Synthesis, Herbicidal Activity against Barnyard Grass, and Photolytic Behavior of Aryl 2,6-Dipyrimidinoxybenzoates.

In this study, we investigated the characteristics and herbicidal potential of bispyribac phenolic esters, which belong to the 2-(pyrimidin-2-yloxy)benzoic acid (PYB) class of acetohydroxyacid synthase (AHAS-)-inhibiting herbicides. These herbicides are primarily used for controlling Poaceae and broadleaf weeds. Among them, bispyribac-sodium stands out as a representative in this class. Surprisingly, other bispyribac esters, including alkanol and phenol esters exhibit considerably reduced herbicidal activity compared to bispyribac-sodium. In contrast, oxime esters (e.g., pyribenzoxim) demonstrate high activity. To further understand and develop novel PYB herbicides, we synthesized and screened a series of bispyribac phenolic esters while investigating their photochemical behaviors. Several compounds displayed excellent herbicidal activity, with compounds Ia-19 and Ic showing impressive 90% effective dosages for fresh weight inhibition of barnyard grass, measuring 0.55 and 0.60 g a.i./hm2, respectively. These values were approximately half of bispyribac-sodium or pyribenzoxim. The results indicate that the herbicidal activity of phenolic esters is influenced by both their binding ability to the AHAS enzyme and their decomposition into bispyribac acid. For instance, bispyribac phenol ester exhibited considerably reduced receptor affinity compared to bispyribac-sodium, and faced challenges in transforming into bispyribac acid, explaining its diminished herbicidal activity. However, introducing a photosensitive nitro group led to a complete transformation. This modification improved its affinity with AHAS and accelerated its decomposition into bispyribac acid, further accelerated by photocatalysis. Consequently, nitro-containing compounds displayed heightened herbicidal activity. The findings from this study open possibilities for structural optimization of phenolic esters through quantitative structure-activity relationship analysis, potentially regulating their activity-releasing period. Furthermore, the high activity of aromatic heterocyclic esters offers new insights into developing novel PYB herbicides.

Design, Synthesis, and Biological Investigations of Novel Carbamoylguanidinyl Nitrobenzoxadiazoles against Chitinolytic Enzymes.

Chitinase has been identified as an important target for insecticides. In this study, a series of novel chitinase inhibitors was designed and synthesized with nitrobenzoxadiazoles. Compound 8d, which contains the N-methylcarbamoylguanidinyl, exhibited high enzyme inhibitory activity and achieved nanomolar inhibition against OfChtI (IC50 = 12.3 nM). Delightfully, it was also found to possess significant inhibitory activity against OfHex1 (IC50 = 1.76 µM). The computational simulation results indicated that compound 8d interacted with OfChtI and OfHex1 in similar modes through hydrogen bonds and hydrophobic and π-π interactions. Insecticidal activity studies revealed that compound 8d showed high mortality against the Lepidoptera Plutella xylostella (mortality rate = 81%) at 200 mg/L. Toxicity studies indicated that compound 8d exhibited negligible toxicity to the natural enemy Trichogramma ostriniae. These results indicate that compound 8d may be a promising candidate for the development of environmentally friendly chitinase inhibitors. Moreover, this study provides a new angle for the design of innovative inhibitors of chitinolytic enzymes.

o-Nitrobenzyl-Based Caged exo-16,17-Dihydro-gibberellin A5-13-acetate for Photocontrolled Release of Plant Growth Regulators.

Caged plant growth regulators (caged PGRs) that release bioactive molecules under irradiation are critical in enhancing the efficacy and mitigating the negative environmental effects of PGRs. The synthetically derived plant growth inhibitor exo-16,17-dihydro-gibberellin A5-13-acetate (DHGA5) regulates the development and stress resilience of plants. We report here the conception of novel caged DHGA5 derivatives wherein the photoremovable protecting groups (PRPGs) serve not only to enable light-controlled release but also to protect the carboxyl group during chemical synthesis. Three o-nitrobenzyl-based caged DHGA5 derivatives with different substituents on the nitrobenzyl moiety were obtained and evaluated for their properties in vitro and in vivo. The photolysis half-life values of caged DHGA5 derivatives 7a, 7b, and 7c under a UV lamp were 15.6 h, 1.2 h, and 28.2 h, respectively. Experiments in vivo showed that 0.2 mM of the caged compounds significantly inhibited the growth of the model plant Arabidopsis thaliana and important crop rice in a precise photoactivated form.

