Lipophilicity pyrethroid insecticides

The compounds featured in Table 1.1 are considered briefly here. Pyrethrins are lipophilic esters that occur in Chrysanthemum spp. Extracts of flower heads of Chrysanthemum spp. contain six different pyrethrins and have been used for insect control (Chapter 12). Pyrethrins act upon sodium channels in a manner similar to p,p -DDT. The highly successful synthetic pyrethroid insecticides were modeled on natural pyrethrins. 

The structures of some pyrethroid insecticides are shown in Figure 12.1. They are all lipophilic esters showing some structural resemblance to the natural pyrethrins. They can all exist in a number of different enantiomeric forms. Permethrin, cypermethrin, and deltamethrin, for example, all have three asymmetric carbon atoms... 

Scott, R.C. and J.D. Ramsey (1987). Comparison of the in vivo and in vitro percutaneous absorption of a lipophilic molecule (cypermethrin, a pyrethroid insecticide), J. Invest. Dermatol, 89, 142-146. 

Some veterans were exposed to these pesticides by intentional application, but because many exposures were accidental, it has been difficult to assess pesticide exposure accurately and therefore a topical dose in exposed veterans. Permethrin was intentionally impregnated into the soldier s uniform fabric at a concentration of 0.125 mg/cm to help control insect infestation while in the dessert. This pyrethroid insecticide consists of four different isomers (Figure 9.1), with the cis isomer more toxic than the trans isomer. Permethrin is a large moleeule (MW = 391.3) and has a log octanol-water partition coefficient of 6.5, which suggests that it could readily partition from the uniform into the lipophilic stratum comeum layer of the soldier s skin. With a transfer rate of 0.49% per day of permethrin from the fabric to skin, the daily dose was estimated to be 6.8 x 10" mg/kg/day (National Research Council... 

In the last century, the development of organophosphorus, carbamate, and organochloride insecticides was followed by synthetic pyrethroids. As a result, pyrethroids are now used frequently in the domestic milieu. Pyrethroid insecticides are synthetically derived from the molecular structure or sharing the same mechanism of action of natural pyrethrins that have broader spectmm of activity, more stability, and residual activity (persists longer than that of natural pyrethrins) and include the following allethrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flumethrin, fluvalinate, tau-fluvalinate, and permethrin (see structure in Fig. 137.2). They are lipophilic compounds and generally of low acute oral toxicity to mammals but are very toxic to aquatic organisms. When synthetic pyrethroids are administered to mammals parenterally, the synthetic pyrethroids are neurotoxic. 

Scott RC, Ramsay JD (1987) Comparison of the in vivo and in vitro percutaneous absorption of a lipophilic molecule (cypermethrin, a pyrethroid insecticide). J Invest Dermatol 89 142-146 Serat WF (1973) Calculation of a safe reentry time into an rachaid treated with a pesticide chemical which produces a measiuable physiological response. Arch Environ Contam Toxicol 1 170-181 Serat WF, Bailey JB (1974) Estimating the relative toxicologic potential of each pesticide in mixture of residues on foliage. Bull Environ Contam Toxicol 12 682-686 Serat WF, Mengle DC, Anderson HP, Kahn E (1975) On the estimation of worker entry intervals into pesticide treated fields with and without the exposure of human subjects. Bull Environ Contam Toxicol 13 506-512... 

Taking the pyrethroids, apart from fenvalerate, they are solids with low water solubility, marked lipophilicity, and low vapor pressure. Fenvalerate is a viscous liquid with an appreciable vapor pressure. Being esters, the pyrethroids are subject to hydrolysis at high pH. They are sufficiently stable to heat and light to be effective insecticides in the field. 

Schemes I-IV illustrate the syntheses of the pyrazole pyrethroids reported here. In scheme-I, condensation of ethyl ethoxy-methyl eneacetoacetate (3) (6) and ethyl ethoxymethylenetrifluoro-acetoacetate (4) (7) with phenyl hydrazine in glacial acetic acid initially at room temperature followed by heating at reflux gave the pyrazolecarboxylates 5 (8) and 6 in yields of 43 and 70%, respectively. Reduction with lithium aluminum hydride gave the alcohols 7 and 8 which were then allowed to react with the DV-acid chloride in Et3N/THF to give the pyrethroid isomer mixtures 9 (2) and 10 (4 3 trans/cis) in 80-85% yield from the carboxylates. Pyrethroid 10 was prepared to determine how the increased lipophilicity over 9 affected insecticidal activity.

A number of studies have examined the role of various factors such as volatility and solubility on the efficacy of soil insecticides.(14) While the soil itself affects the efficacy of soil insecticides, the major determinate of biological activity is the amount of organic material in the soil.(15) Simmons, Lew, Silverman and Ali studied the effect of pyrethroids and some commercial insecticides on 3 instar southern com rootworm larva (Diabrotica undecimpunctata howardii).(16) They found that a combination of calculated lipophilicity and calculated volatility could predict soil pLCso based on the topical pLDso. The volatility was expressed as the log of the vapor pressure in nun Hg. We re-plotted the difference of the topical pLDso - soil pLCso with the calculated logP and calculated log volatility in a 3D graph shown in Figure 9. It can be seen as the compounds become more volatile (logVp < 5) that is a marked increase in soil toxicity. As the compounds become less lipophilic (more hydrophilic), they also become more toxic in the soil. 

---