Design, Synthesis, and Study of the Dual Action Mode of Novel N-Thienyl-1,5-disubstituted-4-pyrazole Carboxamides against Nigrospora oryzae.

Due to the single target but extensive application of commercialized succinate dehydrogenase inhibitors (SDHIs), resistance problems have gradually become apparent in recent years. To solve this problem, a series of novel N-thienyl-1,5-disubstituted-1H-4-pyrazole carboxamide derivatives were designed and synthesized in this work based on the active skeleton 5-trifluoromethyl-4-pyrazole carboxamide. The bioassay results indicated that some target compounds exhibited excellent in vitro antifungal activities against the eight phytopathogenic fungi tested. Among them, the EC50 values of T4, T6, and T9 against Nigrospora oryzae were 5.8, 1.9, and 5.5 mg/L, respectively. The in vivo protective and curative activities of 40 mg/L T6 against rice infected with N. oryzae were 81.5% and 43.0%, respectively. Further studies revealed that T6 not only significantly inhibited the growth of N. oryzae mycelia but also effectively hindered spore germination and germ tube elongation. Morphological studies using scanning electron microscopy (SEM), fluorescence microscopy (FM), and transmission electron microscopy (TEM) found that T6 could affect the mycelium membrane integrity by increasing cell membrane permeability and causing peroxidation of cellular lipids, and these results were further verified by measuring the malondialdehyde (MDA) content. The IC50 value of T6 against succinate dehydrogenase (SDH) was 7.2 mg/L, lower than that of the commercialized SDHI penthiopyrad (3.4 mg/L). Further, ATP content detection and the results after docking T6 and penthiopyrad suggested that T6 was a potential SDHI. These studies demonstrated that active compound T6 could both inhibit the activity of SDH and affect the integrity of the cell membrane at the same time via a dual action mode, which is different from the mode of action of penthiopyrad. Thus, this study provides a new idea for a strategy to delay resistance and diversify the structures of SDHIs.

Potential Fungicide Candidates: A Dual Action Mode Study of Novel Pyrazole-4-carboxamides against Gibberella zeae.

Pyrazole carboxamides are a class of traditional succinate dehydrogenase inhibitors (SDHIs) that have developed into a variety of commercialized fungicides. In the present work, a series of novel 1,5-disubstituted-1H-pyrazole-4-carboxamide derivatives were designed and synthesized based on the active backbone of 5-trifluoromethyl-1H-4-pyrazole carboxamide. Bioassay results indicated that some target compounds exhibited excellent in vitro antifungal activities against six phytopathogenic fungi. Notably, the EC50 values of Y47 against Gibberella zeae, Nigrospora oryzae, Thanatephorus cucumeris, and Verticillium dahliae were 5.2, 9.2, 12.8, and 17.6 mg/L, respectively. The in vivo protective and curative activities of Y47 at 100 mg/L against G. zeae on maize were 50.7 and 44.2%, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis revealed that the large steric hindrance and electronegative groups on the 5-position of the pyrazole ring were important for the activity. The IC50 value of Y47 against succinate dehydrogenase (SDH) was 7.7 mg/L, superior to fluopyram (24.7 mg/L), which was consistent with the docking results. Morphological studies with fluorescence microscopy (FM) and scanning electron microscopy (SEM) found that Y47 could affect the membrane integrity of mycelium by inducing endogenous reactive oxygen species (ROS) production and causing peroxidation of cellular lipids, which was further verified by the malondialdehyde (MDA) content. Antifungal mechanism analysis demonstrated that the target compound Y47 not only had significant SDH inhibition activity but could also affect the membrane integrity of mycelium, exhibiting obvious dual action modes. This research provides a novel approach to the development of traditional SDHIs and their derivatives.

Design, Synthesis and Bioassay of 2-Phenylglycine Derivatives as Potential Pesticide Candidates.

Plant diseases can seriously affect the growth of food crops and economic crops. To date, pesticides are still among the most effective methods to prevent and control plant diseases worldwide. Consequently, to develop potential pesticide molecules, a series of novel 2-phenylglycine derivatives containing 1,3,4-oxadiazole-2-thioethers were designed and synthesized. The bioassay results revealed that G19 exhibited great in vitro antifungal activity against Thanatephorus cucumeris with an EC50 value of 32.4 µg/mL, and in vivo antifungal activity against T. cucumeris on rice leaves at a concentration of 200.0 µg/mL (66.9 %) which was close that of azoxystrobin (73.2 %). Compounds G24 (80.2 %), G25 (89.4 %), and G27 (83.3 %) exhibited impressive in vivo inactivation activity against tobacco mosaic virus (TMV) at a concentration of 500.0 µg/mL, which was comparable to that of ningnanmycin (96.3 %) and markedly higher than that of ribavirin (55.6 %). The antibacterial activity of G16 (63.1 %), G26 (89.9 %), G27 (78.0 %), and G28 (68.0 %) against Xoo at a concentration of 50.0 µg/mL was higher than that of thiadiazole copper (18.0 %) and bismerthiazol (38.9 %). Preliminary mechanism studies on the antifungal activity against T. cucumeris demonstrated that G19 can affect the growth of mycelia by disrupting the integrity of the cell membrane and altering the permeability of the cell. These studies revealed that the amino acid derivatives containing a 1,3,4-oxadiazole moiety exhibited certain antifungal, antibacterial, and anti-TMV activities, and these derivatives can be further modified and developed as potential pesticide molecules.