Novel aurone-derived piperazine sulfonamides: Development and mechanisms of action as immunostimulants against plant bacterial diseases.

Bacterial diseases pose a significant threat to the sustainable production of crops. Given the unsatisfactory performance and poor eco-compatibility of conventional bactericides, here we present a series of newly structured bactericides that are inspiringly designed by aurone found in plants of the Asteraceae family. These aurone-derived compounds contain piperazine sulfonamide motifs and have shown promising in vitro performance against Xanthomonas oryzae pv. oryzae, Xanthomonas oryzae pv. oryzicola and Xanthomonas axonopodis pv. citri, in particular, compound II23 achieved minimum half-maximal effective concentrations of 1.06, 0.89, and 1.78 µg/mL, respectively. In vivo experiments conducted in a greenhouse environment further revealed that II23 offers substantial protective and curative effects ranging between 68.93 and 70.29% for rice bacterial leaf streak and 53.17-64.43% for citrus bacterial canker, which stands in activity compared with lead compound aurone and commercial thiodiazole copper. Additional physiological and biochemical analyses, coupled with transcriptomics, have verified that II23 enhances defense enzyme activities and chlorophyll levels in rice. Significantly, it also stimulates the accumulation of abscisic acid (ABA) and upregulates the expression of key genes OsPYL/RCAR5, OsBIPP2C1, and OsABF1, thereby activating the ABA signaling pathway in rice plants under biological stress from bacterial infections.

Design and synthesis of novel PPO-inhibiting pyrimidinedione derivatives safed towards cotton.

Developing innovative and effective herbicides is of utmost importance since weed management has become a worldwide agricultural production concern, resulting in severe economic losses every year. In this study, a series of new pyrimidinedione compounds were developed via combination of pyrimidinediones with N-phenylacetamide moiety. The herbicidal activity test (37.5-150 g of ai/ha) indicated that most of the new derivatives exhibited excellent herbicidal activity against dicotyledonous weeds, but less against grasses. Among them, compound 34 was identified as the best postemergence herbicidal activities against six species of weeds (Amaranthus retrof lexus, AR; Abutilon theophrasti, AT; Veronica polita, VP; Echinochloa crusgalli, EC; Digitaria sanguinalis, DS; Setaria viridis, SV), which were comparable to the commercial control agent saflufenacil (≥90%). The protoporphyrinogen oxidase (PPO; EC. 1.3.3.4) activity experiment suggested that compound 34 could significantly reduce the PPO content in weeds, the relative expression levels of the PPO gene were verified by real-time quantitative polymerase chain reaction (RT-qPCR), and the results were consistent with the trend of the enzyme activity data. Molecular docking showed that compound 34 could occupy the PPO enzyme catalytic substrate pocket, which played an excellent inhibitory effect on the activity of receptor protein. Meanwhile, the tolerance of compound 34 to cotton was better than that of the commercial agent saflufenacil at 150 g of ai/ha. Thus, compound 34 exhibits the potential to be a new PPO herbicide for weed control in cotton fields. This study provided a basis for the subsequent structural modification and mechanism research of pyrimidinedione derivatives.

Design, Synthesis, and Anti-PVY Biological Activity of 1,3,5-Triazine Derivatives Containing Piperazine Structure.

In this study, a commercial agent with antivirus activity and moroxydine hydrochloride were employed to perform a lead optimization. A series of 1,3,5-triazine derivatives with piperazine structures were devised and synthesized, and an evaluation of their anti-potato virus Y (PVY) activity revealed that several of the target compounds possessed potent anti-PVY activity. The synthesis of compound C35 was directed by a 3D-quantitative structure-activity relationship that used the compound's structural parameters. The assessment of the anti-PVY activity of compound C35 revealed that its curative, protective, and inactivation activities (53.3 ± 2.5%, 56.9 ± 1.5%, and 85.8 ± 4.4%, respectively) were comparable to the positive control of ningnanmycin (49.1 ± 2.4%, 50.7 ± 4.1%, and 82.3 ± 6.4%) and were superior to moroxydine hydrochloride (36.7 ± 2.7%, 31.4 ± 2.0%, and 57.1 ± 1.8%). In addition, molecular docking demonstrated that C35 can form hydrogen bonds with glutamic acid at position 150 (GLU 150) of PVY CP, providing a partial theoretical basis for the antiviral activity of the target compounds.

