Design, synthesis and antifungal evaluation of novel mandelic acid derivatives containing a 1,3,4-oxadiazothioether moiety.

A series of novel mandelic acid derivatives containing a 1,3,4-oxadiazothioether moiety were designed and synthesized. Bioassay results showed that some target compounds exhibited certain antifungal activity against six kinds of pathogenic fungi in vitro. Among the compounds, the EC50 values of T41 against Gibberella saubinetii, Verticillium dahlia and Sclerotinia sclerotiorum were 31.0, 27.0 and 32.1 µg/ml, respectively, and the EC50 value of T14 against S. sclerotiorum was 14.7 µg/ml. The antifungal activity against the resistant fungus S. sclerotiorum indicated that this series of target compounds may have the similar action modes or sites as the commercialized succinate dehydrogenase inhibitor carboxin. A morphological study with fluorescence microscope demonstrated that T41 can significantly destroy the membrane integrity of G. saubinetii.

In vivo antiviral activity and disassembly mechanism of novel 1-phenyl-5-amine-4-pyrazole thioether derivatives against Tobacco mosaic virus.

A series of novel 1-phenyl-5-amine-4-pyrazole thioether derivatives containing a 1,3,4-oxadiazole moiety was designed and synthesised. In vivo antiviral bioassay results showed that most of the target compounds exhibited excellent inactivation activity against Tobacco mosaic virus (TMV). The EC50 values of the inactivation activities for T2, T7, T9, T24, T25 and T27 were 15.7, 15.7, 15.5, 11.9, 12.5 and 16.5 µg/mL, respectively, which were remarkably superior over that of the commercialised antiviral agent ningnanmycin (40.3 µg/mL). Morphological study using AFM and TEM of TMV treated with T24 showed that T24 could significantly shorten the polymerization length of TMV particles and formed a distinct break on the rod-shaped TMV. Investigations for virus infection efficiency on tobacco leaves demonstrated that infectivity of virion had been reduced obviously upon T24 treatment. Subsequently, a strong interaction between T24 and TMV-CP (Kd = 3.8 µM, score 6.11) was observed through MST experiments. Molecular docking study further revealed that target compounds interact with amino acid residue Glu50 in TMV CP, causing disassembly of virion, shorting the length of the virion and reducing the infectivity of virion, and resulting in high inactivating activity of target compounds. This study provides a new insight for discovery of antiviral compounds through a new action mechanism with a new binding site.

Synthesis, Biological Evaluation, and 3D-QSAR Studies of N-(Substituted pyridine-4-yl)-1-(substituted phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide Derivatives as Potential Succinate Dehydrogenase Inhibitors.

A series of new fungicides that can inhibit the succinate dehydrogenase (SDH) was classified and named as SDH inhibitors by the Fungicide Resistance Action Committee in 2009. To develop more potential SDH inhibitors, we designed and synthesized a novel series of N-(substituted pyridine-4-yl)-1-(substituted phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxamide derivatives, 4a-4i, namely, 5a-5h, 6a-6h, and 7a-7j. The bioassay results demonstrated that some title compounds exhibited excellent antifungal activity against four tested phytopathogenic fungi (Gibberella zea, Fusarium oxysporum, Cytospora mandshurica, and Phytophthora infestans). The EC50 values were 1.8 µg/mL for 7a against G. zeae, 1.5 and 3.6 µg/mL for 7c against F. oxysporum and C. mandshurica, respectively, and 6.8 µg/mL for 7f against P. infestans. The SDH enzymatic activity testing revealed that the IC50 values of 4c, 5f, 7f, and penthiopyrad were 12.5, 135.3, 6.9, and 223.9 µg/mL, respectively. The molecular docking results of this series of title compounds with SDH model demonstrated that the compounds could completely locate inside of the pocket, the body fragment formed H bonds, and the phenyl ring showed a π-π interaction with Arg59, suggesting that these novel 5-trifluoromethyl-pyrazole-4-carboxamide derivatives might target SDH. These results could provide a benchmark for understanding the antifungal activity against the phytopathogenic fungus P. infestans and prompt us to discover more potent SDH inhibitors.