Synthesis and antifungal activity of some new pyrido[2,3-d]pyrimidines

Some new pyrido[2,3-d]pyrimidine derivatives (3a-c) were synthesized from 2-amino-5-cyano-6-methoxy-4-(4-methoxyphenyl)pyridine-3-carboxamide. 7-methoxy-5-(4-methoxy phenyl)-4-oxo-2-phenyl-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (3b) and 7-met-hoxy-5-(4-methoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (3c) are used in synthesizing 7a,b, then 8a,b. 7-methoxy-5-(4-methoxyphenyl)-2-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (3a) and 4-hydrazinyl-7-methoxy-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-6-carbonitrile (8b) were condensed with different carbonyl compounds to produce compounds 4, 5, 6 and 9, 10, 11, 12. 3-Methoxy-1-(4-methoxyphenyl)-6-phenyl-7-hydropyridino[2,3-d]1,2,3,4-tetrazolo[1,5-e]pyrimidine-2-carbo-nitrile (13) was synthesized from 8a or 7a. Condensation of 8b with acetophenone to yield 14, which on further reaction gave 15 then 16. 4-Hydrazinyl-7-methoxy-5-(4-methoxyphenyl)-2-phenylpyrido[2,3-d]pyrimidine-6-carbonitrile (8a) also condensed with 4-amino antipyrine giving 17 then 18. Structures of these compounds have been deduced upon the basis of elemental analysis and spectral data. Significant antifungal activities were observed for some of the synthesized compounds

A Charge Simulation Based Computer-Aided Design Implementation of High Voltage Systems Modelling

A Charge Simulation based Computer-Aided Design (CAD) Package which facilitates the development of a charge simulation model for high voltage (HV) systems consisting of a number of electrodes and one or two dielectric regions has been developed. The package calculates the potential and electric field distributions for practical systems. It avoids the necessity for creating individual programs for each system studied by allowing the geometry to be specified using a minimum of entered data. The application of the CAD package to several electrode systems which have analytical solutions is presented. Good agreement, generally within 0.5% was found between the fields produced by the Charge Simulation Method (CSM) and the analytical results. A study of the effect of several parameters controlling the charge simulation model is conducted to determine their optimum ranges. Recommendations for these values are made. It is found that for best simulation, discontinuities in alignment of the simulating charges should be avoided. The rod-plane gap configuration and a HV shielding system are modelled and results are compared with existing literature values. Some simulation quality measures which have not previously been published are given. The computation of fields in a sphere/slab arrangement is conducted and results are presented for a wide range of permittivity ratios and gap spacings. It is found that the maximum electric field strength occurs at the triple point for high dielectric constant unrecessed slabs, and away from the axis for low dielectric constant slabs. Two high. voltage systems which have not been analyzed before using the CSM are studied. One is a rotationally symmetrical triggering electrode configuration. The other is a 22 - shed - V - polymer insulator with a grading ring included to reduce the non-linearity of the voltage distribution. In the triggering electrode system it is found that both the main gap distance and the pilot gap distance affect the potential and the field distributions along the axial main gap line. The location of the maximum electric field changes with both gaps and always occurs on the hemispherical part of the triggering electrode, but not necessarily at the tip. Optimum values for the location and size of the grading ring are determined for the polymer insulator. TI1e simulations of additional complicated three-dimensional field problems with and without axial symmetry using the CSM are presented. A tilted rod-electrode versus ground plane and a hemispherical capped rod electrode versus a grounded plane with another offset hemispherically capped electrode embedded are modelled. A detailed examination of the field distribution for a triggering high voltage system without axial symmetry is also presented

Improvement of dielectric strength and properties of cross-linked polyethylene using nano filler