Discovery of Potent N-Methylcarbamoylguanidino Insect Growth Regulators Targeting OfChtI and OfChi-h.

Insect growth regulators (IGRs) are important insecticides that reduce the harm caused by insects to crops by controlling pest population growth. Chitinases are closely associated with insect growth and are among the most important glycoside hydrolases. Thus, Chitinase is an attractive target for the development of novel insecticides. In this study, we designed and synthesized a series of novel and highly potent insecticides targeting OfChtI and OfChi-h in insects. Enzymatic activity tests showed that most compounds exhibited a potent inhibitory activity against OfCh-h. Binding mode analysis revealed that the target compounds bound to the -1 active subsite of Chitinase through the key pharmacophore N-methylcarbamoylguanidino. Compounds 6e, 6g, 6j, and 6o significantly affected the growth and development of Plutella xylostella at 200 mg/L. Our study provides novel insights for the development of potent insecticide-targeted Chitinase combinations based on receptors and ligands.

Theoretical and Experimental Studies on Plant Light-Dependent Protochlorophyllide Oxidoreductase as a Novel Target for Searching Potential Herbicides.

Herbicide resistance is a prevalent problem that has posed a foremost challenge to crop production worldwide. Light-dependent enzyme NADPH: protochlorophyllide oxidoreductase (LPOR) in plants is a metabolic target that could satisfy this unmet demand. Herein, for the first time, we embarked on proposing a new mode of action of herbicides by performing structure-based virtual screening targeting multiple LPOR binding sites, with the determination of further bioactivity on the lead series. The feasibility of exploiting high selectivity and safety herbicides targeting LPOR was discussed from the perspective of the origin and phylogeny. Besides, we revealed the structural rearrangement and the selection key for NADPH cofactor binding to LPOR. Based on these, multitarget virtual screening was performed and the result identified compounds 2 affording micromolar inhibition, in which the IC50 reached 4.74 µM. Transcriptome analysis revealed that compound 2 induced more genes related to chlorophyll synthesis in Arabidopsis thaliana, especially the LPOR genes. Additionally, we clarified that these compounds binding to the site enhanced the overall stability and local rigidity of the complex systems from molecular dynamics simulation. This study delivers a guideline on how to assess activity-determining features of inhibitors to LPOR and how to translate this knowledge into the design of novel and effective inhibitors against malignant weed that act by targeting LPOR.

Discovery of aromatic 2-(3-(methylcarbamoyl) guanidino)-N-aylacetamides as highly potent chitinase inhibitors.

Chitinases are important glycoside hydrolases that are closely related to bacterial pathogenesis, fungal cell wall remodelling, and insect moulting. Consequently, chitinases have become attractive targets for therapeutic drugs and pesticides. In this study, we designed and synthesised a series of novel chitinase inhibitors based on the N-methylcarbamoylguanidinyl group of the natural product argifin. The most active compound 8h showed strong inhibitory activity against the group I chitinases HsChit1, SmChiB, and OfChi-h, with IC50 values of 0.19 µM, 4.2 nM, and 25 nM, respectively. Binding mode studies revealed that the compound 8h formed π-π stacking/hydrophobic interactions at +1 or +2 subsite of chitinases. In addition, a key hydrogen bond net was formed between the pharmacophore N-methylcarbamoylguanidinyl and key residues at the -1 subsite. Together, the findings of this study provide novel insights into the development of potent small-molecule chitinase inhibitors using a combination of planar structures and N-methylcarbamoylguanidinyl.

High performance of privacy-preserving acute myocardial infarction auxiliary diagnosis based on federated learning: a multicenter retrospective study.

