desnitroimidacloprid and thiacloprid

The invention of imidacloprid, the most important neonicotinoid insecticide, was initiated by replacement of the framework of nithiazine with an imidazolidine ring. Through the finding of 1-(6-chloro-3-pyridylmethyl)-2-nitromethyleneimidazolidine, imidacloprid was invented. At the same time cyanoiminothiazolidinyl neonicotinoid thiacloprid was discovered. These products possess pronounced systemic properties and improved photostability in addition to supreme insecticidal ability. Crystal structure analysis led to the drug-receptor interaction model consisting of the guanidine (amidine) part conjugated to a powerful electron-withdrawing group bearing an H-bond accepting tip such as NO(2) or CN, and the chloronicotinyl group enhances the binding to the receptor. The QSAR study not only supports the key pharmacophore but also clarifies the crucial involvement of the phamacokinetic factors in the insecticidal activity. A concept for strategic and rational design led to the discovery of alkylene-tethered bis-imidacloprid derivatives with unexpected systemic insecticidal property and the unique binding mechanism revealing the second cavity in the neonicotinoid receptor.

Topics: Animals; Aplysia; Drug Design; Drug Stability; Hydrogen Bonding; Imidazoles; Insecticides; Light; Models, Molecular; Neonicotinoids; Nitro Compounds; Periplaneta; Pyridines; Quantitative Structure-Activity Relationship; Thiazines

Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 A in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids.

Topics: Animals; Aplysia; Bridged Bicyclo Compounds, Heterocyclic; Crystallography, X-Ray; Imidazoles; Imidazolines; Kinetics; Ligands; Neonicotinoids; Nicotine; Nicotinic Agonists; Nitro Compounds; Protein Conformation; Pyridines; Receptors, Nicotinic; Thiazines