Power cables insulated with cross-linked polyethylene (XLPE) have been utilized worldwide for distribution and transmission networks. There are several advantages for this type of insulation; it has better electrical, thermal, and mechanical properties compared to other types of insulation in medium and high voltage networks. Many studies aimed to improve the XLPE characteristics through introducing nano fillers to the XLPE matrix. Therefore, this paper investigates the AC (HV) breakdown voltage (dielectric strength) of XLPE after adding nano-sized zeolite (Z) fillers with various concentrations of 1 wt%, 3 wt%, 5 wt% and 7 wt%. The dielectric strength is tested in different temperatures of 30 ⁰C and 250 ⁰C. Additionally, it was tested in low and high salty wet conditions. The dielectric strength of the XLPE has been enhanced by inducing the Z nano filler. The results of the tests were used to train the artificial neural network (ANN) to calculate the dielectric strength of XLPE composites with different concentrations of nano Z filler under different weathering conditions. Thermogravimetric analysis, tensile strength, and elongation at break tests were applied to check the thermal and mechanical characteristics of the samples. Experimental findings show that the optimum concentration of nano Z is 3.64 wt% to enhance the electrical, thermal, and mechanical properties

New insecticide screening platforms indicate that Mitochondrial Complex I inhibitors are susceptible to cross-resistance by mosquito P450s that metabolise pyrethroids

Fenazaquin, pyridaben, tolfenpyrad and fenpyroximate are Complex I inhibitors offering a new mode of action for insecticidal malaria vector control. However, extended exposure to pyrethroid based products such as long-lasting insecticidal nets (LLINs) has created mosquito populations that are largely pyrethroid-resistant, often with elevated levels of P450s that can metabolise and neutralise diverse substrates. To assess cross-resistance liabilities of the Complex I inhibitors, we profiled their susceptibility to metabolism by P450s associated with pyrethroid resistance in Anopheles gambiae (CYPs 6M2, 6P3, 6P4, 6P5, 9J5, 9K1, 6Z2) and An. funestus (CYP6P9a). All compounds were highly susceptible. Transgenic An. gambiae overexpressing CYP6M2 or CYP6P3 showed reduced mortality when exposed to fenpyroximate and tolfenpyrad. Mortality from fenpyroximate was also reduced in pyrethroid-resistant strains of An. gambiae (VK7 2014 and Tiassalé 13) and An. funestus (FUMOZ-R). P450 inhibitor piperonyl butoxide (PBO) significantly enhanced the efficacy of fenpyroximate and tolfenpyrad, fully restoring mortality in fenpyroximate-exposed FUMOZ-R. Overall, results suggest that in vivo and in vitro assays are a useful guide in the development of new vector control products, and that the Complex I inhibitors tested are susceptible to metabolic cross-resistance and may lack efficacy in controlling pyrethroid resistant mosquitoes

Synthesis, antifungal activity and semi-empirical AM1-MO calculations of some new 4-oxo-4H-chromene derivatives

Some new antifungal agents have been prepared through reaction of 4-oxo-4H-chromene-3-carbaldehydes (1a,b) with some active primary amines (2a-e) and amides/thioamides (6a-d) in different conditions. Structures of the products were established on the basis of elemental analysis, IR, 1H NMR, mass spectra and semi-empirical AM1-MO calculations

A high-throughput HPLC method for simultaneous 1 quantification of pyrethroid and 2 pyriproxyfen in long-lasting insecticide-treated nets

Long-lasting insecticide-treated nets (LLINs) play a crucial role in preventing malaria transmission. LLINs should remain effective for at least three years, even after repeated washings. Currently, monitoring insecticides in LLINs is cumbersome, costly, and requires specialized equipment and hazardous solvents. Our aim was to develop a simple, high-throughput and low-resource method for measuring insecticides in LLINs. To extract insecticides, polyethylene-LLIN samples were heated at 85 °C for 45 min in a non-hazardous solvent mix containing dicyclohexylphthalate as an internal standard. The extraction solvent was reduced from 50 to 5 ml using a 0.2 g sample, 90% smaller than the recommended sample size. By optimizing HPLC chromatography, we simultaneously detected pyrethroid and pyriproxyfen insecticides with high sensitivity in LLIN's extract. The method can quantify levels ≥ 0.0015% permethrin, 0.00045% alpha-cypermethrin and 0.00025% pyriproxyfen (w/w) in polyethylene, allowing for insecticide tracking before and after the use of LLINs. This method can be used to assess LLINs with 1% pyriproxyfen (pyriproxyfen-LLIN) or 2% permethrin (Olyset® Net), 1% pyriproxyfen and 2% permethrin (Olyset® Duo), or 0.55% pyriproxyfen and 0.55% alpha-cypermethrin (Royal Gaurd®). One can run 120 samples (40 nets) simultaneously with high precision and accuracy, improving throughput and reducing labour, costs, and environmental impact