Background: Multicenter medical research is becoming a new trend. However, interagency data privacy security protection has become a major bottleneck of multicenter research. Therefore, to overcome this privacy protection issue, the aim of the present study was to apply a self-developed privacy-preserving machine learning framework for researchers who can build models on medical data from multiple sources, while providing privacy protection for both sensitive data and the learned model. Methods: Based on Arya, a novel privacy computing platform developed by Healink, we constructed a privacy-preserving federated learning (FL) model using the fully connected neural network with datasets from 2-3 individual medical institutions. In the dataset, 80% of records were used for joint modeling on acute myocardial infarction (AMI) diagnosis. Modeling efficacy was evaluated with the remaining 20% of records. As the control, 1,500 medical records from 1 medical institution were used for single-center modeling and efficacy evaluation. During the process, the original data were still kept in individual hospital without moving or transferring out of the hospitial. The diagnostic efficacy (sensitivity, positive predictive value, and accuracy) was evaluated. Results: Our privacy-preserving FL model gives reliable AMI diagnostic efficacy. Three-center modeling (79% sensitivity, 88% positive predictive value, and 82.3% accuracy) and two-center modeling (77.8% or 77.6% sensitivity, 86.7% or 85.30% positive predictive value, and 81% or 79.7% accuracy) achieved relative high diagnostic efficacy; and single-center modeling achieved relative low diagnostic efficacy (76% sensitivity, 84.7% positive predictive value, and 79% accuracy). Conclusions: The Arya privacy computing platform is efficient and practical for the FL model, which could promote multicenter medical research securely without sacrificing diagnostic efficacy.

Ultrasensitive antibody production strategy based on hapten property for simultaneous immunoassay.

A high-quality antibody production strategy is significant for immunoassay. In this work, four general haptens were proposed based on the 3D structure and surface electrostatic potential of molecular modeling. It was found that the sensitivity and specificity of polyclonal antibodies (pAbs) mainly depended on the bond angle of shapes liked "V" between haptens and proteins and hydrophobic parts of haptens. The quantified process was employed to obtain pAbs against cyhalofop-butyl and its metabolites (CAFs), with the IC50 value of 4.9 µg·L-1 under optimal conditions. The limit of quantization (LOQ) of the ultrasensitive icELISA in brown rice was 2 µg·kg-1. The recoveries were 74%-110%, with a coefficient of variation (CV) less than 10%. This study indicated that the hapten property approach led to an improved immunoassay.

Investigation on the interaction of pyrethroid pesticides to estrogen receptor alpha through computational and experimental methods.

Pyrethroid insecticides are a group of widely used bio-mimetic synthetic pesticides. However, recent studies reported that they could have an accumulation effect in human which may cause series of health problems. Estrogen receptors (ER) are a class of nuclear receptors that are vital in proper physiological behavior of estrogens. To investigate the reproductive toxicity of pyrethroids, homology modeling, molecular docking, molecular dynamic simulations (MDs) were conducted to explore the interaction between pyrethroids and ERα from atomic scale. The human ERα (2YJA) was selected as a template protein for homology modeling. Then eight typical pyrethroids and positive control estradiol were docked to the modeled protein. The highest scoring bifenthrin and the lowest scoring permethrin were chosen for in-depth analysis. MDs showed that the complex formed by permethrin with ERα had a lower RMSD value and binding free energies compared to bifenthrin. Based on these results from microscopic dimension, exposure experiments were implemented to validate the primary conclusions. VTG concentrations in male zebrafish's blood were significantly higher under permethrin exposure than bifenthrin, suggesting a stronger estrogenic activity and binding propensity. In this regard, the structural characteristics of molecules were analyzed, expecting to provide theoretical references for subsequent drug design and rational drug application.

One-Step construction of Polyimide/NH2-UiO-66 heterojunction for enhanced photocatalytic degradation of sulfonamides.

Photocatalysis treatment is a promising technology to eliminate water pollutants. Herein, we constructed polyimide/NH2-UiO-66 composites (PUs) through a facile one-step solvothermal method for the photocatalytic degradation of sulfonamides. The optimized photocatalyst PU1.5 was superior to the photocatalysts prepared through multi-step methods due to the more exposed (001) facets of polyimide and the better distribution of small NH2-UiO-66 particles. PU1.5 showed the highest photocatalytic activity, which was 9.5 and 92.0 times higher than that of polyimide and NH2-UiO-66. Such improvement was attributed to the improved carrier separation efficiency resulted from direct Z-scheme heterojunction. The probable degradation pathway of sulfathiazole was proposed by the LC-MS/MS and Density Functional Theory (DFT) calculation. Furthermore, the reduced toxicity and the little antibacterial activity of intermediates was investigated by the Quantitative Structure-Activity Relationship (QSAR) analysis and the residual antibiotic activity experiment. The study might provide a new strategy for designing composite photocatalyst to achieve efficient removal of pollutants.

