Three-dimensional Quantitative Structure-activity Relationship Research Articles

Aromatase as a novel target of parabens in human and rat placentas: 3D-quantitative structure-activity relationship and docking analysis

Aromatase (CYP19A1), a pivotal enzyme in the biosynthesis of estradiol from testosterone, is predominantly expressed in reproductive tissues including placentas. This study investigated the effects of paraben acid and nine parabens on the activity of human and rat CYP19A1 using microsomes derived from human and rat placentas and on estradiol secretion in human choriocarcinoma BeWo cells. The results showed that propyl, butyl, hexyl, heptyl, and nonyl parabens significantly inhibited human CYP19A1 activity, with IC50 values of 66.37, 61.08, 55.65, 48.26, and 27.24 μM, respectively. In BeWo cells, these parabens notably diminished estradiol secretion at concentrations of 100 μM. Similarly, rat CYP19A1 was inhibited by these parabens, with IC50 values of 98.07, 70.10, 41.30, 27.93, and 6.33 μM for propyl, butyl, hexyl, heptyl, and nonyl parabens, respectively. Kinetic analysis identified these compounds as mixed inhibitors. Bivariate correlation analysis revealed a negative correlation between the partition coefficient value, molecular weight, the number of carbon atoms in the alcohol moiety, as well as heavy atom number and IC50 values. Three-dimensional quantitative structure-activity relationship analysis highlighted the critical role of hydrophobic regions in determining inhibitory potency. Docking studies suggested that parabens interact with the heme-iron binding site of both human and rat CYP19A1. This study elucidates the inhibitory effects of various parabens on CYP19A1 and their binding mechanisms, thereby providing a deeper understanding of their potential impact on estrogen biosynthesis.

Novel "Phenyl-Pyrazoline-Oxadiazole" Ternary Substructure Derivatives: Synthesis, Insecticidal Activities, and Structure-Activity Relationship Study.

In recent years, isoxazole insecticides or parasiticides targeting the γ-aminobutyric acid receptor, such as fluralaner or fluxametamide, featured a novel chemical structure and exhibited potent insecticidal activity with no-cross resistance. Thus, many research institutes have tried to modify the structures of these agents to find a new insecticide. Previously, the majority of researchers stuck to the "phenyl-isoxazole-phenyl" structure, making modifications only to other components. In this study, the "phenyl-isoxazole-phenyl" ternary motif was modified for the first time based on bioisosterism theory. A series of new derivatives carrying pyrazoline and 1,3,4-oxadiazole moieties were designed and synthesized to investigate their insecticidal activities against the diamondback moth (Plutella xylostella) and fall armyworm (Spodoptera frugiperda). Preliminary bioassay data showed that some of the target compounds exhibited good insecticidal activities against P. xylostella and S. frugiperda. Especially, compound A21 showed insecticidal activity against P. xylostella (LC50 = 1.2 μg/mL) better than commercial insecticide ethiprole (LC50 = 2.9 μg/mL) but worse than parasiticide fluralaner (LC50 = 0.5 μg/mL). Similarly, compound A21 exhibited insecticidal activity to S. frugiperda (LC50 = 13.2 μg/mL) better than commercial insecticide fipronil (LC50 = 78.8 μg/mL) but worse than fluralaner (LC50 = 0.7 μg/mL). Compound A21 could serve as a potential lead compound to control P. xylostella and S. frugiperda. The three-dimensional quantitative structure-activity relationship model revealed that the further introduction of an electron-donating group in the 2- or 3-site may increase the insecticidal activity of A21. Molecular dynamics simulations showed that the hydrogen bond of A21 and receptor was important for the binding receptor. This study has identified a new substructure called "phenyl-pyrroline-oxadiazole" instead of the previously known "phenyl-isoxazole-phenyl" substructure, offering a useful guide for the design of novel insecticide molecules.

Design, Synthesis, and 3D-QASR of Oxazoline Derivatives Containing an S-S Moiety as Potential Acaricide.

