ABSTRACT
This structure-activity relationship study for neonicotinoids with an N-haloacetylimino pharmacophore identifies several candidate compounds showing outstanding insecticidal potency and consequently leads to establishing their molecular recognition at an insect nicotinic receptor structural model, wherein the neonicotinoid halogen atoms (fluorine, chlorine, bromine, and iodine) variously interact with the receptor loops C-D interfacial niche via H-bonding and/or hydrophobic interactions.
Subject(s)
Anabasine/chemical synthesis , Insecticides/chemical synthesis , Receptors, Nicotinic/metabolism , Acetylation , Anabasine/chemistry , Anabasine/pharmacology , Animals , Halogens/chemical synthesis , Halogens/chemistry , Halogens/pharmacology , Hydrophobic and Hydrophilic Interactions , Imines/chemical synthesis , Imines/chemistry , Imines/pharmacology , Insecta/drug effects , Insecticides/chemistry , Insecticides/pharmacology , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Bis-imidacloprid (bis-IMI) analogues with suitable alkylene spacers have plant-systemic insecticidal properties. The alkylene-tethered bis-IMI binds in a unique mode to the insect nicotinic acetylcholine receptor (nAChR) wherein the chloropyridine moieties are embraced by two distinct and distant domains. The heptamethylene spacer optimally bridges these two subsites, yet the linker itself binds in a relatively nonspecific manner. This investigation examines the hypothesis that a bis-IMI analogue with a heteroaromatic tether, which undergoes specific interaction(s) with the newly recognized receptor cavity, may enhance the potency relative to those of the alkylene-tethered derivatives. Remarkably, a novel bis-IMI with a furan-2,5-dimethylene fulcrum showed highest receptor potency and insecticidal activity among the analogues with various chemotype spacers. The nAChR structural model, simulating the binding site interactions of the furan-2,5-dimethylene-tethered bis-IMI, reveals that the furan ring is nestled in a hydrophobic pocket, consisting of three aromatic amino acids, and is stabilized via hydrogen bonding.
Subject(s)
Imidazoles/chemistry , Imidazoles/pharmacology , Insecticides/chemistry , Insecticides/pharmacology , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Animals , Binding Sites , Female , Houseflies/chemistry , Houseflies/drug effects , Insect Proteins/antagonists & inhibitors , Insect Proteins/chemistry , Molecular Conformation , Neonicotinoids , Nicotinic Antagonists , Protein Binding , Receptors, Nicotinic/chemistry , Structure-Activity RelationshipABSTRACT
Neonicotinoids with nitro- or cyanoimino substituents are extensively utilized as plant-mobile (systemic) insecticides controlling the piercing-sucking insect pests. This investigation considers structural features of neonicotinoids with trifluoroacetyl pharmacophores, which may confer enhanced hydrophobicity and effectiveness. Fifteen trifluoroacetyl neonicotinoid analogues [=NC(O)CF(3) and =CHC(O)CF(3)] are therefore prepared to evaluate the hydrophobicity index, toxicity to houseflies (Musca domestica), and binding affinity to the Musca nicotinic receptor. The =NC(O)CF(3) and =CHC(O)CF(3) compounds showed a higher hydrophobicity than that of nitro- or cyanoimino analogues. The intrinsic insecticidal activities (defined by intrathoracic injection with a synergist pretreatment) of test compounds were well-correlated to their target site potencies. Although nitro or cyano neonicotinoids were not toxic via the topical application route in the absence of a synergist, trifluoroacetyl analogues exhibited excellent insecticidal activity under the same condition. Accordingly, the increased hydrophobicity of trifluoroacetyl neonicotinoids presumably improves the penetrability of compound into insect integument and insecticidal effectiveness.
