Natural products as insecticides: the biology, biochemistry and quantitative structure-activity relationships of spinosyns and spinosoids.

The spinosyns, a novel family of insecticidal macrocyclic lactones, are active on a wide variety of insect pests, especially lepidopterans and dipterans. The biological activity of a mixture (spinosad; Tracer, Spin-Tor, Success) of the two most abundant spinosyns (spinosyns A and D) against pest insects is on a par with that of many pyrethroid insecticides. The spinosyns also exhibit a very favorable environmental and toxicological profile, and possess a mode of action that appears unique, with studies to date suggesting that both nicotinic and gamma-aminobutryic acid receptor functions are altered in a novel manner. Compared to pyrethroids such as cypermethrin, spinosyn A is slow to penetrate into insect larvae such as tobacco budworm larvae (Heliothis virescens); however, once inside the insect, spinosyn A is not readily metabolized. To date, more than 20 spinosyns and more than 800 spinosoids (semi-synthetic analogs) have been isolated or synthesized, respectively. Artificial neural network-based quantitative structure activity relationship (QSAR) studies for the spinosyns suggested that modification of the 2',3',4'-tri-O-methylrhamnosyl moiety could improve activity and several spinosoids incorporating these modifications exhibited markedly improved lepidopteran activity compared to spinosad. Multiple linear regression-based QSAR studies also suggest that whole molecule properties such as CLogP and MOPAC dipole moment can explain much of the biological activity observed for the spinosyns and closely related spinosoids.

Recent advances in the chemistry of spinosyns.

The spinosyns are a new class of fermentation-derived insect control agents that are effective against a variety of chewing insect pests. The successful introduction of spinosad into the agricultural marketplace represents an important milestone in the use of natural products for commercial pest control. The development of a natural product presents additional limitations relative to a synthetic material. While the latter affords some degree of control in building appropriate physical attributes such as photostability, a natural product, designed to function in a different environment, is often less suited for traditional spray applications. Despite its intrinsic photolability, spinosad is stable enough to perform under field conditions. In an effort to generate analogs with improved physical characteristics, we have developed a variety of conditions for selectively modifying different portions of the molecule, and we have discovered analogs with greater activity against a broader spectrum of pests. The inability to translate improved greenhouse activity to actual field conditions resulted in a detailed study of the effects of formulations and crystallinity on biological activity. Through this effort, measurably improved field performance of synthetic spinosyn analogs relative to the natural product have now been observed.

Polyfluoro 1,3-diketones as systemic insecticides.

A series of aryl polyfluoro 1,3-diketones were examined for systemic ectoparasiticidal activity in cattle. The compounds demonstrated efficacy against several economically important species of insects and acarina. At dosages of 5 mg/kg X1 or 0.35 mg/kg per day intraruminally, activity was observed against blowfly larvae (Phormia regina), adult stable fly (Stomoxys calcitrans), and lone star tick (Amblyomma americanum). In vivo activity was not directly related to in vitro activity, showing a stronger dependence on perfluoroalkyl-chain length and aryl-group substitution.

Synthesis and antimicrobial evaluation of 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin, EL-870) and related cyclic amino derivatives.

A series of 20-deoxo-20-cyclic (alkylamino) derivatives of tylosin, desmycosin, macrocin and lactenocin was prepared by reductive amination of the C-20 aldehyde group. The majority of the compounds were prepared using metal hydrides (sodium cyanoborohydride or sodium borohydride) as the reducing agents and a suitable cyclic alkylamine. Subsequently, a more convenient procedure was developed using formic acid as a reducing agent. The C-20 amino derivatives prepared from desmycosin exhibited good in vitro antimicrobial activity against Pasteurella haemolytica and Pasteurella multocida (MIC range of 0.78 approximately 6.25 micrograms/ml) as well as Mycoplasma species (MIC range of 0.39 approximately 6.25 micrograms/ml). Several derivatives showed excellent oral efficacy against infections caused by P. multocida in chicks. One of these derivatives, 20-deoxo-20-(3,5-dimethylpiperidin-1-yl)desmycosin (tilmicosin or EL-870) was selected for development as a therapeutic agent for pasteurellosis in calves and pigs.