Expedient Discovery for Novel Antifungal Leads Targeting Succinate Dehydrogenase: Pyrazole-4-formylhydrazide Derivatives Bearing a Diphenyl Ether Fragment

Abstract

The pyrazole-4-carboxamide scaffold containing a flexible amide chain has emerged as the molecular skeleton of highly efficient agricultural fungicides targeting succinate dehydrogenase (SDH). Based on the above vital structural features of succinate dehydrogenase inhibitors (SDHI), three types of novel pyrazole-4-formylhydrazine derivatives bearing a diphenyl ether moiety were rationally conceived under the guidance of a virtual docking comparison between bioactive molecules and SDH. Consistent with the virtual verification results of a molecular docking comparison, the in vitro antifungal bioassays indicated that the skeleton structure of title compounds should be optimized as an N′-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide scaffold. Strikingly, N′-(4-phenoxyphenyl)-1H-pyrazole-4-carbohydrazide derivatives 11o against Rhizoctonia solani, 11m against Fusarium graminearum, and 11g against Botrytis cinerea exhibited excellent antifungal effects, with corresponding EC 50 values of 0.14, 0.27, and 0.52 μg/mL, which were obviously better than carbendazim against R. solani (0.34 μg/mL) and F. graminearum (0.57 μg/mL) as well as penthiopyrad against B. cinerea (0.83 μg/mL). The relative studies on an in vivo bioassay against R. solani, bioactive evaluation against SDH, and molecular docking were further explored to ascertain the practical value of compound 11o as a potential fungicide targeting SDH. The present work provided a non-negligible complement for the structural optimization of antifungal leads targeting SDH.

Synthesis of novel antibacterial and antifungal quinoxaline derivatives

“…cucumerinum ( FO ) , Colletotrichum truncatum ( CT ), Phytophthora capsici ( PC ), Colletotrichum gloeosporioides ( CG ), Rhizoctonia solani ( RS ), Fusarium graminearum ( FG ), Phytophthora sojae ( PS ), Phytophthora palmivora ( PP ), Botrytis cinerea ( BC ), and Phytophthora litchii ( PL ) were evaluated by a mycelial growth rate method. 33–35 The experimental details for the twelve fungi are presented in the ESI. †…”

“…Fusarium graminearum (FG), Phytophthora sojae (PS), Phytophthora palmivora (PP), Botrytis cinerea (BC), and Phytophthora litchii (PL) were evaluated by a mycelial growth rate method. [33][34][35] The experimental details for the twelve fungi are presented in the ESI. †…”

Synthesis and Bioactivity of Novel Sulfonate Scaffold-Containing Pyrazolecarbamide Derivatives as Antifungal and Antiviral Agents

“…As shown in Scheme 1 , the key intermediate 4 was synthesized using a previously published three-step procedure ( Wang et al, 2020 ). White powder, yield 46%.…”

Design, Synthesis and Antifungal/Nematicidal Activity of Novel 1,2,4-Oxadiazole Derivatives Containing Amide Fragments

“…Among them, fluopyram is a novel fungicide and nematicide with a distinct structure, which was successfully developed by Bayer in 2012; it has an amide bridge can be combined with SDH [17,18]. As a fungicide, it has not been found to be cross-resistant with other fungicides or SDHI fungicides [19,20]. Thus, the modification of the amide-bridged chain is likely to bring out a novel binding mode, further slowing down the development of resistance [14,21].…”