Improving the performance of spray operators through monitoring and evaluation of insecticide concentrationsof pirimiphos-methyl during indoor residual spraying for malaria control on Bioko Island

Background: Quality control of indoor residual spraying (IRS) is necessary to ensure that spray operators (SOs) deposit the correct concentration of insecticide on sprayed structures, while also confrming that spray records are not being falsifed. Methods: Using high-performance liquid chromatography (HPLC), this study conducted quality control of the organophosphate insecticide pirimiphos-methyl (Actellic 300CS), during the 2018 IRS round on Bioko Island, Equatorial Guinea. Approximately 60 SOs sprayed a total of 67,721 structures in 16,653 houses during the round. Houses that were reportedly sprayed were randomly selected for quality control testing. The SOs were monitored twice in 2018, an initial screening in March followed by sharing of results with the IRS management team and identifcation of SOs to be re-trained, and a second screening in June to monitor the efectiveness of training. Insecticide samples were adhesive-lifted from wooden and cement structures and analysed using HPLC. Results: The study suggests that with adequate quality control measures and refresher training, suboptimal spraying was curtailed, with a signifcant increased concentration delivered to the bedroom (diference=0.36, P<0.001) and wooden surfaces (diference 0.41, P=0.001). Additionally, an increase in efective coverage by SOs was observed, improving from 80.7% in March to 94.7% in June after re-training (McNemar’s test; P=0.03). Conclusions: The ability to randomly select, locate, and test houses reportedly sprayed within a week via HPLC has led to improvements in the performance of SOs on Bioko Island, enabling the project to better evaluate its own performance. Keywords: Malaria, Indoor residual spraying, Vector control, Quality control, Bioko Islan

Chlorfenapyr metabolism by mosquito P450s associated with pyrethroid resistance identifies potential activation markers

Chlorfenapyr is a pro-insecticide increasingly used in combination with pyrethroids such as a-cypermethrin or deltamethrin in insecticide treated bednets (ITNs) to control malaria transmitted by pyrethroid-resistant mosquito populations. Chlorfenapyr requires P450 activation to produce tralopyril and other bioactive metabolites. Pyrethroid resistance is often associated with elevated levels of chemoprotective P450s with broad substrate specificity, which could influence chlorfenapyr activity. Here, we have investigated chlorfenapyr metabolism by a panel of eight P450s commonly associated with pyrethroid resistance in An. gambiae and Ae. aegypti, the major vectors of malaria and arboviruses. Chlorfenapyr was activated to tralopyril by An. gambiae CYP6P3, CYP9J5, CYP9K1 and Ae. aegypti, CYP9J32. The Kcat/KM value of 0.66 μM−1 min−1 for CYP9K1 was, 6.7 fold higher than CYP6P3 and CYP9J32 (both 0.1 μM−1 min−1) and 22-fold higher than CYP9J5 (0.03 μM−1 min−1). Further investigation of the effect of -cypermethrin equivalent to the ratios used with chlorfenapyr in bed nets (~ 1:2 molar ratio) resulted in a reduction in chlorfenapyr metabolism by CYP6P3 and CYP6K1 of 76.8% and 56.8% respectively. This research provides valuable insights into the metabolism of chlorfenapyr by mosquito P450s and highlights the need for continued investigation into effective vector control strategies