To mitigate the detrimental effects of agricultural pest mites on crop yield, an active substructure splicing strategy was employed to modify etoxazole by introducing an S-S moiety. The target products were obtained efficiently via a bilateral disulfurating reagent (DSMO), which was developed by our group. The leaf dip method was used to evaluate the activities of the designed target compounds against the eggs and larvae of the spider mite (Tetranychus cinnabarinus). Most of the target compounds exhibited good efficacy in controlling the larvae and eggs of T. cinnabarinus. Based on these results, a three-dimensional quantitative structure-activity relationship (3D-QSAR) model was established to guide the construction of compound 7l. Notably, compound 7l exhibited a better activity against T. cinnabarinus eggs (LC50 = 0.0035 mg/L) compared to etoxazole (LC50 = 0.2990 mg/L). Greenhouse bioassays indicated that compound 7l exhibits excellent acaricidal activity against egg of T. cinnabarinus, which is better than the etoxazole at 1.0 mg/L. Additionally, some of the compounds showed inhibitory effects against Dickeya zeae (D. zeae), Xanthomonas campestris pv campestris (Xcc), Xanthomonas oryzae pvoryza (Xoo), and Xanthomonas oryzae pvoryzicola (Xoc). Furthermore, compounds 7l not only exhibited relatively potent against Plutella xylostella activities (LC50 = 24.0 mg/L) but also had low toxicity (LC50 > 11.0 μg/bee) to Apis mellifera. In conclusion, the current experimental results suggest that oxazoline derivatives containing an S-S moiety have the potential to serve as lead compounds for the development of novel acaricide agents.

Design, synthesis, evaluation, pharmacophore modeling, and 3D-QSAR of lappaconitine analogs as potential analgesic agents.

Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds 5a, 5c, 5e, 6, and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED50 values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure-activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.

Design, Synthesis, Antifungal Evaluation, and Three-Dimensional Quantitative Structure-Activity Relationship of Novel 5-Sulfonyl-1,3,4-thiadiazole Flavonoids.

Plant pathogenic fungi frequently disrupt the normal physiological and biochemical functions of plants, leading to diseases, compromising plant health, and ultimately reducing crop yield. This study aimed to address this challenge by identifying antifungal agents with innovative structures and novel mechanisms of action. We designed and synthesized a series of flavonoid derivatives substituted with 5-sulfonyl-1,3,4-thiadiazole and evaluated their antifungal activity against five phytopathogenic fungi. Most flavonoid derivatives demonstrated excellent antifungal activity against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Rhizoctorzia solani (R. solani), Fusarium graminearum (F. graminearum), and Colletotrichum orbiculare (C. orbiculare). Specifically, the EC50 values of 38 target compounds against R. solani were below 4 μg/mL, among which the compounds C13 (EC50 = 0.49 μg/mL), C15 (EC50 = 0.37 μg/mL), and C19 (EC50 = 0.37 μg/mL) had the most prominent antifungal activity, superior to that of the control drug carbendazim (EC50 = 0.52 μg/mL). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of the cellular ultrastructures of R. solani mycelia and cells after treatment with the compound C19 revealed sprawling growth of hyphae, a distorted outline of their cell walls, and reduced mitochondrial numbers. Studying the 3D-QSAR between the molecular structure and antifungal activity of 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoid derivatives could significantly improve conventional drug molecular design pathways and facilitate the development of novel antifungal leads.

The 3D-QSAR Study, Molecular Docking, and ADMET Analysis of Darunavir Derivatives of HIV-1 Protease Inhibitors

Background: Acquired Immunodeficiency Syndrome (AIDS) is one of most prevalent infectious diseases in the world , and HIV-1 protease (PR) is a vital target of drug design. Nowadays, three-dimensional quantitative structure-activity relationships (3D-QSAR) are applied to help design new protease inhibitions (PIs). Objective: The primary objective of this study is to apply the 3D-QSAR study to a series of 42 derivatives of Darunavir (DRV) and to design new molecules possessing high antivirus activity. Methods: Partial Least Squares (PLS) were used to cross-validate the dataset of compounds, and the optimal number of principal components (ONC), cross-validate coefficient (q²), standard error of estimate (SEE), non-cross-validated correlation coefficient (R²) and fisher test value (F) were calculated to assess model robustness. In this study, the CoMSIA-DAH model (q²=0.754, r²= 0.988, rpred2=0.57) possessed the highest predicted activity. Newly designed molecules were analyzed by docking studies with compound 25 taken as a template. Results: Within eight newly designed drugs, compound N02 possessed the highest antivirus activity (IC50=0.00461 nM) predicted by the CoMSIA-DAH model. The Surflex-Dock module of SYBYL-X 2.0 was used to affirm the predicted anti-PR activity of the newly designed compounds and the results of docking complex structure could be visualized. All newly designed molecules were in agreement with CSore above four and the docking study revealed that Asp29, Asp30, Ile50, Asp124, Asp128, Asp129 and Ile149 were critical residues in the process of inhibiting PR. Conclusion: One of the main aspects of this study is the successful design of a series of molecules with excellent investigatory values, which elucidates explicit quantitative structure-activity relationships of DRV derivatives and will provide significant suggestions for future pharmaceutical research.

