Recent advances in bioactive pyrazoles.

Novel 1,2,4-oxadiazoles and trifluoromethylpyridines related to natural products: synthesis, structural analysis and investigation of their antitumor activity

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 EC50 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.

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

The molecular design of spin-crossover complexes relies on controlling the spin state of a transition metal ion by proper chemical modifications of the ligands. Herein, the first N,N'-disubstituted 2,6-bis(pyrazol-3-yl)pyridines (3-bpp) are reported that, against the common wisdom, induce a spin-crossover in otherwise high-spin iron(II) complexes by increasing the steric demand of a bulky substituent, an ortho-functionalized phenyl group. As N,N'-disubstituted 3-bpp complexes have no pendant NH groups that make their spin state extremely sensitive to the environment, the proposed ligand design, which may be applicable to isomeric 1-bpp or other families of popular bi-, tri- and higher denticity ligands, opens the way for their molecular design as spin-crossover compounds for future breakthrough applications.

Towards the Molecular Design of Spin-Crossover Complexes of 2,6-Bis(pyrazol-3-yl)pyridines.

Succinate dehydrogenase inhibitors (SDHIs) have emerged in fungicide markets as one of the fastest-growing categories that are widely applied in agricultural production for crop protection. Currently, the structural modification focusing on the flexible amide link of SDHI molecules is being gradually identified as one of the innovative strategies for developing novel highly efficient and broad-spectrum fungicides. Based on the above structural features, a series of pyrazole-4-acetohydrazide derivatives potentially targeting fungal SDH were constructed and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, and Botrytis cinerea. Strikingly, the in vitro EC50 values of constructed pyrazole-4-acetohydrazides 6w against R. solani, 6c against F. graminearum, and 6f against B. cinerea were, respectively, determined as 0.27, 1.94, and 1.93 μg/mL, which were obviously superior to that of boscalid against R. solani (0.94 μg/mL), fluopyram against F. graminearum (9.37 μg/mL), and B. cinerea (1.94 μg/mL). Concurrently, the effects of the substituent steric, electrostatic, hydrophobic, and hydrogen-bond fields on structure-activity relationships were elaborated by the reliable comparative molecular field analysis and comparative molecular similarity index analysis models. Subsequently, the practical value of pyrazole-4-acetohydrazide derivative 6w as a potential SDHI was ascertained by the relative surveys on the in vivo anti-R. solani preventative efficacy, inhibitory effects against fungal SDH, and molecular docking studies. The present results provide an indispensable complement for the structural optimization of antifungal leads potentially targeting SDH.

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

In search of environmentally benign compounds with high biological activity, low toxicity and low resistance, 8 novel benzoyl hydrazines containing pyrazole were designed and synthesized. All compounds were characterized by 1H NMR spectra and HRMS. The preliminary results of biological activity assessment indicated that most of title compounds exhibited certain insecticidal activities against Mythimna separata Walker at 200 mg·L−1 but excellent fungicidal activities against six fungus at 50 mg·L−1, which were better than the control.

Design, Synthesis and Biological Activities of Novel Benzoyl Hydrazines Containing Pyrazole

The invention relates to a bisamide derivative, a preparation method for the same and application thereof The bisamide derivative is a compound represented by the general formula (I) in the original text, wherein R1 refers to H (hydrogen), halogen, cyan, nitryl, amino, acetamido, trifluoroacetamide radical, trifluoroacetamide radical, benzamido, para toluene sulfonate, para toluene oxygen acetamido or 2,4-dihalide phenoxyacetamide radical; R2 refers to C1-C5 alkyl, cyclopropane radical, five-membered or six-membered heterocyclic radical; m refers to 0, 1 or 2; n refers to 0 or 1; R3 refers to H, cyan, trifluoroacetyl, amino-acetyl, trifluoroacetamide radical acetyl, acetamido-acetyl, hydroxyl, guanidyl, amino sulfo-carbonyl, amino-acetyl sulfo-carbonyl, trifluoroacetamide radical sulfo-carbonyl or acetamido sulfo-carbonyl; R4 refers to H or methyl; R5 refers to H or methyl; R6 refers to H or methyl; R7 refers to H or methyl; and Ym refers to halogen, nitryl, C1-C6 alkyl, C1-C6 alkoxy, trifluoro-methyl, trifluoro-ethyoxyl or sevo-fluoro-isopropyl By the aid of the bisamide derivative, drug resistance of an original compound is improved, insecticidal activity is improved, and production cost is reduced

Pengfei Liu

Papers

Design, Synthesis and Biological Activities of Novel Benzoyl Hydrazines Containing Pyrazole

Bisamide derivative, preparation method for same and application thereof

Synthesis and biological activities of novel anthranilic diamides analogues containing benzo[b]thiophene