Discovery of a Novel Class of Acylthiourea-Containing Isoxazoline Insecticides against Plutella xylostella.

Isoxazoline structures are widely found in natural products and are rich in biological activities. This study discloses the development of a series of novel isoxazoline derivatives by introducing acylthiourea fragments to access insecticidal activity. All synthetic compounds were examined for their insecticidal activity against Plutella xylostella, with results showing moderate to strong activity. Based on this, the structure-activity relationship analysis was carried out via the constructed three-dimensional quantitative structure-activity relationship model to further guide the structure optimization, resulting in the optimal compound 32. The LC50 of compound 32 against Plutella xylostella was 0.26 mg/L, demonstrating better activity than the positive control, ethiprole (LC50 = 3.81 mg/L), avermectin (LC50 = 12.32 mg/L), and compounds 1-31. The insect GABA enzyme-linked immunosorbent assay demonstrated that compound 32 might act on the insect GABA receptor, and the molecular docking assay further illustrated the mode of action of compound 32 with the GABA receptor. In addition, the proteomics analysis indicated that the action of compound 32 on Plutella xylostella was multi-pathway.

Carbene-Catalyzed Asymmetric Construction of Atropisomers.

Atropisomeric molecules have found proven applications and have shown promising potential in chemistry and medicine. The design of N-heterocyclic carbene (NHC) catalyzed reactions to construct atropisomerically enriched molecules has emerged as an important research topic in recent years. These reactions include kinetic resolutions, asymmetric desymmetrizations, central-to-axial chirality conversions, and cycloadditions. This Minireview evaluates and summarizes the progress in NHC-based organic catalysis for access to atropisomers, and briefly states our personal perspectives on the future advancement of this topic. NHC catalysis has provided rich and unique reaction modes that have led to success in the asymmetric synthesis of central-chiral molecules. It is expected that similar success could also be achieved in developing NHC catalysis to prepare atropisomeric molecules, including those not easily accessible by other methods.

Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products.

A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.

Gold and Carbene Relay Catalytic Enantioselective Cycloisomerization/Cyclization Reactions of Ynamides and Enals.

The combined use of gold as transition metal catalyst and N-heterocyclic carbene (NHC) as organic catalyst in the same solution for relay catalytic reactions was disclosed. The ynamide substrate was activated by gold catalyst to form unsaturated ketimine intermediate that subsequently reacted with the enals (via azolium enolate intermediate generated with NHC) effectively to form bicyclic lactam products with excellent diastereo- and enantio-selectivities. The gold and NHC coordination and dissociation can be dynamic and tunable events, and thus allow the co-existence of both active metal and carbene organic catalysts in appreciable concentrations, for the dual catalytic reaction to proceed.

N-Heterocyclic Carbene Catalyzed Radical Coupling of Aldehydes with Redox-Active Esters.

N-Heterocyclic carbene catalyzed radical reactions are challenging and underdeveloped. In a recent study, Ohmiya, Nagao and co-workers found that aldehyde carbonyl carbon centers can be coupled with alkyl radicals under NHC catalysis. An elegant aspect of this study is the use of a redox-active carboxylic ester that behaves as an single-electron oxidant to convert the Breslow intermediate into a radical adduct and concurrently release an alkyl radical intermediate as a reaction partner.

Formation of 1,4,2-Dithiazolidines or 1,3-Thiazetidines from 1,1-Dichloro-2-nitroethene and Phenylthiourea Derivatives.

A method for preparation of 1,4,2-dithiazolidine or 1,3-thiazetidine heterocycles was developed by reactions of phenylthioureas with 1,1-dichloro-2-nitroethene. The solvent has a significant influence on the type of product formation. 1,4,2-Dithiazolidines were formed in the aprotic solvent chloroform, while in the protic solvent ethanol, 1,3-thiazetidines were the main products.

Bactericidal bissulfone B7 targets bacterial pyruvate kinase to impair bacterial biology and pathogenicity in plants.

