Synthesis, Bioactivity Evaluation,3D‐QSAR, and Molecular Docking of Novel Pyrazole‐4‐carbohydrazides as Potential Fungicides Targeting Succinate Dehydrogenase

Abstract

Main observation and conclusion To screen novel antifungal agents targeting the succinate dehydrogenase (SDH), a series of pyrazole‐4‐carbohydrazides were rationally designed, synthesized, and characterized under the guidance of the structures of succinate dehydrogenase inhibitors (SDHIs). Bioassay results in vitro indicated that most of the target compounds exhibited excellent activity against Rhizoctonia solani (R. solani), Fusarium graminearum (F. graminearum), Botrytis cinerea (B. cinerea) and Colletotrichum capsica (C. cinerea). Compounds 7d, 7l, 7t and 7x were identified as the most promoting candidates, and their anti‐F. graminearum EC50 values were as low as 0.56, 0.47, 0.46 and 0.49 μg/mL, respectively, presenting the similar antifungal activity as that of the commonly used fungicide carbendazim (0.43 μg/mL). The 3D‐QSAR models were built for a systematic structure‐activity relationship profile to explore more potent pyrazole‐4‐carbohydrazides as novel fungicides. Molecular docking of 7d, 7l and 7r with SDH was performed to reveal the binding modes in active pocket and analyze the interactions between the molecules and the SDH protein.

Synthesis, 3D-QSAR and Molecular Docking Study of Nopol-Based 1,2,4-Triazole-Thioether Compounds as Potential Antifungal Agents

“…Plant diseases caused by phytopathogens have always been one of the main reasons for crop yield reduction, and the use of fungicides is the most critical method to effectively control crop diseases in agriculture ( Wang et al, 2017 ). However, the frequent use and misuse of many traditional pesticides have caused environmental pollution, pesticide residual toxicity, and the emergence of resistant phytopathogenic fungi isolates ( Jiao et al, 2021 ; Qi et al, 2021 ). Therefore, the development of novel effective antifungal agents is of great significance.…”

Novel Pyrazole-4-acetohydrazide Derivatives Potentially Targeting Fungal Succinate Dehydrogenase: Design, Synthesis, Three-Dimensional Quantitative Structure–Activity Relationship, and Molecular Docking

“…Inc., China). , The initially synthesized compounds 6a – 6v were randomly divided into two sections that contain the training set including 18 compounds and the testing set involving four compounds. Three-dimensional molecular conformations were successively optimized by Gasteiger–Huckel charge, Tripos force field, and Powell conjugate gradient algorithm until the obtained convergence criteria in molecular energies reached 0.005 kcal/mol. , Three-dimensional structures of compounds 6a – 6v were aligned on the common scaffold of template molecule 6f that exhibited the best in vitro anti-R. solani effect among the 22 synthesized compounds (Figure ).…”

“…Biotech. Inc., China) to generate their three-dimensional conformations. , Three-dimensional molecular conformations were successively optimized by the Gasteiger–Huckel charge, Tripos force field, and Powell conjugate gradient algorithm until the obtained convergence criteria in molecular energies reached 0.001 kcal/mol. ,, The three-dimensional structures of 6w , fluopyram, and SDH were further treated by AutoDockTools 1.5.6 to generate the docking input files that were further processed by AutoDock 4.2.6 to finish molecular docking studies . The obtained three-dimensional binding modes of bioactive molecules with SDH were shown by PyMol 1.7.6 and were further treated by Discovery Studio 4.5 to gain the corresponding two-dimensional binding modes. , …”

“…Hydrazide derivatives have attracted continuous concerns as important nitrogenous compounds that were widely utilized in agricultural practices for crop protection. − The most representative types of them are the arylhydrazide derivatives exhibiting antifungal effects against phytopathogenic microorganisms, such as meixiuyihao, fenamidone, and famoxadone (Figure ). ,, Meanwhile, in the structural optimization of bioactive leads, converting the rigid amide bond in bioactive molecules into a flexible hydrazide fragment has been widely regarded as a feasible modification that could strengthen the interactions of constructed molecules with biological enzymes within living organisms. ,, For example, 2 H -chromen-2-one, 1,2,3-triazole, quinazolin-4­(3 H )-one, 1,3,4-oxadiazole, and 1,3,5-thiadiazine-2-thione derivatives bearing an arylhydrazide moiety were further reported for their more salient antifungal effects than those of the corresponding compounds bearing an aryl amide moiety. ,,− Furthermore, our previous work surprisingly found that converting the pyrazole-4-carboxamide fragment of SDHI fungicides into a pyrazole-4-formylhydrazide scaffold could still maintain their inhibitory effects against fungal SDH. , Obviously, the above explorations laid the necessary basis for the development of novel agricultural fungicides bearing an arylhydrazide fragment.…”

“…3,6,28−31 Furthermore, our previous work surprisingly found that converting the pyrazole-4-carboxamide fragment of SDHI fungicides into a pyrazole-4-formylhydrazide scaffold could still maintain their inhibitory effects against fungal SDH. 20,25 Obviously, the above explorations laid the necessary basis for the development of novel agricultural fungicides bearing an arylhydrazide fragment. Considering the structural features of SDHI fungicides and the vital utilization of hydrazide fragments in the structural optimization of antifungal leads, the main aims of this work are to (i) reasonably conceive potential SDHI surrogates by tactfully turning the quaternary amide link in SDHI leads into a newfangled acetohydrazide fragment as well as reasonably introducing a fluorine-containing pyrazole core into the polar segment of the above acetohydrazide derivatives, as shown in Figure 2; (ii) generate a series of novel pyrazole-4acetohydrazide derivatives as potential SDHI surrogates (Scheme 1) and evaluate their in vitro and in vivo inhibitory effects against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea; and (iii) analyze their structure−activity relationship via three-dimensional qualitative structure− activity relationship (3D-QSAR) models and further investigate their potential interaction models with SDH.…”