Fluorinated pyrazoles play an important role in medicinal chemistry, drug discovery, agrochemistry, coordination chemistry, and organometallic chemistry. Since the early 1990s, their popularity has grown exponentially. Moreover, more than 50% of all contributions on the topic have been published in the last 5 years. In this review, analysis of novel synthetic approaches to fluorinated pyrazoles that appeared in recent years is performed. A particular emphasis is devoted to a detailed consideration of reaction mechanisms. In addition, the reasons that have led to the ever-increasing popularity of fluorinated pyrazoles in various areas of science are discussed. At the end of the review, several potentially interesting but yet mostly unknown classes of fluorinated pyrazoles are outlined.

Fluorinated Pyrazoles: From Synthesis to Applications.

A series of novel chalcone derivatives containing the 1,2,4-triazine moiety were synthesized and their structures were confirmed by 1H NMR, 13C NMR and elemental analyses. Antiviral bioassays revealed that most of the compounds exhibited good antiviral activity against tobacco mosaic virus (TMV) at a concentration of 500 μg mL−1. The designated compound 4l was 50% effective in terms of curative and protective activities against TMV with 50% effective concentrations (EC50) of 10.9 and 79.4 μg mL−1, which were better than those of ningnanmycin (81.4 and 82.2 μg mL−1). Microscale thermophoresis (MST) also showed that the binding of compound 4l to coat protein (TMV-CP) yielded a Kd value of 0.275 ± 0.160 μmol L−1, which was better than that of ningnanmycin (0.523 ± 0.250 μmol L−1). At the same time, molecular docking studies for 4l with TMV-CP (PDB code:1EI7) showed that the compound was embedded well in the pocket between the two subunits of TMV-CP. Meanwhile, compound 4a demonstrated excellent antibacterial activities against Ralstonia solanacearum (R. solanacearum), with an EC50 value of 0.1 μg mL−1, which was better than that of thiodiazole-copper (36.1 μg mL−1) and bismerthiazol (49.5 μg mL−1). The compounds act by causing folding and deformation of the bacterial cell membrane as observed using scanning electron microscopy (SEM). The chalcone derivatives thus synthesized could become potential alternative templates for novel antiviral and antibacterial agents.

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Novel chalcone derivatives containing a 1,2,4-triazine moiety: design, synthesis, antibacterial and antiviral activities

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.

Neocryptolepine is an alkaloid isolated from traditional African herbal medicine Cryptolepis sanguinolenta, and its broad spectrum of biological activities has been illuminated in past decades. In this study, neocryptolepine and its derivatives (1-49) were designed and synthesized from economical and readily available starting materials. Their structures were confirmed by proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and mass spectrometry. The synthesized compounds were screened for their antifungal profile against six agriculturally important fungi Rhizoctonia solani, Botrytis cinerea (B. cinerea), Fusarium graminearum, Mycosphaerella melonis, Sclerotinia sclerotiorum, and Magnaporthe oryzae. The results of in vitro assay revealed that compounds 5, 21, 24, 35, 40, 45, and 47 presented remarkable antifungal activity against the fungi tested with EC50 values lower than 1 μg/mL. Significantly, compound 24 displayed the most effective inhibitory potency against B. cinerea (EC50 = 0.07 μg/mL), and the data from in vivo experiments revealed that compound 24 demonstrated comparable protective activity with the positive control boscalid. Preliminary mechanism studies indicated that compound 24 showed impressive spore germination inhibitory effectiveness and lower cytotoxicity than azoxystrobin, imparted on normal function of the cell membrane and cell wall, and arrested the normal function of the nucleus. Besides the excellent inhibitory activity against agriculturally important phytopathogenic fungi tested, the designed assemblage possesses several benefits with a high profile of variation in synthesized molecules, the ease of synthesis, and good cost-effectiveness of commercially available synthetic reagents, all of these have highlighted the potential worth of compound 24 as a new and highly efficient agricultural fungicide.

Design, Synthesis, and Antifungal Evaluation of Neocryptolepine Derivatives against Phytopathogenic Fungi.

