Fluopyram analogues containing an indole moiety: synthesis, biological activity and molecular docking study.

Abstract

Succinate dehydrogenase (SDH) has been identified as one of the ideal targets for the development of novel nematicides. However, the resistance of nematodes to fluopyram, one of the commercialized SDH inhibitors, is becoming a growing concern. Since expanding the structural diversity around an active scaffold is a useful strategy for drug development, herein a series of fluopyram analogues with a broad, biologically relevant indole moiety were synthesized and evaluated for nematicidal activity against C. elegans. Fifty-six novel target compounds were synthesized and characterized by ¹H NMR, ¹³C NMR, and HRMS. The bioscreen results revealed that a few compounds such as C16 and D21 with LC_50/72 h values of 8.65 mg/L and 6.83 mg/L, respectively, showed compatible activity to that of the commercial nematicide tioxazafen (LC_50/72 h = 5.98 mg/L). Molecular docking indicated that these compounds could effectively bind to the active site of SDH by forming hydrogen bonds with Trp215 and Tyr96, and causing a cation-π interaction with Arg74. The work suggests that indole-containing derivatives may represent a promising template for the development of new nematicides.