N-Hetaryl-[2(1H)-pyridinyliden]cyanamides: A New Class of Systemic Insecticides

The new chemical class N-hetaryl-[2(1H)-pyridinylidene]cyanamides were inspired by the long known five-ring structure 2-chloro-5-[2-(nitro-methylene)-1-imidazolidinyl]-pyridine (Shell) and the current development candidate flupyrimin (Meiji Seika Pharma) via scaffold hopping and the concept for designing "shortened structures" by omitting the "methylene link" as a structural feature. The most active N-hetaryl-[2(1H)-pyridinylidene]cyanamides can be synthesized on a technical scale by a simple manufacturing procedure. As full nicotinic acetylcholine receptor (nAChR) agonists, the compounds bind with low affinity at the orthosteric binding site of nAChR. In molecular modeling studies, structural differences are visible in the superposition of active N-[6'-(trifluoromethyl)[1(2H),3'-bipyridin]-2-ylidene]cyanamide onto imidacloprid (IMD) and sulfoxaflor (SXF) in bound conformation. On the basis of their physicochemical properties, the most active xylem systemic candidates offer excellent aphicidal activity in vegetables and cotton, when applied as a foliar spray, by soil drench application, or, in particular, as seed dressing for seed treatment uses. Selected candidates show good plant compatibility and reveal a better risk profile with respect to bee pollinators than the majority of currently registered nAChR competitive modulators for seed treatment uses. Applied as a seed dressing in greenhouse profiling, good to excellent control of different aphid species has been observed. In field trials, an interesting level of activity potential against cereal grain aphids (inclusive virus vector control), corn rootworm, and wireworm could be demonstrated. According to molecular modeling investigations (Fukui functions, dipole moments, and electrostatic potentials), there is a broad scope for structure optimization of the chemical class leading to proposals for novel bicyclic insecticides.