The discovery of novel 3‐nitropyridin‐2‐amine‐based 2,3‐dihydroimidazo[1,2‐a]pyridin‐5( 1 H )‐one insecticides

BACKGROUND: Nicotinic acetylcholine receptor (nAChR) competitive modulators, especially neonicotinoid insecticides represented by imidacloprid and thiamethoxam, have been highly effective in controlling Aphis fabae. However, the outdoor use of imidacloprid and thiamethoxam has been banned in the European Union (EU) since 2018 due to risk to bees. Additionally, their long-term and widespread use has led to increasingly severe resistance problems. The effective management of Aphis fabae thus requires the continuous development of novel insecticides, particularly those with novel structures and low toxicity to bees. RESULTS: In the pursuit of novel insecticides, a series of nitropyridine compounds were synthesized and evaluated. Compounds 1a (6-methoxy-N-methyl-3-nitropyridin-2-amine) and 1b (6-methoxy-N,N-dimethyl-3-nitropyridin-2-amine), both containing the substructure 2-nitroethene-1,1-diamine, demonstrated insecticidal activity against Aphis fabae. Further derivatization, by replacing the methyl group of compound 1b with (2-chloropyridin-5-yl)methyl from imidacloprid or (2-chlorothiazol-5-yl)methyl from thiamethoxam, yielded compounds 2b and 3b, respectively, which displayed significantly enhanced insecticidal activity against Aphis fabae. During the optimization of compound 2b, compound 6a-4 was unexpectedly discovered as a by-product, exhibiting potent efficacy and a new 1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one structure. Further structural optimization, by introducing dihydroimidazo[1,2-a]pyridin-5(1H)-one, finally led to the discovery of three highly effective 3-nitropyridin-2-amine-based 2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one insecticides: compounds 6a-1 (1-((2-chloropyridin-5-yl)methyl)-8-nitro-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one), 6b-1 (1-((2-chlorothiazol-5-yl)methyl)-8-nitro-2,3-dihydroimidazo[1,2-a]pyridin-5(1H)-one), and 7a-1 (1-((2-chloropyridin-5-yl)methyl)-8-nitro-2,3-dihydroimidazo[1,2-a]pyridine-5(1H)-thione). CONCLUSION: Compounds 6a-1, 6b-1, and 7a-1 exhibit excellent insecticidal activity against Aphis fabae. Their insecticidal potency is superior to or comparable to that of commercial insecticides, such as imidacloprid, nitenpyram, triflumezopyrim, and flupyrimin. Moreover, they demonstrate low toxicity to rats, bees, and fish.