The prevention and control of rice bacterial leaf blight (BLB) disease has not yet been achieved due to the lack of effective agrochemicals and available targets. Herein, we develop a series of novel bissulfones and a novel target with a unique mechanism to address this challenge. The developed bissulfones can control Xanthomonas oryzae pv. oryzae (Xoo), and 2-(bis(methylsulfonyl)methylene)-N-(4-chlorophenyl) hydrazine-1-carboxamide (B7) is more effective than the commercial drugs thiodiazole copper (TC) and bismerthiazol (BT). Pyruvate kinase (PYK) in Xoo has been identified for the first time as the target protein of our bissulfone B7. PYK modulates bacterial virulence via a CRP-like protein (Clp)/two-component system regulatory protein (regR) axis. The elucidation of this pathway facilitates the use of B7 to reduce PYK expression at the transcriptional level, block PYK activity at the protein level, and impair the interaction within the PYK-Clp-regR complex via competitive inhibition, thereby attenuating bacterial biology and pathogenicity. This study offers insights into the molecular and mechanistic aspects underlying anti-Xoo strategies that target PYK. We believe that these valuable discoveries will be used for bacterial disease control in the future.

Innovative Arylimidazole-Fused Phytovirucides via Carbene-Catalyzed [3+4] Cycloaddition: Locking Viral Cell-To-Cell Movement by Out-Competing Virus Capsid-Host Interactions.

The control of potato virus Y (PVY) induced crop failure is a challengeable issue in agricultural chemistry. Although many anti-PVY agents are designed to focus on the functionally important coat protein (CP) of virus, how these drugs act on CP to inactivate viral pathogenicity, remains largely unknown. Herein, a PVY CP inhibitor -3j (S) is disclosed, which is accessed by developing unusually efficient (up to 99% yield) and chemo-selective (> 99:1 er in most cases) carbene-catalyzed [3+4] cycloaddition reactions. Compound -3j bears a unique arylimidazole-fused diazepine skeleton and shows chirality-preferred performance against PVY. In addition, -3j (S) as a mediator allows ARG191 (R191) of CP to be identified as a key amino acid site responsible for intercellular movement of virions. R191 is further demonstrated to be critical for the interaction between PVY CP and the plant functional protein NtCPIP, enabling virions to cross plasmodesmata. This key step can be significantly inhibited through bonding with the -3j (S) to further impair pathogenic behaviors involving systemic infection and particle assembly. The study reveals the in-depth mechanism of action of antiviral agents targeting PVY CP, and contributes to new drug structures and synthetic strategies for PVY management.

Status and Perspective on Green Pesticide Utilizations and Food Security.

Pesticides protect crops against pests, and green pesticides are referred to as effective, safe, and eco-friendly pesticides that are sustainably synthesized and manufactured (i.e., green chemistry production). Owing to their high efficacy, safety, and ecological compatibility, green pesticides have become a main direction of global pesticide research and development (R&D). Green pesticides attract attention because of their close association with the quality and safety of agricultural produce. In this review, we briefly define green pesticides and outline their significance, current registration, commercialization, and applications in China, the European Union, and the United States. Subsequently, we engage in an in-depth analysis of the impact of newly launched green pesticides on the environment and ecosystems. Finally, we focus on the potential risks of dietary exposure to green pesticides and the possible hazards of chronic toxicity and carcinogenicity. The status of and perspective on green pesticides can hopefully inspire green pesticide R&D and applications to ensure agricultural production and safeguard human and ecological health.

Synthesis, Bioactivities, and Antibacterial Mechanism of 5-(Thioether)-N-phenyl/benzyl-1,3,4-oxadiazole-2-carboxamide/amine Derivatives.

1,3,4-Oxadiazole thioethers have shown exciting antibacterial activities; however, the current mechanism of action involving such substances against bacteria is limited to proteomics-mediated protein pathways and differentially expressed gene analysis. Herein, we report a series of novel 1,3,4-oxadiazole thioethers containing a carboxamide/amine moiety, most of which show good in vitro and in vivo bacteriostatic activities. Compounds A10 and A18 were screened through CoMFA models as optimums against Xanthomonas oryzae pv. oryzae (Xoo, EC50 values of 5.32 and 4.63 mg/L, respectively) and Xanthomonas oryzae pv. oryzicola (Xoc, EC50 values of 7.58 and 7.65 mg/L, respectively). Compound A10 was implemented in proteomic techniques and activity-based protein profiling (ABPP) analysis to elucidate the antibacterial mechanism and biochemical targets. The results indicate that A10 disrupts the growth and pathogenicity of Xoc by interfering with pathways associated with bacterial virulence, including the two-component regulation system, flagellar assembly, bacterial secretion system, quorum sensing, ABC transporters, and bacterial chemotaxis. Specifically, the translational regulator (CsrA) and the virulence regulator (Xoc3530) are two effective target proteins of A10. Knocking out the CsrA or Xoc3530 gene in Xoc results in a significant reduction in the motility and pathogenicity of the mutant strains. This study contributes available molecular entities, effective targets, and mechanism basis for the management of rice bacterial diseases.