A series of penta-1,4-dien-3-one oxime ether derivatives containing a quinoxaline moiety were synthesized and their antibacterial and antiviral activities were evaluated. Bioassay activity indicated that some of the compounds displayed significant antibacterial and antiviral activities. In particular, some title compounds were found to show remarkable antiviral activities against tobacco mosaic virus (TMV). Compound 6i showed remarkable curative, protective and inactivation activity against TMV, with a 50% effective concentration (EC50) of 287.1, 157.6 and 133.0 μg mL−1, respectively. These results were better than or comparable to those of ningnanmycin (356.3, 233.7 and 121.6 μg mL−1, respectively). Microscale thermophoresis (MST) also showed that the binding of compound 6i to TMV coat protein (TMV-CP) gave a Kd value of 0.115 ± 0.092 μmol L−1, which was better than that of ningnanmycin (0.523 ± 0.254 μmol L−1). Meanwhile, the EC50 values of compound 6k against Xanthomonas axonopodis pv. Citri (Xac) and Xanthomonas oryzae pv. oryzae (Xoo) were 16.8 and 33.4 μg mL−1 respectively, and that of compound 6i against Ralstonia solanacearum (Rs) was 33.9 μg mL−1. These results were better than those of bismerthiazol (44.3, 42.5 and 62.4 μg mL−1, respectively). The mechanism of antibacterial action of compound 6k against Xac was analysed through scanning electron microscopy (SEM). This study indicated that the title compounds are valuable in the search for novel agrochemicals.

Synthesis, antiviral and antibacterial activities and action mechanism of penta-1,4-dien-3-one oxime ether derivatives containing a quinoxaline moiety

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.

Novel 1,3,5-thiadiazine-2-thione derivatives containing a hydrazide moiety: Design, synthesis and bioactive evaluation against phytopathogenic fungi in vitro and in vivo

A series of novel 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N′-phenylacethydrazide derivatives were designed, synthesized and evaluated for their antifungal activities against Fusarium graminearum (Fg), Rhizoctonia solani (Rs), Botrytis cinerea (Bc) and Colletotrichum capsici (Cc). The bioassay results in vitro showed that most of the title compounds exhibited impressive antifungal activities against the above plant fungi. Particularly, the compounds 5c, 5f, 5g, 5i, 5m and 5p displayed desirable anti-Rs activities, with the corresponding EC50 values of 0.37, 0.32, 0.49, 0.50, 0.46 and 0.45 µg/mL, respectively, which are superior to the positive control carbendazim (0.55 µg/mL). Further in vivo bioassay results showed that the anti-Rs activity of title compound 5f at 200 µg/mL reached 95.84% on detached rice leaves and 93.96% on rice plants. Featuring convenient synthesis, novel structures and desirable antifungal activity, these 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N′-phenylacethydrazide derivatives could be further studied as the potential candidates of novel agricultural fungicides.

Design and synthesis of novel 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N'-phenylacethydrazide derivatives as potential fungicides.

A series of novel pyrazole carboxamide and niacinamide derivatives containing a benzimidazole moiety were designed and synthesized as antifungal candidate agents. All target compounds were characterized by FTIR, 1H NMR, 13C NMR, HRMS and elemental analysis techniques. The structure of compound T1 was further confirmed by single crystal X-ray diffraction analysis. The antifungal activities of the target compounds were evaluated in vitro against four phytopathogenic fungi (namely Botrytis cinerea, Rhizoctonia solani, Fusarium graminearum and Alternaria solani) by the mycelium growth inhibition method. The bioassay results indicated that some of the compounds exhibited good antifungal activity against B. cinerea at 100 μg ML−1 compared to other three fungi. In order to better explore the structure–activity relationship (SAR), the EC50 values of target compounds against B. cinerea were measured and assessed. Subsequently, a 3D quantitative structure–activity relationship (3D-QSAR) study was carried out using the comparative molecular field analysis (CoMFA) technique based on the inhibitory activities of tested compounds against B. cinerea. Molecular modelling results revealed fine predictive ability with cross-validated q2 and non-cross-validated r2 values of 0.578 and 0.850, respectively.

Mengqi Wang

Papers

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

Novel 1,3,5-thiadiazine-2-thione derivatives containing a hydrazide moiety: Design, synthesis and bioactive evaluation against phytopathogenic fungi in vitro and in vivo

Design and synthesis of novel 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N'-phenylacethydrazide derivatives as potential fungicides.

Design, synthesis, antifungal activity and 3D-QSAR study of novel pyrazole carboxamide and niacinamide derivatives containing benzimidazole moiety

Design, Synthesis and 3D-QSAR of New Quinazolin-4(3H)-one Derivatives Containing a Hydrazide Moiety as Potential Fungicides