Human Biotransformation Pathway of Temephos Using an In Silico Approach.

Temephos is an organophosphorothioate (OPT) larvicide used for controlling vectors of diseases such as dengue, chikungunya, and Zika. OPTs require a metabolic activation mediated by cytochrome P540 (CYP) to cause toxic effects, such as acetylcholinesterase (AChE) activity inhibition. There is no information about temephos biotransformation in humans, and it is considered to have low toxicity in mammals. Recent studies have reported that temephos-oxidized derivatives cause AChE inhibition. The aim of this study was to propose the human biotransformation pathway of temephos using in silico tools. The metabolic pathway was proposed using the MetaUltra program of MultiCase software as well as the Way2Drug and Xenosite web servers. The results show the following three essential reactions of phase I metabolism: (1) S-oxidation, (2) oxidative desulfurization, and (3) dephosphorylation, as well as the formation of 19 possible intermediary metabolites. Temephos dephosphorylation is the most likely reaction, and it enables phase II metabolism for glucuronidation to be excreted. However, the CYP-dependent metabolism showed that temephos oxon can be formed, which could lead to toxic effects in mammals. CYP2B6, 2C9, and 2C19 are the main isoforms involved in temephos metabolism, and CYP3A4 and 2D6 have minor contributions. According to computational predictions, the highest probability of temephos metabolism is dephosphorylation and phase II reactions that do not produce cholinergic toxic effects; nonetheless, the participation of CYPs is highly possible if the primary reaction is depleted.

Characterization of acetylcholinesterase from elm left beetle, Xanthogaleruca luteola and QSAR of temephos derivatives against its activity.

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.

Synthesis and crystal structure of new temephos analogues as cholinesterase inhibitor: molecular docking, QSAR study, and hydrogen bonding analysis of solid state.

A series of temephos (Tem) derivatives were synthesized and characterized by 31P, 13C, and 1H NMR and FT-IR spectral techniques. Also, the crystal structure of compound 9 was investigated. The hydrogen bonding energies (E2) were calculated by NBO analysis of the crystal cluster. The activities and the mixed-type mechanism of Tem derivatives were evaluated using the modified Ellman's and Lineweaver-Burk's methods on cholinesterase (ChE) enzymes. The inhibitory activities of Tem derivatives with a P═S moiety were higher than those with a P═O moiety. Docking analysis disclosed that the hydrogen bonds occurred between the OR (R=CH3 and C2H5) oxygen and N-H nitrogen atoms of the selected compounds and the receptor site (GLN and GLU) of ChEs. PCA-QSAR indicated that the correlation coefficients of the electronic variables were dominant compared to the structural descriptors. MLR-QSAR models clarified that the net charges of nitrogen and phosphorus atoms contribute important electronic function in the inhibition of ChEs. The validity of the QSAR model was confirmed by a LOO cross-validation method with q2=0.965 between the training and testing sets.

Evaluación de la resistencia a insecticidas de una cepa de Aedes aegypti de El Salvador / Assessing the insecticide resistance of an Aedes aegypti strain in El Salvador

Evaluar el nivel de susceptibilidad a insecticidas de una cepa de Aedes aegypti procedente de El Salvador y describir los posibles mecanismos de resistencia al temefós...(AU)

Larvicidal efficacy of new formulations of temephos in non-woven sachets against larvae of Aedes aegypti (L.) (Diptera: Culicidae) in water-storage containers.

Three new formulations of temephos (LAVIFOS SG 1%, MOSQ SG 1% and AZAI-SS ZG 1%) were evaluated for larvicidal efficacy against larvae of Aedes aegypti (L.) in water-storage jars under field-simulated conditions. LAVIFOS SG 1% and MOSQ SG 1% are sand granule formulations, whereas AZAI-SS ZG 1% is zeolite granule formulation. Each formulation contained 1% temephos as an active ingredient. Each formulation was packed in a non-woven sachet at quantity of 20 g per sachet and placed in a 200-liter glazed clay jar to obtain a dosage of 1 mg/l (one sachet per jar). Each treatment and control (jar without larvicide) was replicated four times. A concurrent set of treatments and controls were carried out in parallel, but the water in each treated and control jars was removed and refilled weekly. All jars (treatment and control) were challenged weekly by adding 25 third-instar larvae per jar and assessment was made of larval mortality by counting pupal skins one week after the addition of larvae. The three formulations provided complete larvicidal efficacy (100%) for at least 24 weeks post-treatment (the length of this study). In the jars where all the water was removed and refilled weekly, LAVIFOS SG 1%, and MOSQ SG 1% provided complete larvicidal efficacy for at least 24 weeks post-treatment, whereas AZAI-SS ZG 1% showed complete larvicidal efficacy for 16 weeks post-treatment. AZAI-SS ZG 1% still demonstrated a high degree of larvicidal activity (93-99%) from 17 to 24 weeks post-treatment. The present study reveals an excellent residual efficacy of the three new formulations of temephos against larvae of Aedes aegypti in water-storage jars lasting for at least 16 to 24 weeks post-treatment. These new formulations will make the control of DHF vectors in Thailand more cost effective as they are removable and retrievable sachets that can be reused after cleaning the water-storage containers.

Studies on persistence of temephos in sandy loam soil under field and laboratory conditions.

Persistence of temephos was studied in soils under field and laboratory conditions in sandy loam soil to evaluate the effect of moisture and formulations on persistence. The insecticide was applied as 50 EC and 1 % S.G. granules @1 kg a.i. ha-1 on surface of the soil' and residues were determined spectrophotometrically. The soil was fortified separately with dilute emulsion of EC and suspension of granular formulation at 5 ppm level and incubated at different moisture levels at 25:1:1 degrees C for 90 days. The residues of temephos from both the formulations persisted upto 55 days in soil when applied @1 kg a.i. ha(-1). In 40 days 92 and 91.43 per cent temephos was dissipated from soil treated with EC and granular formulations, respectively. There was no leaching or downward movement of the toxicant beyond 7.5 cm. The half-life of temephos under field condition for EC and granular formulations were 18.14 and 20.44 days, respectively. Statistically, there was no significant effect of two formulations of temephos on its persistence. But at three different moisture conditions viz. airdry, field capacity and sub-merged, the difference was significant at 5% level.

Efficacy of two temephos formulations against Chironomus salinarius (Diptera: Chironomidae) in the saltwater lagoon of Venice, Italy.

Two formulations of the organophosphorus insecticide, temephos (Abathion Granulare, 1% AI granular and Tambro Compresse, 2% AI tablet) were evaluated against Chironomus salinarius midge larvae in 50 x 50 m experimental plots in the saltwater lagoon of Venice, Italy. Each formulation was applied at 0.2 and 0.4 kg AI/ha. Abathion Granulare produced 56 to 73% larval reduction at 0.2 kg AI/ha and 69 to 83% reduction at 0.4 kg AI/ha during 3 wk after treatment. Abathion Granulare lost effectiveness at 4 wk after application at both rates. Posttreatment larval reductions resulting from Tambro Compresse applications ranged from 77 to 86% for 3 wk, and 82 to 92% for 4 wk at rates of 0.2 and 0.4 kg AI/ha, respectively. The tablet formulation (Tambro Compresse) gave better control of C. salinarius (magnitude and duration) than the granular formulation (Abathion Granulare) in these evaluations.