Quantitative structure-activity relationships of imidacloprid and its analogs with substituents at the C5 position on the pyridine ring in the neuroblocking activity

Abstract

IntroductionImidacloprid (1, XϭH in Fig. 1) began the era of a structurally as well as a physiologically new type of insecticides having highly effective and widely used chemicals for crop protection and veterinary pest control. 1) Starting from this compound, variously modified neonicotinoids were developed as highly effective insecticides.2) Early modification researches focused overwhelmingly on the imidazolidine moiety of imidacloprid and cyclic and acyclic isosters were contrived. Recently, a non-aromatic neonicotinoids bearing a saturated heterocyclic ring in place of the pyridine ring, dinotefuran, was developed. 3,4) For further evolution of the structure to give a new class of neonicotinoids, quantitative analyses of the structure-activity relationship of neonicotinoids and analogous compounds are one of the most important tools, and have been widely performed for this class of compounds by means of conformational, 5) three-dimensional 6-8) as well as substituent-effect analyses.9,10) The conformational analysis, however, was conducted only for limited structures related to dinotefuran, so that the results obtained cannot be generalized. The other analyses were mostly carried out for the imidazolidine moiety of imidacloprid and the corresponding parts of the series compounds. Although a number of variously substituted benzyl analogs of imidacloprid were prepared, 11) their substituent effects have not been quantitatively analyzed.To conduct more detail quantitative analysis of the aromatic-ring part, we prepared a set of compounds with various substituents at the 5-position on the pyridine ring of imidacloprid and measured their insecticidal activity.12,13) Here, we report their substituent effects obtained by means of the quantitative analysis of neuroblocking activity. This work is also connected with a recent finding of the extraordinary binding affinity of 5-azidoimidacloprid (21, XϭN 3 , Fig. 1) to insect nAChR.14,15) We will be able to view the new information about the azido group in light of the quantitative analysis of a set of substituents at this position.Quantitative structure-activity relationships of imidacloprid and its analogs with substituents at the C5 position on the pyridine ring in the neuroblocking activity Two nerve activities of imidacloprid analogs with various substituents at the 5-position of the pyridine ring were measured: the conduction blockage in the excised central nerve cord of the American cockroach, and the binding inhibition of a radioligand, [ 3 H]imidacloprid, to the membrane preparation of housefly-head homogenates. Neuroblocking activity was quantitatively analyzed using physicochemical substituent parameters. The greater the electron-releasing resonance effect, the higher the activity. The introduction of sizable and alkoxy substituents was unfavorable. The nerve-binding activity of the tested compounds was linearly related to the neuroblocking activity with one exception. The higher the binding activity, the higher the blocking activity. © Pesticide Science Soc...

Insecticidal and Neuroblocking Potencies of Variants of the Imidazolidine Moiety of Imidacloprid-Related Neonicotinoids and the Relationship to Partition Coefficient and Charge Density on the Pharmacophore

“…The excitation duration time (the time until the blocking begins) and the frequency of nerve impulses is in principle proportional to the binding capacity to the receptor and the quantity of the ligand on it. One can estimate the neuroexcitation or neuroblocking capacity of a ligand by comparing the minimum concentration to induce the two-phase electric episode (18,22,24). Figure 4 exemplifies the time courses for compound 13, in which each symbol indicates cumulative counts for every 30 s in each nerve preparation at three concentrations.…”

“…In the neonicotinoid field, questions regarding how the lipophilicity difference among the functional groups (dNNO 2 , dCHNO 2 , dNCN) or the cyclic/acyclic bioisosteres or the size difference among the alkyl substituents affects the biological response have been addressed (4,18).…”

Preparation of 5-chloro-6-fluoroimidacloprid analogs and comparison of their insecticidal activity in a laboratory test with a 6-chloro-5-fluoro analog

“…Similar high potency comparable with that of imidacloprid has also been observed for the nerve-blocking activity of central nerve cord of American cockroaches. 2) In contrast, 5-chloro-6-fluoro derivatization resulted in reduced activity, irrespective of the type of the azolidine ring conjugated with ϭNNO 2 or NCN. The activity of all tested compounds, including imidacloprid, was low against lepidopteran common cutworms, which is a typical symptom of neonicotinoid insecticides.…”

Insecticidal and neuroblocking potencies of variants of the thiazolidine moiety of thiacloprid and quantitative relationship study for the key neonicotinoid pharmacophore

“…The neuroexcitation or neuroblocking capacity of a ligand can be estimated by comparing the minimum concentration to induce the two-phase electric episode. 17,21,37) Generally, the dose for excitation of the nerve is smaller than that for the following blockade. Between these two effects, the neuroblocking measurements seems to be related more significantly to the insecticidal tendency than the neuroexcitation, so we evaluated only the BC in the present study.…”