Structure-Based Discovery of New Succinate Dehydrogenase Inhibitors via Scaffold Hopping Strategy.

Scaffold hopping strategy has become one of the most successful methods in the process of molecular design. Seeking to develop novel succinate dehydrogenase inhibitors (SDHIs), we employed a scaffold hopping strategy to design compounds featuring geminate dichloralkenes (gem-dichloralkenes) fragment. After stepwise modifications, a series of N-cyclopropyl-dichloralkenes-pyrazole-carboxamide derivatives was synthesized. Among them, compounds G28 (IC50 = 26.00 nM) and G40 (IC50 = 27.00 nM) were identified as the best inhibitory activity against porcine SDH, with IC50 values reaching the nanomolar range, outperforming the lead compound pydiflumetofen. Additionally, the greenhouse assay indicated that compounds G37 (EC90 = 0.031 mg/L) and G34 (EC90 = 1.67 mg/L) displayed extremely high activities against wheat powdery mildew (WPM) and cucumber powdery mildew (CPM), respectively. Computational results further revealed that the gem-dichloralkene fragment and fluorine substituted pyrazole form an extra hydrophobic interaction and dipolar-dipolar interaction with SDH. In summary, our study provides a novel gem-dichloralkene scaffold with outstanding fungicidal properties, obtained through scaffold hopping, that holds great potential for future research on PM control.

Discovery of N-Methoxy-(biphenyl-ethyl)-pyrazole-carboxamides as Novel Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase (SDH) inhibitor is one of the research hotspots for the development of fungicides. Herein, we describe the design and synthesis of N-methoxy-(biphenyl-ethyl)-pyrazole-carboxamide derivatives with enhanced fungicidal activity by employing fragment combination strategy. The SDH enzymatic activity was evaluated for 24 title compounds, and compound 7s was identified as the highest activity against porcine SDH with an IC50 value of 0.014 µM, 205-fold greater than that of fluxapyroxad. Furthermore, the greenhouse experiments showed that compound 7u exhibited potent fungicidal activity against wheat powdery mildew with an EC50 value of 0.633 mg/L, higher activity than fluxapyroxad and benzovindiflupyr. The computational results showed that the fluorine atom substituted on the pyrazole ring formed an extra dipolar-dipolar interaction with C_S42 and then increased the van der Waals interaction between the compound and SDH. The structural and mechanistic insights obtained from the present work will provide a valuable clue to developing novel SDH inhibitors.

Comparison of Gut Microbiota Between Infants with Atopic Dermatitis and Healthy Controls in Guangzhou, China.

PURPOSE: Evidence on the role of the gut microbiota in atopic dermatitis is inconsistent as human intestinal microbiota is influenced by geography. This cross-sectional study therefore aimed to compare differences in the gut microbiota of infants with atopic dermatitis and healthy infants in Guangzhou, China, by analyzing their stool. PATIENTS AND METHODS: The composition of the intestinal microbiota was analyzed from the stool samples of 20 infants with atopic dermatitis (AD group) and 25 healthy infants (non-AD group) (1-6 months old), using full-length 16S rRNA gene sequencing. The Wilcoxon test was used to analyze the relative abundance of bacteria by phylum, family, genus, and species between groups; microbial community richness and diversity were compared between the two groups. RESULTS: There were no significant differences in the microbial community richness and diversity between the two groups. At the phylum level, 11 bacterial phyla were found; most sequences belonged to one of the three dominant bacterial phyla - Firmicutes, Proteobacteria, and Bacteroidetes. The top 10 microbes at the phylum, family, and genus levels showed no significant changes in their composition within the gut microbiota between the AD and non-AD groups. A decrease in the ratio of the Streptococcus genus was found in atopic dermatitis group when compared with healthy controls (p=0.048). CONCLUSION: A decrease in the abundance of Streptococcus was found in children with AD. The role of Streptococcus in the development of AD needs to be confirmed in a large cohort study.