Design, Synthesis, and Insecticidal Activity of Pyridino[1,2-a]pyrimidines Containing Indole Moeites at the 1-Position.

Research on mesoionic structures in pesticide design has gained significant attention in recent years. However, the 1-position of pyridino[1,2-a]pyrimidine is usually designed with 2-chlorothiazole, 2-chloropyridine, or cyano moieties commonly found in neonicotinoid insecticides. In order to enrich the available pharmacophore library, here, we disclose a series of new pyridino[1,2-a]pyrimidine mesoionics bearing indole-containing substituents at the 1-position. Most of these target compounds are confirmed to have good insecticidal activity against aphids through bioevaluation. In addition, a three-dimensional structure-activity relationship model is established to allow access to optimal compound F45 with an LC50 value of 2.97 mg/L. This value is comparable to the property achieved by the positive control triflumezopyrim (LC50 = 2.94 mg/L). Proteomics and molecular docking analysis suggest that compound F45 has the potential to modulate the functioning of the aphid nervous system through its interaction with neuronal nicotinic acetylcholine receptors. This study expands the existing pharmacophore library for the future development of new mesoionic insecticides based on 1-position modifications of the pyridino[1,2-a]pyrimidine scaffold.

Design, Synthesis and Proteomics-Based Analysis of Novel Triazinone Derivatives Containing Amide Structures as Safer Protoporphyrinogen IX Oxidase Inhibitors.

Resistant weeds severely threaten crop yields as they compete with crops for resources required for survival. Trifludimoxazin, a protoporphyrinogen IX oxidase (PPO) inhibitor, can effectively control resistant weeds. However, its crop safety record is unsatisfactory. Consequently, a scaffold-hopping strategy is employed in this study to develop a series of new triazinone derivatives featuring an amide structure. Most compounds depicted excellent herbicidal activity across a broad spectrum at 37.5-150 g ai/ha, among which (R)-I-5 was equivalent to flumioxazin. (R)-I-5 demonstrated significant crop tolerance to rice and wheat, even at 150 g ai/ha. (R)-I-5 exhibited superior pharmacokinetic features compared to flumioxazin and trifludimoxazin. This was depicted by the absorption, distribution, metabolism, excretion, and toxicity predictions. Notably, proteomics-based analysis was applied for the first time to investigate variations among plant proteins before and after herbicide application, shedding light on the conservative and divergent roles of PPO.

Design, Synthesis, Antibacterial Activity, and Mechanisms of Novel Benzofuran Derivatives Containing Disulfide Moieties.

The unsatisfactory effects of conventional bactericides and antimicrobial resistance have increased the challenges in managing plant diseases caused by bacterial pests. Here, we report the successful design and synthesis of benzofuran derivatives using benzofuran as the core skeleton and splicing the disulfide moieties commonly seen in natural substances with antibacterial properties. Most of our developed benzofurans displayed remarkable antibacterial activities to frequently encountered pathogens, including Xanthomonas oryzae pv oryzae (Xoo), Xanthomonas oryzae pv oryzicola (Xoc), and Xanthomonas axonopodis pv citri (Xac). With the assistance of the three-dimensional quantitative constitutive relationship (3D-QSAR) model, the optimal compound V40 was obtained, which has better in vitro antibacterial activity with EC50 values of 0.28, 0.56, and 10.43 µg/mL against Xoo, Xoc, and Xac, respectively, than those of positive control, TC (66.41, 78.49, and 120.36 µg/mL) and allicin (8.40, 28.22, and 88.04 µg/mL). Combining the results of proteomic analysis and enzyme activity assay allows the antibacterial mechanism of V40 to be preliminarily revealed, suggesting its potential as a versatile bactericide in combating bacterial pests in the future.

Design, Synthesis, and Insecticidal Activity of Novel Isoxazoline Diacylhydrazine Compounds as GABA Receptor Inhibitors.

