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

Abstract

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. By optimization of lead compound SCU2028, thirty novel aromatic carboxamides Ia-o and IIa-o without containing pyrazol group were designed, synthesized and characterized by 1 H NMR, 13 C NMR and HRMS. In vitro antifungal activities showed that most of compounds Ia-o and IIa-o exhibited good antifungal activities against Rhizoctonia solani. And 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 considerable 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 the higher antifungal activity against R. solani than compound SCU2028 (EC50 = 7.63 mg/L). Furthermore, in vitro inhibitory activity against fungal SDH showed inhibitory ability of compound IIc was considerable 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 the SDH. Novel aromatic carboxamides without containing pyrazol group had the potential as a class of SDHI, and the strategy of replacing the pyrazol group with the other aryl in the "core" moiety might offer an alternative option in discovery of SDHI fungicides. This article is protected by copyright. All rights reserved.