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., EC50 = 0.03 mg/L) and Botrytis cinerea (B.c., EC50 = 0.04
mg/L) than fluxapyroxad (R.s., EC50 = 0.02 mg/L; B.c., EC50 = 0.20 mg/L) and boscalid (R.s., EC50 = 0.29 mg/L; B.c., EC50 = 0.42 mg/L). Furthermore, compound A20 was successfully screened and exhibited good inhibitory activity
against porcine SDH, its IC50 value was 3.73 μM,
which has considerable potency compared with fluxapyroxad (IC50 = 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.