Pesticides are intensively employed to manage pests, but they pose a great challenge, developing pesticide resistance. So, searching for novel chemical structures is crucial to overcoming insecticide resistance. Herein, a new functionalized pyridine derivative 4 was effectively constructed in a one-step reaction through reacting four components, including piperonal, ethyl cyanoacetate, 2-acetylthiophene, and ammonium acetate, under ultrasonic conditions. Treatment of the derivative 5 with hydrazine hydrate in ethanol afforded the acetohydrazide derivative 8 that was utilized as a key precursor for the synthesis of Schiff's bases and other nicotinonitriles. Moreover, new acetohydrazone derivatives (19–21) were furnished by the reaction of 8 with isatin, n-vinylpyrrolididone, and galactose, respectively. The data obtained from the spectral measurements was the basis for elucidating the structures of the new derivatives