administration. During the forties and fifties, chlorinated hydrocarbon insecticides, applied as dips or sprays, were used with variable results to control D. hominis . In the sixties and seventies, a number of organophosphorus compounds (ronnel, trichlorphon, ruelene, coumaphos, etc.) were applied using different routes of administration (orally, subcutaneously, intramuscularly, as a spray, or as a “spot-on”). Recently, the results of numerous trials conducted in Paraguay, Brazil and Colombia have shown that ivermectin, a compound characterized by a broad-spectrum of activity against both endo- and ectoparasites of cattle, is fully effective against the three larval stages of D. hominis of cattle.

Reagents and Synthetic Methods 15. Phenyl Dichlorophos-Phate-Dimethylfurmamide Complex. A Modified One-Pot Procedure for Esterification of Carboxylic Acids

Abstract The most frequently used reagents for the one-pot conversion of carboxylic acids into esters have recently reviewed1. A considerable number of organophosphorus compounds have been used extensively as coupling agents. H-J. Liu et al2 described a reagent phenyl dichlorophosphate to activate the carboxy group for synthesis of esters. During our studies directed towards ester synthesis, we became interested in this reagent. We have found that this reagent reacts rapidly with car boxylic acids in the presence of organic tertiary base but the possible intermediate mixed anhydride 5 undergoes a rapid disproportion such as in the case of the phthaloylglycine and 3,5-dinitrobenzoic acid.

Esterase mediated hydrolysis of naphthyl esters, malathion, methoprene, and cecropia juvenile hormone in Culex pipiens pipiens

Larval homogenates of C. p. pipiens degraded α-naphthyl esters, malathion and Cecropia C 18-juvenile hormone, but did not degrade methoprene (isopropyl-11-methoxy-3,7,11-trimethyl-2,4,-dodecadienoate) or hydroprene (ethyl-3,7,11-trimethyl-2,4-dodecadienoate). Hog liver carboxylesterase (E.C.3.1.1.1) degraded all these compounds. On the basis of inhibition data obtained with a number of organophosphorus compounds and p- chloromercuriphenyl sulphonic acid, it is concluded that in C. p. pipiens larvae the esterase hydrolysing α-naphthyl esters and the esterase hydrolysing malathion are similar (B-esterase), and different from the esterase hydrolysing C 18-juvenile hormone (A-esterase).

Photoelectronic spectra and intramolecular intractions in compounds of tetracoordinated phosphorus

1. The photoelectronic spectra of a number of organophosphorus compounds of the type of WPXYZ were obtained and interpreted for the first time. 2. The upper orbital is primarily localized on the pπ-orbitals of the W atom, participates in the bonding of WP, and has little conjugation with the orbitals of the unshared pairs of the substituents. Exceptions are nitrogen-containing substituents. 3. Series of atoms W with respect to decreasing influence on the ionization potentials of the UEP of the substituents XYZ were established: for nonnitrogen-containing substituents OP > SP > P, and for nitrogen-containing substituents SP > OP > P.

The reaction of organophosphorus compounds with hydrolytic enzymes.: The inhibition of horse liver aliesterase

Reaction rate constants were determined for the inhibition of horse liver aliesterase by a number of organophosphorus compounds with the general formula R 1R 2P(O)X at pH 7.7 and 25°. The influence of the structure of the groups R 1 and R 2 on the rate of inhibition is generally very small. The influence of the structure of the group X is much greater. There seems to be, however, only a slight correlation between the rate of the enzyme inhibition and the strength of the P—X bond. In two cases the influence of the temperature on the reaction rate was investigated. In both cases the activation enthalpy was found to be of the same order as in alkaline hydrolysis ; the activation entropy was very much higher than in the hydrolytic reactions. A colorimetric assay method for aliesterase is described.

The decomposition of some organophosphorus insecticides and related compounds in plants

To discover the reactions undergone in plants by organophosphorus compounds of the type used as insecticides the non-ionizable metabolites of several compounds were studied. Octamethylpyrophosphoramide (schradan) is degraded in four species of plants. Low yields of heptamethylpyrophosphoramide and a powerful anticholinesterase are obtained besides ionizable compounds. Oxidation of schradan with hydrogen peroxide and with oxygenated liver slices gives the same products in similar proportions. Thus plants probably degrade schradan by oxidation, producing mainly compounds unstable in water, which are hydrolyzed to substituted phosphoric acids. The powerful anticholinesterase is believed to be hydroxymethyl-heptamethylpyrophosphoramide from its chloroform/water partition coefficient and its yield in plants. It may, however, be octamethylpyrophosphoramidic oxide. Turnip plants also degrade the dimethylamide, monomethylamide,n-butylamide,isopropylamide and ethyl ester of tetramethylphosphorodiamidic acid. As these compounds contain no acidic group which can be removed by hydrolysis after oxidation, high yields of compounds extractable from water by chloroform are obtained. None of the parent compounds are hydrolyzed, nor are butyl or wopropyl groups removed in one step. Probably the dimethylamide is demethylated to the monomethylamide in a way similar to schradan. The physical properties of the degradation products of the other compounds indicate that only the dimethylamido groups are attacked, the other groups being inert.OO-diethylO-ethylthioethyl phosphorothionate is converted in plants to at least three compounds extractable by chloroform. Their structures are unknown.OO-diethylS-ethylthioethyl phosphorothiolate is oxidized rapidly in plants toOO-diethylS-ethylsulphinylethyl phosphorothiolate and another compound of unknown structure, both of which are more stable in plants than the parent compound. The same products are formed by the action of hydrogen peroxide on the parent compound. Thus a number of organophosphorus compounds are degraded by oxidation in plants. There is no evidence that their hydrolysis is catalyzed.