Discovery of Novel Spiropiperidinyl-α-methylene-γ-butyrolactones as Antifungal and Antitoxin Agents Targeting Oxysterol Binding Protein.

Corn ear rot and fumonisin caused by Fusarium verticillioides pose a serious threat to food security. To find more highly active fungicidal and antitoxic candidates with structure diversity based on naturally occurring lead xanthatin, a series of novel spiropiperidinyl-α-methylene-γ-butyrolactones were rationally designed and synthesized. The in vitro bioassay results indicated that compound 7c showed broad-spectrum in vitro activity with EC50 values falling from 3.51 to 24.10 µg/mL against Rhizoctonia solani and Alternaria solani, which was more active than the positive controls xanthatin and oxathiapiprolin. In addition, compound 7c also showed good antitoxic efficacy against fumonisin with a 48% inhibition rate even at a concentration of 20 µg/mL. Fluorescence quenching and the molecular docking validated both 7c and oxathiapiprolin targeting at FvoshC. RNA sequencing analysis discovered that FUM gene cluster and protein processing in endoplasmic reticulum were downregulated. Our studies have discovered spiropiperidinyl-α-methylene-γ-butyrolactone as a novel FvoshC target-based scaffold for fungicide lead with antitoxin activity.

Fungicidal Activity of New Pyrrolo[2,3-d]thiazoles and Their Potential Action on the Tryptophan Metabolic Pathway and Wax Biosynthesis.

The main challenge in the development of agrochemicals is the lack of new leads and/or targets. It is critical to discover new molecular targets and their corresponding ligands. YZK-C22, which contains a 1,2,3-thiadiazol-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole skeleton, is a fungicide lead compound with broad-spectrum fungicidal activity. Previous studies suggested that the [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole scaffold exhibited good antifungal activity. Inspired by this, a series of pyrrolo[2,3-d]thiazole derivatives were designed and synthesized through a bioisosteric strategy. Compounds C1, C9, and C20 were found to be more active against Rhizoctonia solani than the positive control YZK-C22. More than half of the target compounds provided favorable activity against Botrytis cinerea, where the EC50 values of compounds C4, C6, C8, C10, and C20 varied from 1.17 to 1.77 µg/mL. Surface plasmon resonance and molecular docking suggested that in vitro potent compounds C9 and C20 have a new mode of action instead of acting as pyruvate kinase inhibitors. Transcriptome analysis revealed that compound C20 can impact the tryptophan metabolic pathway, cutin, suberin, and wax biosynthesis of B. cinerea. Overall, pyrrolo[2,3-d]thiazole is discovered as a new fungicidal lead structure with a potential new mode of action for further exploration.

Design, synthesis and systemic acquired resistance of 2-benzothiadiazolylquinoline-4-carboxamides by COI1 based virtual screening.

Coronatine-insensitive 1 (COI1) has been identified as a target receptor of plant elicitor coronatine (COR). To discover novel plant elicitor leads, most of the potential molecules among 129 compounds discovered from the ZINC database by docking based virtual screening targeting COI1 were quinoline amides. On this lead basis, 2-benzothiadiazolylquinoline-4-carboxamides were rationally designed and synthesized for bioassay. All target compounds did not show significantly in vitro antifungal activity, compounds 4d, 4e and 4o displayed good in vivo systemic acquired resistance activity for Arabidopsis thaliana against Hyaloperonospora arabidopsidis isolate Noco2 with over 80% of inhibitory rate at the concentration of 50 µM. These results indicate that 2-benzothiadiazolylquinoline-4-carboxamides are promising plant elicitor leads for further study.

Synthesis of fungicidal morpholines and isochromenopyridinones via acid-catalyzed intramolecular reactions of isoindolinones.

Acid-catalyzed intramolecular cyclization or rearrangement of isoindolinone derivatives is described. 3-Hydroxy/ethoxy-3,4-dihydro-6H-[1,4]-oxazino-[3,4-a]-isoindol-6-ones are obtained in moderate to good yields. Further acid-catalyzed intramolecular rearrangement reactions give 6H-isochromeno-[4,3-b]-pyridin-6-ones. The mild reaction conditions with convenient starting materials show broad substrate scope and provide the target compounds as novel pesticide leads with good fungicidal or systemical acquired resistance activities.

