Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

The conformational restriction switch concept has beenadoptedas a major tool for structural optimization of pharmaceuticals inorder to expand the chemical structure scope and improve therapeuticactivity against specific proteins. Several of the 1-aminocyclobutanecarboxylicacid derivatives produced in this way exhibited satisfactory antifungalactivity in vitro compared with positive control boscalid. In vitroantifungal tests revealed that compound A21 had comparable,even higher antifungal activity against Rhizoctoniasolani (R.s., EC50 = 0.03 mg/L) and Botrytis cinerea (B.c., EC50 = 0.04mg/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 activityagainst porcine SDH, its IC50 value was 3.73 & mu;M,which has considerable potency compared with fluxapyroxad (IC50 = 3.76 & mu;M). The mode of action was determined usingSEM and membrane potential research. The effects of the substituentsteric hindrance, electrostatic property, hydrophobicity, and hydrogen-bondfields on structure-activity relationships were elaboratedby the reliable models of comparative molecular field analysis andcomparative molecular similarity index analysis. Furthermore, densityfunctional theory simulations, molecule electrostatic potential, andmolecular docking were also used to study the probable binding modeof target compounds with flexible fragments. The results showed thatthe scaffold of 1-aminocyclobutanecarboxylic acid derivatives couldbe used as lead for discovering new succinate dehydrogenase inhibitors.

Automated summary

The conformational restriction switch concept is used to optimize the structure of pharmaceuticals, resulting in derivatives with satisfactory antifungal activity. Compound A21 exhibited comparable or even higher antifungal activity than fluxapyroxad and boscalid. Compound A20 showed good inhibitory activity against porcine SDH and had considerable potency compared with fluxapyroxad. The effects of substituent hindrance, electrostatic property, hydrophobicity, and hydrogen-bond fields on structure-activity relationships were elaborated using reliable models. The scaffold of 1-aminocyclobutanecarboxylic acid derivatives can be used as a lead for discovering new succinate dehydrogenase inhibitors.