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

Abstract

AbstractBackgroundSuccinate 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.ResultsBy optimization of lead compound SCU2028, 30 novel aromatic carboxamides Ia‐o and IIa‐o without a pyrazol group were designed, synthesized and characterized by 1H NMR, 13C 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 (EC50 = 0.02 mg/L), with the 2‐chloro‐3‐pyridyl moiety, and compounds Io (EC50 = 0.03 mg/L) and IIo (EC50 = 0.02 mg/L), with the 4‐methyl‐2‐trifluoromethylthiazolyl moiety, all exhibited the equivalent antifungal activities against R. solani with compound SCU2028 (EC50 = 0.03 mg/L) and bixafen (EC50 = 0.04 mg/L). Additionally, in pot tests, compound IIc (EC50 = 3.63 mg/L) also had higher antifungal activity against R. solani than compound SCU2028 (EC50 = 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.ConclusionNovel 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.