Discovery of Benzothiazolylpyrazole-4-Carboxamides as Potent Succinate Dehydrogenase Inhibitors through Active Fragment Exchange and Link Approach

Abstract

Succinate dehydrogenase (SDH) is an attractive target for developing green fungicides to manage agricultural pathogens in modern agriculture research. Herein, in this work, we report the discovery of benzothiazolylpyrazole-4-carboxamides I-III as potent SDH inhibitors using active fragment exchange and link approach. The results of the fungicidal activity assays showed that some of the synthesized compounds exhibited excellent inhibition against the tested fungi. Systematic structure−activity relationship studies led to the discovery of compound Ip, N- (1-((4,6-difluorobenzo[d]thiazol-2-yl)thio)propan-2-yl)-3-(difluoromethyl)-N-methoxy-1-methyl-1H-pyrazole-4-carboxamide, which showed higher fungicidal activity against Fusarium graminearum Schw (EC 50 = 0.93 μg/mL) than the commercial fungicides thifluzamide (EC 50 > 50 μg/mL) and boscalid (EC 50 > 50 μg/mL). The molecular simulation studies suggested that hydrophobic interactions were the primary driving forces between ligands and SDH. Promisingly, we found that Ip could stimulate the growth of wheat seedlings and Arabidopsis thaliana and increase the biomass of the treated plants. Preliminary studies on the plant growth promoter mechanism of Ip indicated that it could increase nitrate reductase activity in planta, that, in turn, stimulates the growth of plants.

Understanding the Effects of Ligand Configuration on Protoporphyrinogen IX Oxidase with Rationally Designed 3-(N-Phenyluracil)but-2-enoates

“…Herein, in this study, we designed 3-( N -phenyluracil)­but-2-enoates I – IV through active fragments exchange and link (AFEL), an approach developed by us to discover the lead compounds of the enzyme (Figure ). − Our results showed that the E -configuration of 3-( N -phenyluracil)­but-2-enoates I – IV showed higher bioactivity than their corresponding Z -configuration analogues. Most of the synthesized E -configuration compounds exhibited higher N.…”

Recent Advances in Design and Development of Diazole and Diazine Based Fungicides (2014–2023)

“…Yin and colleagues designed and synthesized a new series of compounds containing benzothiazolylpyrazole-4-carboxamides as a potent SDH inhibitor scaffold, using an active fragment exchange and link approach. 54 According to the fungicidal activity assays, some of the synthesized compounds, namely compound 26, exhibited excellent inhibition against the tested fungi (Figure 6d). Compound 26 showed higher fungicidal activity against Fusarium graminearum (F. graminearum) (EC 50 = 0.93 mg•L −1 ) than thifluzamide (EC 50 > 50 mg•L −1 ) and boscalid (EC 50 > 50 mg•L −1 ), which are commercial fungicides.…”

“…Yin and colleagues designed and synthesized a new series of compounds containing benzothiazolylpyrazole-4-carboxamides as a potent SDH inhibitor scaffold, using an active fragment exchange and link approach . According to the fungicidal activity assays, some of the synthesized compounds, namely compound 26 , exhibited excellent inhibition against the tested fungi (Figure d).…”

Design and optimization of novel succinate dehydrogenase inhibitors against agricultural fungi based on Transformer model

“…This type of fungicides has become the next most popular fungicide after quinone outside respiration inhibitors and ergosterol biosynthesis inhibitor fungicides. SDHIs can block the mitochondrial tricarboxylic acid cycle and respiratory chain electron transport [2], thereby exerting its fungicidal activity by inhibiting the activity of succinate dehydrogenase [3]. As of now, there were 24 SDHIs on the fungicide resistance action committee [4][5].…”

“…Molecules can be generated based on RNN models [8][9][10]. The generative model based on variational autoencoder (VAE) consists of two networks: (1) encoder, which maps the input into a low-dimensional latent vector; (2) decoder, which maps the latent vector into the newly generated data [11]. Both the encoder and decoder can be common RNN or convolutional neural networks (CNN) models.…”