A series of isoxazoline derivatives containing diacylhydrazine moieties were designed and synthesized as potential insecticides. Most of these derivatives exhibited good insecticidal activities against Plutella xylostella, and some compounds exhibited excellent insecticidal activities against Spodoptera frugiperda. Especially, D14 showed outstanding insecticidal activity against P. xylostella (LC50 = 0.37 µg/mL), which was superior to that of ethiprole (LC50 = 2.84 µg/mL) and tebufenozide (LC50 = 15.3 µg/mL) and similar to that of fluxametamide (LC50 = 0.30 µg/mL). Remarkably, the insecticidal activity of D14 against S. frugiperda (LC50 = 1.72 µg/mL) was superior to that of chlorantraniliprole (LC50 = 3.64 µg/mL) and tebufenozide (LC50 = 60.5 µg/mL) but lower than that of fluxametamide (LC50 = 0.14 µg/mL). The results of electrophysiological experiments, molecular docking, and proteomics experiments indicate that compound D14 acts by interfering with the γ-aminobutyric acid receptor to control pests.

Inactivating Activities and Mechanism of Imidazo[1,2-c]pyrimidin-5(6H)-one Nucleoside Derivatives Incorporating a Sulfonamide Scaffold.

Twenty-eight imidazo[1,2-c]pyrimidin-5(6H)-one nucleoside derivatives incorporating a sulfonamide scaffold with preferable inactivating activities on pepper mild mottle virus (PMMoV) were designed and synthesized. Then, compound B29 with illustrious inactivating activity against PMMoV was received on the basis of the three-dimensional quantitative structure-activity relationship (3D-QSAR) model, with the EC50 of 11.4 µg/mL, which was superior to ningnanmycin (65.8 µg/mL) and template molecule B16 (15.3 µg/mL). Furthermore, (1) transmission electron microscopy (TEM) indicated that B29 could cause severe fracture of virions; (2) microscale thermophoresis (MST) and molecular docking further demonstrated that B29 had faintish binding affinities with PMMoV CPR62A (Kd = 202.84 µM), PMMoV CPL144A (Kd = 141.57 µM), and PMMoV CPR62A,L144A (Kd = 332.06 µM) compared to PMMoV CP (Kd = 4.76 µM); and (3) western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results of pCB-GFP-PMMoV CPR62A, pCB-GFP-PMMoV CPL144A, and pCB-GFP-PMMoV CPR62A,L144A were consistent with MST and confocal. In brief, the above results indicated that the amino acids at positions 62 and 144 of PMMoV CP might be the key amino acid sites of B29 acted on.

Design, Synthesis, and Insecticidal Activity of Mesoionic Pyrido[1,2-a]pyrimidinone Containing Isoxazole/Isoxazoline Moiety as a Potential Insecticide.

Bean aphid (Aphis craccivora) resistance to commonly used insecticides has made controlling these pests increasingly difficult. In this study, we introduced isoxazole and isoxazoline, which possess insecticidal activity, into pyrido[1,2-a]pyrimidinone through a scaffold hopping strategy. We designed and synthesized a series of novel mesoionic compounds that exhibited a range of insecticidal activities against A. craccivora. The LC50 values of compounds E1 and E2 were 0.73 and 0.88 µg/mL, respectively, better than triflumezopyrim (LC50 = 2.43 µg/mL). Proteomics and molecular docking analyses showed that E1 might influence the A. craccivora nervous system by interacting with neuronal nicotinic acetylcholine receptors (nAChRs). This research offers a new approach to the advancement of novel mesoionic insecticides.

Immune Mechanism of Ethylicin-Induced Resistance to Xanthomonas oryzae pv. oryzae in Rice.

Ethylicin (ET) was reported to be promising in the control of rice bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo). The detailed mechanism for this process remains unknown. Disclosed here is an in-depth study on the action mode of ET to Xoo. Through plant physiological and biochemical analysis, it was found that ET could inhibit the proliferation of Xoo by increasing the content of defense enzymes and chlorophyll in rice (Oryza sativa ssp. Japonica cv. Nipponbare). Label-free quantitative proteomic analysis showed that ET affected the rice abscisic acid (ABA) signal pathway and made the critical differential calcium-dependent protein kinase 24 (OsCPK24) more active. In addition, the biological function of OsCPK24 as a mediator for rice resistance to Xoo was determined through the anti-Xoo phenotypic test of OsCPK24 transgenic rice and the affinity analysis of the OsCPK24 recombinant protein in vitro and ET. This study revealed the molecular mechanism of ET-induced resistance to Xoo in rice via OsCPK24, which provided a basis for the development of new bactericides based on the OsCPK24 protein.