Rational Exploration of Novel SDHI Fungicide through an Amide-β-ketonitrile Bioisosteric Replacement Strategy

Abstract

The identification of succinate dehydrogenase inhibitor (SDHI) fungicides bearing a novel scaffold is of great importance to control pathogenic fungi. Difluoromethyl-pyrazole β-ketonitrile derivatives were rationally designed through an innovative amide-β-ketonitrile bioisosteric replacement strategy and evaluated for their antifungal activities. In preliminary fungicidal screening, our new β-ketonitrile compounds showed outstanding in vitro activity. Compounds A7 and A14 exhibited EC 50 values of 0.116 and 0.165 μg/mL against Sclerotinia sclerotiorum, respectively, and A14 also displayed an EC 50 of 0.0774 μg/mL against Rhizoctonia solani. Furthermore, A14 exhibited moderate in vivo protective activity against rice sheath blight on rice plants. Results from SDH enzymatic assays demonstrated that A14 possesses significant inhibitory effect toward porcine heart SDH, with an IC 50 value of 0.183 μM, which was 20-fold more potent than that of fluxapyroxad (IC 50 = 3.76 μM). A docking study indicated that Hbonds, cation−π interactions, and edge-to-face π−π interactions play key roles in the binding of A14 with R. solani SDH. The CoMSIA model guided the approach to further structural optimizations and indicated that hydrophobic and steric substituents on the benzene ring have decisive effects on the fungicidal activity against R. solani. The present work describes for the first time the successful bioisosteric replacement of the common SDHI amide moiety by a β-ketonitrile group and highlights the potential of βketonitriles as an innovative novel SDHI subclass.

Novel Acaricidal Silico-Containing Pyrazolyl Acrylonitrile Derivatives Identified through Rational Carbon–Silicon Bioisosteric Replacement Strategy

“…13,14,35 As shown in Table 3, the clogP value, which was the fundamental physicochemical property of target compounds related to acaricidal activities, was calculated by the Canvas program (Schrodinger, LLC, 2015). 39 The clogP values of our novel silicon-containing pyrazolyl acrylonitrile derivatives ranged from 5.24 to 6.96, which was close to that of the positive control cyenopyrafen (clogP = 5.45), demonstrating the acaricides likeness and potential acaricidal activities of the title compounds. The detailed synthetic procedures and structural characterizations of intermediates and the target compounds as well as 1 H and 13 C spectra are listed in the Supporting Information.…”

“…Our target compounds A1–A27 were accessible by nucleophilic substitution and esterification reactions according to the reported method as shown in Scheme . ,, As shown in Table , the c logP value, which was the fundamental physicochemical property of target compounds related to acaricidal activities, was calculated by the Canvas program (Schrödinger, LLC, 2015) . The c logP values of our novel silicon-containing pyrazolyl acrylonitrile derivatives ranged from 5.24 to 6.96, which was close to that of the positive control cyenopyrafen ( c logP = 5.45), demonstrating the acaricides likeness and potential acaricidal activities of the title compounds.…”

Discovery of Novel Diamides Scaffold Containing Monofluoro-acrylamides Activating the Insect Ryanodine Receptor

“…q 2 (cross-validated correlation) was obtained by the “leave-one-out” method. Other statistical parameters including r 2 (optimum number of components), F -value (Fisher value), and SEE (standard error of estimate) were employed for CoMFA and CoMSIA models predictive ability evaluation. , …”

“…Other statistical parameters including r 2 (optimum number of components), F-value (Fisher value), and SEE (standard error of estimate) were employed for CoMFA and CoMSIA models predictive ability evaluation. 38,39 Calcium Imaging Experiments in M. separata Neurons. These experiments were performed on M. separata neurons.…”

Computation-Directed Molecular Design, Synthesis, and Fungicidal Activity of Succinate Dehydrogenase Inhibitors

“…Succinate dehydrogenase (SDH) is an ideal fungicide target, and SDH inhibitors (SDHIs) exert their fungicidal activity by disrupting the mitochondrial tricarboxylic acid cycle and respiration chain. − SDHIs have been widely used to control destructive phytopathogens, such as Rhizoctonia cerealis (R. cerealis), Botrytis cinerea (B.…”