Role of Thylakoid Lipids in Protochlorophyllide Oxidoreductase Activation: Allosteric Mechanism Elucidated by a Computational Study.

Light-dependent protochlorophyllide oxidoreductase (LPOR) is a chlorophyll synthetase that catalyzes the reduction of protochlorophyllide (Pchlide) to chlorophyllide (Chlide) with indispensable roles in regulating photosynthesis processes. A recent study confirmed that thylakoid lipids (TL) were able to allosterically enhance modulator-induced LPOR activation. However, the allosteric modulation mechanism of LPOR by these compounds remains unclear. Herein, we integrated multiple computational approaches to explore the potential cavities in the Arabidopsis thaliana LPOR and an allosteric site around the helix-G region where high affinity for phosphatidyl glycerol (PG) was identified. Adopting accelerated molecular dynamics simulation for different LPOR states, we rigorously analyzed binary LPOR/PG and ternary LPOR/NADPH/PG complexes in terms of their dynamics, energetics, and attainable allosteric regulation. Our findings clarify the experimental observation of increased NADPH binding affinity for LPOR with PGs. Moreover, the simulations indicated that allosteric regulators targeting LPOR favor a mechanism involving lid opening upon binding to an allosteric hinge pocket mechanism. This understanding paves the way for designing novel LPOR activators and expanding the applications of LPOR.

Structure and Function of the Refined C-Terminal Loop in Imidazole Glycerol Phosphate Dehydratase from Different Homologs.

IGPD is an essential metalloenzyme that catalyzes histidine biosynthesis. We found that its C-terminus loop region has a vital role in determining enzyme activity but has been hardly mentioned before. In this work, we focused on the dynamic feature and function of C-Loop in Arabidopsis thaliana and Saccharomyces cerevisiae IGPD (At_IGPD and Sc_IGPD, respectively). Due to the high flexibility of this region, we performed a total of 3.4 µs of accelerated molecular dynamics simulation to enhance sampling. Inhibitor C348 in At-IGPD exhibited instability in the later stage of simulation, while the characteristic sequence in Sc_IGPD reduced solvent interference and significantly restrained the interaction mode. For the C-Loop-assisted ligand-binding process, we proposed a "Lock-Lid" model. Meanwhile, the dissociated ligand in At_IGPD served as a probe, a metastable pocket was determined at the root of C-Loop, and its rationality was proved by theoretical verification and enzyme mutation experiments. This study complemented the important structural features of C-Loop and provided a basis for the design of selective inhibitors. Considering the absence in mammals, we suggested that IGPD could be a promising germicide target.

Study on the binding mechanism of thiamethoxam with three model proteins:spectroscopic studies and theoretical simulations.

As a top-selling neonicotinoid insecticide widely used in the field, thiamethoxam is an environmental pollutant because of the accumulation in ecosystem and has also been reported that it has potential risks to the health of mammals even humans. In order to understand the binding mechanism of thiamethoxam with biological receptors, spectroscopic techniques and theoretical simulations was used to explore the specific interactions between thiamethoxam and proteins. Interestingly, the results indicated that hydrophobic interaction as the main driving force, thiamethoxam formed a single binding site complex with proteins spontaneously, resulting in a decrease in the esterase-like activity of human serum albumin. The results of computer simulation showed that there were hydrophobic, electrostatic and hydrogen bonding interactions between thiamethoxam and receptors. The results of experiment and computer simulation were mutually confirmed, so a model was established for the interaction between the two which uncovered the structural characteristics of the binding site. This research provided new insights for the structure optimization of thiamethoxam, as well as gave an effective reference for evaluating the risk of thiamethoxam systemically in the future.

Identification of novel insect ß-N-acetylhexosaminidase OfHex1 inhibitors based on virtual screening, biological evaluation, and molecular dynamics simulation.

