In an effort to discover new chemistry for the control of harmful agricultural pests, a pharmacophore was derived from 256 neonicotinic insecticidal compounds tested in an in vitro housefly head [imidacloprid] binding assay. Statistical models were constructed from whole insect data (cotton aphid, whitefly and cockroach) using this pharmacophore. The models were validated and then used to evaluate novel structures. A number of targets predicted to be good neonicotinic insecticides were subsequently prepared. These ranged from simple heteroatom replacements to re-configured linkers and substantially modified binding elements. For example, the classic nitroimino function that is common to several neonicotinic insecticides was replaced by an isoxazalone ring in one case and a fluoropyridyl moiety in another. The resulting compounds demonstrated sufficient biological activity to warrant further exploration. In another instance, simplifying the linker led to a novel area with commercial levels of activity. The design, synthesis and structure activity relationships of several molecules that were predicted to have good neonicotinic insecticidal activity are presented. The overall performance and usefulness of these pharmacophore based models is also discussed.

Pharmacophore based design and synthesis of novel neonicotinic insecticides

248th National Meeting (2014)

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