Novel therapeutic agents for H5N1 influenza virus through 3D-QSAR, molecular docking, ADMET prediction, and DFT based global reactivity descriptors

Avian influenza is a severe respiratory disease that can cause catastrophic outbreaks in domestic poultry and wild birds as well as significant risks to people. This has motivated many researchers to develop new, effective neuraminidase (NA) inhibitors to treat this serious infection. In this context, this study aims to develop new potential NA inhibitors using five computational methods. A three-dimensional quantitative structure-activity relationship (3D-QSAR) comparative molecular similarity indices analysis (CoMSIA) was performed on a set of N-substituted Oseltamivir derivatives as anti-influenza agents. As a result, the best CoMSIA model was robust and predictive (R2 = 0.966, Q2 = 0.772, and Rpred2 = 0.721). Based on the contour map analysis, 17 new NA inhibitors with high-predicted inhibitory activity were developed. Molecular docking was used to discover the binding modes and interactions between the 17 newly designed NA compounds and the corresponding NA protein. Based on the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, the compounds C10, C11, C12, C15, C16, and C17 have good drug-likeness and pharmacokinetics properties and could be new promising anti-influenza drugs. The six leading compounds further went through biological activity spectra prediction and quantum method density functional theory (DFT) study, which confirmed the trends and the utility of 3D-QSAR CoMSIA and molecular docking in developing new NA inhibitors.

Synthesis, antifungal activity, and 3d-QSAR study of L-carvone-based pyrazole-oxime ester compounds

Natural products can provide versatile substructures with potential bioactivity and biocompatibility for exploring bioactive compounds. Herein, to explore novel natural product-derived antifungal agents, 21 unreported L -carvone-based pyrazole-oxime ester compounds 6a-6u were synthesised using L-carvone as raw material, and structurally characterised by means of FT-IR,1H NMR,13C NMR, and HRMS. The results of the in vitro bioactivity tests showed that the target compounds exhibited certain antifungal activity against the eight tested plant fungi at the concentration of 50 mg/L, especially for Physalospora piricola. The inhibition rates of compounds 6e (R = m-Cl) and 6c (R = m-F) against P. piricola were 88.3% and 83.9%, respectively, both better than that of the positive control chlorothalonil. Compound 6e (R= m-Cl) with the most significant antifungal activity deserves further investigation as the potential leading compound. In addition, the structure-activity relationships (SARs) of the target compounds were investigated by establishing an effective three-dimensional quantitative structure-activity relationship (3D-QSAR) model.

Synthesis and Biological Evaluation of Pyrazole-Pyrimidones as a New Class of Correctors of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Cystic fibrosis (CF) is caused by the functional expression defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Despite the recent success in CFTR modulator development, the available correctors only partially restore the F508del-CFTR channel function, and several rare CF mutations show resistance to available drugs. We previously identified compound 4172 that synergistically rescued the F508del-CFTR folding defect in combination with the existing corrector drugs VX-809 and VX-661. Here, novel CFTR correctors were designed by applying a classical medicinal chemistry approach on the 4172 scaffold. Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted to propose a plausible binding site and design more potent and effective analogs. We identified three optimized compounds, which, in combination with VX-809 and the investigational corrector 3151, increased the plasma membrane density and function of F508del-CFTR and other rare CFTR mutants resistant to the currently approved therapies.

