Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

The conformational restriction switch concept has been adopted as a major tool for structural optimization of pharmaceuticals in order to expand the chemical structure scope and improve therapeutic activity against specific proteins. Several of the 1-aminocyclobutanecarboxylic acid derivatives produced in this way exhibited satisfactory antifungal activity in vitro compared with positive control boscalid. In vitro antifungal tests revealed that compound A21 had comparable, even higher antifungal activity against Rhizoctonia solani ( R . s ., EC 50 = 0.03 mg/L) and Botrytis cinerea ( B . c ., EC 50 = 0.04 mg/L) than fluxapyroxad ( R . s ., EC 50 = 0.02 mg/L; B . c ., EC 50 = 0.20 mg/L) and boscalid ( R . s ., EC 50 = 0.29 mg/L; B . c ., EC 50 = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activity against porcine SDH, its IC 50 value was 3.73 μM, which has considerable potency compared with fluxapyroxad (IC 50 = 3.76 μM). The mode of action was determined using SEM and membrane potential research. The effects of the substituent steric hindrance, electrostatic property, hydrophobicity, and hydrogen-bond fields on structure–activity relationships were elaborated by the reliable models of comparative molecular field analysis and comparative molecular similarity index analysis. Furthermore, density functional theory simulations, molecule electrostatic potential, and molecular docking were also used to study the probable binding mode of target compounds with flexible fragments. The results showed that the scaffold of 1-aminocyclobutanecarboxylic acid derivatives could be used as lead for discovering new succinate dehydrogenase inhibitors.