Chitin can be widely found in the fungal cell wall, nematode eggshells, and the exoskeleton of arthropods; however, it is completely absent from higher plants and mammals. The process of chitin degradation is essential for both growth and maturation of insects. Thus, inhibiting chitin degradation is a promising strategy for the control and management of pests. The chitinolytic ß-N-acetyl-D-hexosaminidase OfHex1 of Ostrinia furnacalis (one of the most destructive pests) has been suggested as a potential target for the design of eco-friendly pesticides. This study presents the sequential virtual screening of the ZINC library with 8 million compounds, targeting OfHex1. After confirmation via enzyme inhibition experiments, compound 5 exhibited potential inhibitory activity against OfHex1 with a Ki of 28.9 ± 0.5 µM and significant selectivity (IC50 > 100 µM against HsHexB and hOGA). Molecular dynamics simulations combined with binding free energy and free energy decomposition calculations were conducted to investigate the molecular basis underlying the potency of these inhibitors toward OfHex1. The present work provides useful information for the future rational design of novel and potent OfHex1 inhibitorsCommunicated by Ramaswamy H. Sarma.

Design, synthesis biological activity, and docking of novel fluopyram derivatives containing guanidine group.

Succinate dehydrogenase (SDH), a crucial bridge enzyme between the respiratory electron transfer chain and tricarboxylic acid (or Krebs) cycle, has been identified as an ideal target for the development of effective fungicide. In this study, a series of 24 novel SDH inhibitors (SDHIs) were designed, synthesized, and characterized by 1H NMR, 13C NMR, and HRMS. In vitro fungicidal activity experiments, most of the compounds exhibited broad-spectrum antifungal activities against five plant pathogenic fungi. Compounds 9j and 9k showed excellent activities against Pythium aphanidermatum with EC50 values of 9.93 mg/L and 10.50 mg/L, respectively, which were superior to the lead compound Fluopyram with an EC50 value of 19.10 mg/L. Furthermore, the toxicity of these compounds was also tested against Meloidogyne incognita J2 nematodes. The results indicated that compound 9x exhibited moderate nematicidal activity (LC50/48 h = 71.02 mg/L). Molecular docking showed that novel guanidine amide of 9j formed hydrogen bonds with crucial residues, which was crucial to the binding of an inhibitor and SDH. This present work indicates that these derivatives may serve as novel potential fungicides targeting SDH.

APAn, a Class of ABA Receptor Agonism/Antagonism Switching Probes.

In plants, biosynthesized ABA undergoes two important physiological processes of signal transduction and metabolism simultaneously. In this study, we described a class of ABA receptor agonist/antagonist switching probes APAn, which can regulate the agonistic activity or antagonistic activity according to the length of a 6'-alkoxyl chain. From APA1 to APA6, with the extension of the alkoxyl chain, it showed a gradually increased receptor-binding potential and decreased HAB1 inhibition activity. Theoretical analysis based on molecular docking and molecular dynamics simulation revealed that some factors outside the ligand-binding pocket in receptors could also affect the binding of the ligand to the receptor, for example, the van der Waals interaction between the alkyl chain in APAn and the 3'-tunnel of ABA receptors made it bind more tightly than iso-PhABA. This enhanced binding made it an antagonist rather than a weakened agonist.

Synthesis of ureido thioglycosides as novel insect ß­N­acetylhexosaminidase OfHex1 inhibitors.

The insect ß-N-acetylhexosaminidase OfHex1 from Ostrinia furnacalis (one of the most destructive agricultural pests) has been considered as a promising pesticide target. In this study, a series of novel and readily available ureido thioglycosides were designed and synthesized based on the catalytic mechanism and the co-crystal structures of OfHex1 with substrates. After evaluation via enzyme inhibition experiments, thioglycosides 11c and 15k were found to have inhibitory activities against OfHex1 with the Ki values of 25.6 µM and 53.8 µM, respectively. In addition, all these ureido thioglycosides exhibited high selectivity toward OfHex1 over hOGA and HsHexB (Ki > 100 µM). Furthermore, to investigate the inhibitory mechanism, the possible binding modes of 11c and 15k with OfHex1 were deduced based on molecular docking analysis. This work may provide useful structural starting points for further rational design of potent inhibitors of OfHex1.

Computational and experimental investigations on the interactions of aryloxy-phenoxy-propionate herbicides to estrogen receptor alpha in zebrafish.