3D-QSAR Combination with Molecular Dynamics Simulations to Effectively Design the Active Ryanodine Receptor Agonists against Spodoptera frugiperda.

Computer-aided molecular modeling was applied to design a series of Spodoptera frugiperda RyR agonists. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. MD simulations in the complex with S. frugiperda native, mutant RyR, and mammalian RyR1 under physiological conditions were used to validate the detailed binding mechanism. Binding free energy calculation by molecular mechanics generalized surface area (MM-GBSA) explained the role of key amino acid residues in ligand-receptor binding. Therefore, 14 new compounds were effectively designed and synthesized, and a bioassay indicated that compounds A-2 and A-3 showed comparable activity to that of chloranthraniliprole with LC50 values of 0.27, 0.18, and 0.20 mg L-1, respectively, against S. frugiperda. Most target compounds also displayed good activity against Mythinma separata at 0.1 mg L-1. Molecular docking and MM-GBSA calculations demonstrated that A-3 had a better binding capacity with native and mutant S. frugiperda RyRs.

FKBP5 genetic variants are associated with respiratory- and sleep-related parameters in Chinese patients with obstructive sleep apnea.

Introduction: Obstructive sleep apnea (OSA) has been associated with psychiatric disorders, especially depression and posttraumatic stress disorder (PTSD). FKBP5 genetic variants have been previously reported to confer the risk of depression and PTSD. This study aimed to investigate the association of single nucleotide polymorphisms (SNPs) in the FKBP5 gene with OSA and OSA-related quantitative traits. Methods: Four SNPs within the FKBP5 gene (rs1360780, rs3800373, rs9296158, rs9470080) were genotyped in 5773 participants with anthropometric and polysomnography data. Linear regression and logistic regression analyses were performed to evaluate the relationship between FKBP5 SNPs and OSA-related traits. Binary logistic regression was used to assess the effect of SNPs on OSA susceptibility. Interacting genes of SNPs were assessed based on the 3DSNP database, and expression quantitative trait loci (eQTL) analysis for SNPs was adopted to examine the correlation of SNPs with gene expression. Gene expression analyses in human brains were performed with the aid of Brain Atlas. Results: In moderate-to-severe OSA patients, all four SNPs were positively associated with AHIREM, and rs9296158 showed the strongest association (ß = 1.724, p = 0.001). Further stratified analyses showed that in men with moderate OSA, rs1360780, rs3800373 and rs9470080 were positively associated with wake time (p = 0.0267, p = 0.0254 and p = 0.0043, respectively). Rs1360780 and rs3800373 were 28 and 29.4%more likely to rate a higher ordered MAI category (OR (95% CI) = 1.280 (1.042 - 1.575), p = 0.019; OR (95% CI) = 1.294 (1.052 - 1.592), p = 0.015, respectively). Rs9296158 and rs9470080 increased the risk of low sleep efficiency by 25.7 and 28.1% (OR (95% CI) = 1.257 (1.003 - 1.575), p = 0.047; OR (95% CI) = 1.281 (1.026-1.6), p = 0.029, respectively). Integrated analysis of eQTL and gene expression patterns revealed that four SNPs may exert their effects by regulating FKBP5, TULP1, and ARMC12. Conclusion: Single nucleotide polymorphisms in the FKBP5 gene were associated with sleep respiratory events in moderate-to-severe OSA patients during REM sleep and associated with sleep architecture variables in men with moderate OSA. FKBP5 variants may be a potential predisposing factor for sleep disorders, especially in REM sleep.

Tandem Synthesis of 1,2,3-Thiadiazoles with 3,4-Dichloroisothiazoles and Hydrazines under External Oxidant- and Sulfur-Free Conditions.

