Novel aromatic carboxamide potentially targeting fungal succinate dehydrogenase: Design, synthesis, biological activities and molecular dynamics simulation studies.

Background: Succinate dehydrogenase inhibitors (SDHIs) emerging in fungicide markets are widely used in crop protection. Currently, the structural modification focusing on a structurally diverse 'core' moiety (aryl) of SDHIs is being gradually identified as one of the innovative strategies for developing novel, highly effective and low resistant fungicides.

Results: By optimization of lead compound SCU2028, 30 novel aromatic carboxamides Ia-o and IIa-o without a pyrazol group were designed, synthesized and characterized by H NMR, C NMR and high resolution mass spectrum (HRMS). In vitro antifungal activities showed that most of the compounds Ia-o and IIa-o exhibited good antifungal activities against Rhizoctonia solani. Among them, compounds Ic and IIc (EC  = 0.02 mg/L), with the 2-chloro-3-pyridyl moiety, and compounds Io (EC  = 0.03 mg/L) and IIo (EC  = 0.02 mg/L), with the 4-methyl-2-trifluoromethylthiazolyl moiety, all exhibited the equivalent antifungal activities against R. solani with compound SCU2028 (EC  = 0.03 mg/L) and bixafen (EC  = 0.04 mg/L). Additionally, in pot tests, compound IIc (EC  = 3.63 mg/L) also had higher antifungal activity against R. solani than compound SCU2028 (EC  = 7.63 mg/L). Furthermore, in vitro inhibitory activity against fungal SDH showed the inhibitory ability of compound IIc was equivalent with that of compound SCU2028, and molecular dynamics simulation of the SDH-compound IIc complex suggested that compound IIc could strongly bind to and interact with the binding site of SDH.

Conclusion: Novel aromatic carboxamides without a pyrazol group have potential as a class of SDHIs, and the strategy of replacing the pyrazol group with another aryl in the 'core' moiety might offer an alternative option in discovery of SDHI fungicides. © 2023 Society of Chemical Industry.