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Plant pathogenic fungi seriously threaten agricultural production. There is an urgent need to develop novel fungicides with low toxicity and high efficiency. In this study, we designed and synthesized 44 pyrazolo[3,4-d]pyrimidin-4-one derivatives and evaluated them for their fungicidal activities. The bioassay data revealed that most of the target compounds possessed moderate to high in vitro antifungal activities. Especially compound g22 exhibited remarkable antifungal activity against Sclerotinia sclerotiorum with an EC50 value of 1.25 mg/L, close to that of commercial fungicide boscalid (EC50 = 0.96 mg/L) and fluopyram (EC50 = 1.91 mg/L). Moreover, compound g22 possessed prominent protective activity against S. sclerotiorum in vivo for 24 h (95.23%) and 48 h (93.78%), comparable to positive control boscalid (24 h (96.63%); 48 h (93.23%)). Subsequent studies indicated that compound g22 may impede the growth and reproduction of S. sclerotiorum by affecting the morphology of mycelium, destroying cell membrane integrity, and increasing cell membrane permeability. In addition, the application of compound g22 did not injure the growth or reproduction of Italian bees. This study revealed that compound g22 is expected to be developed for efficient and safe agricultural fungicides.

Inspired by commercially established fluxapyroxad as the lead compound of novel efficient antifungal ingredients, novel pyrazole carboxylate derivatives containing a flexible thiazole backbone were successfully designed, synthesized, and detected for their in vitro and in vivo biological activities against eight agricultural fungi. The antifungal bioassay results showed that compound 24 revealed excellent bioactivities against Botrytis cinerea and Sclerotinia sclerotiorum, with median effective concentrations (EC50) of 0.40 and 3.54 mg/L, respectively. Compound 15 revealed remarkable antifungal activity against Valsa mali, with an EC50 value of 0.32 mg/L. For in vivo fungicide control against B. cinerea and V. mali, compounds 3 and 24 at 25 mg/L, respectively, displayed prominent efficacy on cherry tomatoes and apple branches. Molecular docking results demonstrated that compound 15 could form an interaction with several crucial residues of succinate dehydrogenase (SDH), and the in vitro enzyme assay indicated that the target compound 15 displayed an inhibitory effect toward SDH, with an IC50 value of 82.26 μM. The experimental results indicated that phenyl pyrazole carboxylate derivatives displayed a weak antifungal property and low activity compared to the other title substituent pyrazole carboxylate derivatives. Compounds 3, 15, and 24 are promising antifungal candidates worthy of further fungicide development due to their prominent effectiveness.

BACKGROUND To promote the discovery and development of new fungicide with novel scaffolds or modes of action, a series of novel 5-(2-chloroethyl)-1-phenyl-6-(pyridin-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized, and evaluated for their antifungal activities. RESULTS The bioassay data showed that compound 8IIId (EC50 = 1.93 mg L-1 ) is superior to boscalid (EC50 = 6.71 mg L-1 ) against Valsa mali. We introduced chiral groups on the structure of 8IIId, and two chiral configurations were respectively synthesized, which are 8Vc and 8Vd. Surprisingly, 8Vc showed significant antifungal activities against Valsa mali and Physalospora piricola with EC50 values of 0.22 and 0.55 mg L-1 . Physiological and biochemical studies showed that the primary action mechanism of compound 8Vc on Valsa mali may involve changing mycelial morphology and increasing cell membrane permeability. CONCLUSION These results demonstrated that 8Vc could be further modified as fungicide and provided a valuable reference for antifungal agents with pyrazolo[3,4-d]pyrimidin-4-one skeleton. © 2021 Society of Chemical Industry.

The design and synthesis of novel coumarin-thiazolyl ester derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8p exhibited excellent antibacterial activity against four bacteria strains with MIC values of 0.05, 0.05, 8, and 0.05 μg/mL, respectively. In vitro drug-resistant bacterial inhibition experiments indicated that compound 8p exhibited the best bacteriostatic effect in the selected compounds and four positive control drugs with MIC values of 4 μg/mL. In vitro enzyme inhibitory assay showed that compound 8p exhibited potent inhibition against DNA gyrase with IC50 values of 0.13 μM. The molecular docking model indicated that compounds 8p can bind well to the DNA gyrase by interacting with amino acid residues. This study demonstrated that the compound 8p can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

The design and synthesis of novel multi-substituted benzo-indole pyrazole Schiff base derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activities against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella. In addition, we selected 20 compounds for the in vitro antibacterial activities assay of 6 drug-resistant bacteria strains. The result revealed compound 8I-w exhibited excellent antibacterial activity against 4 drug-resistant E. coli bacteria strains with IC50 values of 7.0, 17.0, 13.5, and 1.0 μM, respectively. In vitro enzyme inhibitory assay showed that compound 8I-w displayed potent inhibition against DNA gyrase with IC50 values of 0.10 μM. The molecular docking model indicated that compounds 8I-w can bind well to the DNA gyrase by interacting with various amino acid residues. This study demonstrated that the compound 8I-w can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.

In this work, a total of 36 novel 5-(nicotinamido)-1-phenyl-1H-pyrazole-4-carboxylic acid derivatives were designed and synthesized successfully by introducing a carboxyl group based on the N-(1-(4-chlorophenyl)-4-cyano-1H-pyrazol-5-yl)-6-methoxynicotinamide. Among them, the growth inhibition assays on agar plates showed that compound 5IV-d(5-(2-chloronicotinamido)-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid) exhibited the significant antifungal activity against four important fruit and main crop disease fungi (i.e., Valsa mali Miyabe et Yamada, Botryosphaeria dothidea, Helminthosporium maydis and Rhizoctonia cerealis) with EC50 values of 22.6, 14.5, 17.6 and 18.2 μM, respectively. In addition, 5IV-d showed the excellent inhibitory effect against SDH enzymes with IC50 values ranging from 9.4 to 15.6 μM. In vivo bioassay and molecular docking were applied to explore the potential in practical application and combination of modified structure and SDH. The results of structure-activity relationships indicates that the methoxy substitution at the benzene ring attached to the pyrazole ring and a wide variety of substituents could be responsible for the promising antifungal efficacy of the designed compounds. This study demonstrated that the compound 5IV-d can act as the most potent SDH inhibitor in the reported series of compounds.