When the amount of pesticide exceeds the self-purification ability of the environment, it will be enriched in the human body through the atmosphere, soil, water circulation, etc., threatening human health. Aryloxy-phenoxy-propionate (APP) herbicides are a class of acetyl-CoA carboxylase (ACCase) inhibitor herbicides, widely used in field-weeding of soybean, cabbage, peanut and other crops. However, due to the water circulation, surface runoff and the agronomic practices such as watering irrigation, APP herbicides have the risk of polluting water and destroying the living environment of aquatic organisms. In this paper, a multistep framework combining homology modeling, molecular docking and molecular dynamic simulations were adopted to explore the interactions between APP herbicides and zebrafish estrogen receptor α (ERα) to investigate the estrogenic activities of the herbicides. The structure of zebrafish ERα was modeled by homology modeling, using the human's estrogen receptor α (PDB ID:2YJA) as the template. Then, eight typical APP herbicides were selected to dock with the zebrafish ERα, and it was determined that there were clear interactions between the herbicides and the receptor. The binding patterns of Quizalofop-P-ethyl (QPE), Clodinafop-propargyl (CP) and Haloxyfop-P (HP) with ERα were further investigated by molecular dynamics and binding free energy calculation. The results showed the van der Waals force and electrostatic force were the main driving forces for maintaining the stability of the complex system. In order to verify the theoretical prediction, an exposed experiment was conducted to study the effects of different concentrations of herbicides on VTG level of zebrafish in vivo and the results were consistent with the computational method. The results of this study revealed the mechanism of the action between APP herbicides and zebrafish estrogen receptors, and also provided ideas for optimizing the herbicides.

Discovery of Novel Inhibitors Targeting Human O-GlcNAcase: Docking-Based Virtual Screening, Biological Evaluation, Structural Modification, and Molecular Dynamics Simulation.

ß-N-Acetylhexosaminidases have emerged as promising targets for drug and pesticide discovery due to their critical physiological functions in various cellular processes. In particular, human O-GlcNAcase (hOGA) from the glycoside hydrolase family 84 (GH84) has gained significant attention. This enzyme was found to be linked to various diseases such as diabetes, cancer, and Alzheimer's disease (AD). In this study, to develop novel hOGA inhibitors with suitable pharmaceutical properties, virtual screening of the Drugbank database was performed using a docking-based approach targeting hOGA. Chlorhexidine (4, Ki = 4.0 µM) was identified as a potent hOGA inhibitor with excellent selectivity (Ki > 200 µM against human ß-N-acetylhexosaminidase B) and subjected to structural modifications and SAR studies. Furthermore, molecular dynamics simulations as well as binding free energy and free energy decomposition calculations were carried out to investigate the basis for the efficiency of potent inhibitors against hOGA. This present work revealed the new application of the disinfectant chlorhexidine and provided useful information for the future design of hOGA inhibitors.

Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase.

ß-N-acetylhexosaminidases represent an important class of exoglycosidases and have emerged as the promising targets for drug and pesticide discovery. Among these, human O-GlcNAcase (hOGA) has been reported to be closely linked to several diseases such as Alzheimer's disease, diabetes, and cancer. Potent hOGA inhibitors with high selectivity are therefore of great significance for the regulation of the corresponding physiological processes. In this study, several classes of novel and readily available thioglycosyl-naphthalimides bearing the amide linker were designed and synthesized. To investigate their potency and selectivity, the inhibitory efficiencies toward hOGA and human ß-N-acetylhexosaminidase B (HsHexB) were assayed. Especially, compounds 10a (K i = 0.61 µM) and 16l (K i = 0.72 µM) exhibited excellent inhibitory potency against hOGA and high selectivity (HsHexB, K i > 100 µM). In addition, during the preparation of these thioglycosyl-naphthalimides, a new practical method was developed for the synthesis of ureido glycosides from trichloroethyl carbamates at room temperature and normal pressure without catalyst. Furthermore, the possible binding modes of hOGA with 10a, 10d, and 16j were studied using molecular docking and molecular dynamics simulations to explore the molecular basis for the potency of these thioglycosides. This work present here provides useful clues for the further structural optimization toward hOGA.