1,2,3-Thiadiazoles are among the most important heterocyclic motifs, with wide applications in natural products and medicinal chemistry. Herein, we disclose a tandem reaction for the synthesis of structurally diverse 1,2,3-thiadiazoles from 3,4-dichloroisothiazol-5-ketones and hydrazines. This method is characterized by mild external oxidant- and sulter-free reaction conditions, a broad substrate scope, and easy purification.

Novel Fluorinated Aniline Anthranilic Diamides Improved Insecticidal Activity Targeting the Ryanodine Receptor.

The diamide insecticides show exceptional activity against Lepidoptera insects via activation of ryanodine receptors (RyRs). In the present study, a series of anthranilic diamides containing a fluoroaniline moiety were designed, synthesized, and evaluated for insecticidal potency. Most titled compounds exerted moderate to remarkably high activity against Mythimna separata, Plutella xylostella, and Spodoptera frugiperda. The insecticidal activity of compound II l and II ac against M. separata was 26.7 and 26.7% at 0.1 mg L-1, respectively, equivalent to that of chlorantraniliprole (0.1 mg L-1, 30.0%). Compounds II l, II y, and II z exhibited 8.0-, 1.8-, and 4.7-fold higher potency than chlorantraniliprole against P. xylostella, respectively, as compared with their LC50s. Compounds II k and II aa showed good insecticidal activity against S. frugiperda with LC50 of 0.56 and 0.46 mg L-1, respectively, comparable to that of the commercial insecticide chlorantraniliprole with LC50 of 0.31 mg L-1. Calcium imaging experiments indicated RyRs as the action target. Molecular docking suggested a higher binding energy of 8.647 kcal/mol between II l and the M. separata RyR than the 7.820 kcal/mol between chlorantraniliprole and the M. separata RyR. Meanwhile, the docking results of II l with mutated P. xylostella RyR at site G4946E showed that II l could have a good inhibition effect on the resistant P. xylostella. The density functional theory calculations suggested the importance of the fluoroaniline moiety in potency. Those novel anthranilic diamides containing a fluorinated aniline moiety are good insecticidal candidates.

Improving Insecticidal Activity of Chlorantraniliprole by Replacing the Chloropyridinyl Moiety with a Substituted Cyanophenyl Group.

Insect ryanodine receptors (RyRs) are molecular targets of the anthranilic diamide insecticides. In the present study, a new series of anthranilic diamides containing a cyanophenyl pyrazole moiety were rationally designed by active-fragment assembly and computer-aided design using the 3D structure of Plutella xylostella RyRs as a receptor and chlorantraniliprole as a ligand. Most of the titled compounds showed good toxicity against Mythimna separate, P. xylostella, and Spodoptera frugiperda. Compounds CN06, CN11, and CN16 with corresponding LC50 values of 0.15, 0.29, and 0.52 mg·L-1, respectively, against M. separate showed comparable activity to that of chlorantraniliprole (0.13 mg·L-1). Surprisingly, CN06, CN11, and CN16 with corresponding LC50 values of 1.6 × 10-5, 3.0 × 10-5, and 2.8 × 10-5 mg·L-1, respectively, against P. xylostella were at least 5-fold more active than chlorantraniliprole (1.5 × 10-4 mg·L-1). In the case of S. frugiperda, CN06, CN11, and CN16 had good potency but lower than chlorantraniliprole in terms of LC50 values (0.58, 0.54, and 0.56 mg·L-1 versus 0.31 mg·L-1). Molecular docking of CN06 and chlorantraniliprole to P. xylostella RyRs validated the molecular design, and the calcium imaging technique further proved the potential target of CN06 as RyRs. Compounds CN06, CN11, and CN16 could be more effective than chlorantraniliprole in targeting the resistant RyR mutants of S. frugiperda (G4891E, I4734M) through the binding mode and energy obtained by molecular docking. Density functional theory calculations (DFT) and electrostatic potential (ESP) studies gave the structure-activity relationship. Compounds CN06, CN11, and CN16 could be used as potent insecticide leads for further optimization.