Synthesis of Alkylene-Tethered Bis-Imidacloprid Derivatives as Highly Insecticidal and Nerve-Exciting Agents with Potent Affinity to [³H] Imidacloprid-Binding Sites on Nicotinic Acetylcholine Receptor

Abstract

Bivalent molecules of bis-Imidacloprid with 2-10 alkylene tethers as well as tethers containing an ethenylene, ethynylene, phenylene and oxide joint were prepared. These dimeric chloronicotinyl molecules were highly Insecticidal against American cockroaches on injection at 2-30 nanomolar doses. The minimum lethal dose of the most potent hexamethylene derivative was close to that of imidacloprid, and the potency was augmented up to about thirty-five-fold following pretreatment with metabolic inhibitors, while the binding affinity to [3H] imidacloprid-binding sites on the nicotinic acetylcholine receptor was weaker than that of imidacloprid by a factor of 160. The hexamethylene derivative elicited impulses in cockroach central nerves with an initial excitation and subsequent block at a potency comparable to imidacloprid.

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

“…30,31) Since the sixth abdominal ganglion of the American cockroach contains nAChR, 32) we chose this preparation for the electrophysiological experiments. As reported previously for various neonicotinoids, 17,19,21) compound 6 (Fig. 2) and all other compounds (data not shown) also showed a biphasic phenomenon consisting of increasing and decreasing phases in the frequency of spontaneous firing during treatment.…”

“…7,11,20) The binding assay was conducted according to the procedure reported previously. [20][21][22] The membrane fraction (3 mg protein/ml, 200 ml) was placed in a disposable glass tube (12ϫ75 mm) containing the test compound dissolved in DMSO (2 ml). After incubation at 24°C for at least 10 min, [ 3 H]IMI (50 ml), which was prepared by dilution with sodium phosphate buffer (10 mM) containing sodium chloride (50 mM) and Triton-X (1 g/liter), pH 7.4, was added so as to make a final concentration of [ 3 H]IMI 10 nM, and the mixture was incubated at 24°C for 60 min.…”

Unexpected plant-systemic insecticidal properties of alkylene-tethered bis-imidacloprid derivatives

“…As previously mentioned, they have high biological potency when injected or in binding to nAChR, or as nerve-blocking agents. 11,14,16) As discussed, these twin molecules are disqualified in each respective criterion for drug-like molecules despite the marked insecticidal potency. A prodrug concept could be an explanation to warrant a contradiction of the selection rule.…”

“…Recently, we devised a unique neonicotinoid structure of alkylene-tethered twin neonicotinoids and reported their biological properties. [11][12][13][14][15][16][17] These new molecules obviously violate the Rule of Five. For example, the hexamethylene bis-IMI derivative, whose insecticidal potency is comparable to that of IMI after injection into American cockroaches, 11) has a large molecular mass of 594, H-bond acceptors as many as 12, and excessive 13 rotatable bonds.…”

“…The other twin compounds with a shorter or longer tether had lower activity at this dose. The result that the potency of hexamethylene derivative (6) was modest was unexpected because it has comparable potency to IMI (1) after injection into the American cockroach, and blocking potential for cockroach central nerves, 11,14) and high binding affinity to the [ 3 H]IMI site of housefly head nAChR. 11) Another telling result is that p-xylenyl derivative (13) was obviously superior to the m-isomer (12).…”