Discovery of FM-2665 as a Potent Arylpyrazole Insecticidal and Acaricidal Candidate: Rational Design via Pyridine Bioisosterism and Terminal Alkyl Optimization.
Sixteen novel arylpyrazole derivatives were designed using tigolaner as a scaffold reference and synthesized to examine the effects of pyridine bioisosterism and terminal alkyl modification. Among the synthesized compounds, FM-2665 (A14) showed the highest overall activity against Plutella xylostella, Tetranychus cinnabarinu, and Myzus persicae, with LC50 values of 0.127, 0.604, and 0.496 mg/L, respectively. On the basis of the LC50 values, FM-2665 was 6.68-fold more potent than tigolaner against P. xylostella. Molecular docking and DFT calculations suggested that additional predicted contacts involving Gln96 and Val126, together with a narrower HOMO-LUMO gap, may contribute to the observed structure-activity relationship. These calculations do not establish receptor affinity, and direct functional validation of GABAR antagonism remains necessary. FM-2665 therefore represents a promising lead for further optimization and safety evaluation.