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1.
Pestic Biochem Physiol ; 157: 122-137, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31153459

ABSTRACT

Novel phospho guanidine and phospho pyrazine derivatives were synthesized and characterized by 31P, 13C, 1HNMR and IR spectroscopy to obtain novel and human-safe insecticides. Compound 35 [(C4H4N2NH)2P(O)(C6H6)] was investigated by X-ray crystallography. The inhibitory effects of synthesized compounds were evaluated on human and insect acetylcholinesterase (AChE) using in vitro Ellman method. A few of these compounds, which had low human toxicity, were selected for assessing the killing effects (in vivo) on the elm leaf beetle (X.luteola). The in vitro and in vivo results indicated that compounds bearing both phosphoryl groups and aromatic systems were found to possess a good selectivity for the inhibition of insect AChE over human AChE; up to 550-fold selectivity was achieved for compound 19. Docking studies were performed to explain reasons for the selective behavior of AChE inhibitors. Additionally, the quantitative structure-activity relationship (QSAR) and density functional theory (DFT) results of AChEs demonstrated that the size, shape, dipole moment, and ability to form hydrogen bond played the main role in both models. In addition, the aromatic π - π interactions and charge of the amide nitrogen had a major effect on insecticidal activity of the compounds. The present research can be helpful to gain a better understanding of the interactions between the insect AChE and its inhibitors and introduces compounds which are capable of becoming human-safe insecticides.


Subject(s)
Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/chemical synthesis , Guanidines/chemistry , Pyrazines/chemistry , Acetylcholinesterase/metabolism , Animals , Cholinesterase Inhibitors/pharmacology , Coleoptera/drug effects , Humans , Insecticides/chemical synthesis , Insecticides/chemistry , Insecticides/pharmacology , Molecular Docking Simulation , Molecular Structure , Quantitative Structure-Activity Relationship , Structure-Activity Relationship
2.
Pestic Biochem Physiol ; 136: 12-22, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28187825

ABSTRACT

Insect acetylcholinesterase (AChE) is the principal target for organophosphate (OP) and carbamate (CB) insecticides. In this research, an AChE from third instar larvae of elm left beetle, Xanthogaleruca luteola was purified by affinity chromatography. The enzyme was purified 75.29-fold with a total yield of 8.51%. As shown on denaturing SDS-PAGE, the molecular mass of purified AChE was 70kDa. The enzyme demonstrated maximum activity at pH7 and 35°C. Furthermore, a series of temephos (Tem) derivatives with the general structure of P(O)XP(O) (1-44) were prepared, synthesized and characterized by 31P, 13C, 1H NMR and FT-IR spectral techniques. The toxicity of 36 new Tem derivatives was screened on the third instar larvae and the compound compound 1,2 cyclohexane-N,N'-bis(N,N'-piperidine phosphoramidate) exhibited the highest insecticidal potential. The method of kinetic analysis is applied in order to obtain the maximum velocity (Vmax), the Michaelis constant (Km) and the parameters characterizing the inhibition type for inhibitors with >75% mortality in preliminary bioassay. The inhibition mechanism was mixed and inhibitory constant (Ki) was calculated as 4.70µM-1min-1 for this compound. Quantitative structure-activity relationship (QSAR) equations of these compounds indicated that the electron orbital energy has major effect on insecticidal properties.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Coleoptera/enzymology , Insect Proteins/metabolism , Insecticides/pharmacology , Temefos/pharmacology , Acetylcholinesterase/isolation & purification , Animals , Insect Proteins/isolation & purification , Insecticides/chemistry , Larva/enzymology , Quantitative Structure-Activity Relationship , Temefos/analogs & derivatives , Temefos/chemistry
3.
J Agric Food Chem ; 61(28): 6776-85, 2013 Jul 17.
Article in English | MEDLINE | ID: mdl-23796225

ABSTRACT

Twelve new compounds of acephate (Ace) analogues were synthesized and characterized by (31)P, (13)C, and (1)H NMR and IR spectroscopy. The probable insecticide potential of these compounds as well as 23 previously prepared molecules with a general skeleton of RC(O)-NH-P(O)X1X2 was predicted by PASS software. Docking analysis showed that hydrophobic interaction and hydrogen bonding were created between the functional groups of Ace derivatives and the receptor sites of acetylcholinesterase. PCA-QSAR indicated that the electronic descriptors are dominated in comparison with the structural descriptors. The experimental-QSAR (R(2) = 0.903 and VIF < 2.997) and DFT-QSAR (R(2) = 0.990 and VIF ≤ 10) models clarified that the net charge of functional groups contributes an important function in an inhibition mechanism. Validity and integrity of this model were confirmed by the LOO cross-validation method with q(2) = 0.940 and low residuals between the training and testing sets. The correlation matrix of DFT-QSAR model confirmed the molecular docking results.


Subject(s)
Acetylcholinesterase/metabolism , Binding Sites , Molecular Docking Simulation , Organothiophosphorus Compounds/chemistry , Phosphoramides/chemistry , Quantitative Structure-Activity Relationship , Chemical Phenomena , Cholinesterase Inhibitors/chemistry , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Insecticides/chemistry , Linear Models , Models, Molecular
4.
J Enzyme Inhib Med Chem ; 23(4): 556-61, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18666002

ABSTRACT

Phosphoramido acid esters (CH(3))(2)NP(O)X(p-OC(6)H(4)-CH(3)) (containing P-Cl (1), P-O (2), P-F (3), P-CN (5), and P-N (4,6) bonds, X for 2, 4 and 6 is OCH(3), (C(2)H(5))(2)N and morpholin) have been synthesized to investigate the structure-activity study of AChE enzyme inhibition, through the parameters logP, delta(31)P and IC(50). After their characterization by (31)P, (31)P{(1)H}, (13)C, (1)H NMR, IR and mass spectroscopy, the parameters logP and delta(31)P ((31)P chemical shift in NMR) were used to evaluated the lipophilicity and electronical properties. The ability of compounds to inhibit human AChE was predicted by PASS software (version 1.193), and experimentally evaluated by a modified Ellman's assay.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Organophosphorus Compounds/chemistry , Acetylcholinesterase/chemistry , Cholinesterase Inhibitors/pharmacology , Crystallography, X-Ray , Esters/chemistry , Esters/pharmacology , Humans , Kinetics , Structure-Activity Relationship
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