Discovery of Novel Aminocyclobutanecarboxylic Acid Derivatives as Succinate Dehydrogenase Inhibitors

Abstract

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.

Discovery of Trifluorobutene Amide Derivatives as Potential Nematicides: Design, Synthesis, Nematicidal Activity Evaluation, SAR, and Mode of Action Study

“…The pMEC values of the compounds were calculated as the negative logarithm of their minimal effective concentration (MEC) values, where MEC is expressed as the molar concentration (μM). Partial least-squares (PLS) analysis was used to establish statistical parameters including q 2 (cross-validated correlation), r 2 (optimum number of components), noncrossvalidated correlation (ONC), standard error of estimate (SEE), and F -value to evaluate the statistical significance and predictive ability of the CoMFA model. , …”

“…Partial least-squares (PLS) analysis was used to establish statistical parameters including q 2 (cross-validated correlation), r 2 (optimum number of components), noncrossvalidated correlation (ONC), standard error of estimate (SEE), and F-value to evaluate the statistical significance and predictive ability of the CoMFA model. 24 Biological Activity and SAR. In Vitro Nematicidal Activity of Compounds C1−C22 against M. incognita.…”

“…Target-based molecule design has been a widely used approach in pesticide discovery in recent years . However, the lack of information on nematode targets makes it difficult to design new nematicidal molecules based on this approach; therefore, scaffold hopping design strategies are a very useful tool in the finding of nematicidal lead.…”

“…21 Target-based molecule design has been a widely used approach in pesticide discovery in recent years. 24 However, the lack of information on nematode targets makes it difficult to design new nematicidal molecules based on this approach; therefore, scaffold hopping design strategies are a very useful tool in the finding of nematicidal lead. Among such strategies, the reversal of functional groups is a common method with a great track record of delivering new innovations in drug and pesticide design.…”

Design, synthesis and antifungal activity of novel α‐methylene‐γ‐butyrolactone derivatives containing benzothiophene moiety

“…In vivo antifungal activity assay Rice plants with consistent growth at the end of tillers were selected for in vivo activity tests against R. solani according to the method in the literature. 27,28 Suspensions of 150, 100 and 50 mg L −1 of the highly active compound were prepared with 0.1% aqueous Tween 80. The commercial agent tebuconazole (430 g L −1 suspension agent) was used as a positive control, diluted to 150 mg L −1 with water.…”