Unveiling the potential of novel 5α-reductase inhibitors via ligand based drug design, molecular docking and ADME predictions to manage BPH

Benign prostatic hyperplasia (BPH), a prevalent condition among elderly males characterized by the non-cancerous enlargement of the prostate gland is due to the increased stromal and epithelial cell numbers. The enlargement is driven by an active dihydrotestosterone (DHT), synthesized from its prohormone testosterone under the catalytic effect of 5α-reductase Type-II (5-AR2) enzyme. To reduce the increased DHT levels and ultimately to control prostate growth, inhibition of the 5-AR represent an interesting therapeutic target. The 3D crystallography structure 5-AR2, a member of the steroid 5-AR family belonging to the class of oxidoreductase has been resolved recently and opened the door to develop selective novel inhibitors of 5-AR Type-II isoform using molecular modeling techniques. The Force field and Gaussian-field three-dimensional quantitative structure–activity relationship (3D-QSAR) models have been developed using 42 selective 5-AR2 inhibitors belonging to chemical class of steroidal androstene. Partial least squares analysis produced statistically significant model with R2training = 0.9367, 0.9459 and predictability Q2test = 0.7233, 0.8595. Developed 3D-QSAR model include steric, electrostatic, hydrophobic, and hydrogen bond acceptor and donor field indicators, whereas the potential field contributions indicated the importance of steric feature in governing their biological activity. Protein-ligand interaction pattern analysis revealed that amino acid residues GLU57, ARG114, TYR91 present in the active site of 5-AR2 are crucial for lower energy complexes with good binding affinity. Identified hits were finally adjudged for their druggability by determining in-silico pharmacokinetic parameters. Further, RMSD, binding free energy calculations and post MD analysis demonstrated the enhanced binding affinity with better ΔGbind value (-79.6 ± 3.9 kcal/mol) of identified ligand A-10 than the reference molecule finasteride (-69.13 ± 4.69 kcal/mol). Combined approach of ligand-based and structure-based models have provided an improved understanding of the structural properties of androstene class that may be further used to develop novel 5-AR2 inhibitors to be useful in BPH.

Reduced estrogenic risks of a sunscreen additive: Theoretical design and evaluation of functionally improved salicylates

Salicylic esters (SEs), the widely used ultraviolet (UV) absorbers in sunscreen products, have been found to have health risks such as skin sensitization and estrogenic effects. This study aims to design SE substitutes that maintain high UV absorbance while reducing estrogenicity. Using molecular docking and Gaussian09 software for initial assessments and further application of a combination of two-dimensional and three-dimensional quantitative structure–activity relationships (2D-QSAR and 3D-QSAR, respectively) models, we designed 73 substitutes. The best-performing molecules, ethylhexyl salicylate (EHS)−5 and EHS-15, significantly reduced estrogenicity (44.54 % and 17.60 %, respectively) and enhanced UV absorbance (249.56 % and 46.94 %, respectively). Through screening for human health risks, we found that EHS-5 and EHS-15 were free from skin sensitivity and eye irritation and exhibited reduced skin permeability compared with EHS. Furthermore, the photolysis and synthetic pathways of EHS-5 and EHS-15 were deduced, demonstrating their good photodegradability and potential synthesizability. In addition, we analyzed the mechanisms underlying the changes in estrogenic effects and UV absorption properties. We identified covalent hydrogen bond basicity and acidity Propgen value for atomic molecular properties and the highest occupied molecular orbital eigenvalue as the main factors affecting the estrogenic effect and UV absorbance of SEs, respectively. This study focuses on the design and screening of SEs, exhibiting enhanced functionality, reduced health risks, and synthetic feasibility.

Three-Dimensional Quantitative Structure-Activity Relationship Study of Transient Receptor Potential Vanilloid 1 Channel Antagonists Reveals Potential for Drug Design Purposes.

Transient receptor potential vanilloid 1 (TRPV1) was reported to be a putative target for recovery from chronic pain, producing analgesic effects after its inhibition. A series of drug candidates were previously developed, without the ability to ameliorate the therapeutic outcome. Starting from previously designed compounds, derived from the hybridization of antagonist SB-705498 and partial agonist MDR-652, we performed a virtual screening on a pharmacophore model built by exploiting the Cryo-EM 3D structure of a nanomolar antagonist in complex with the human TRPV1 channel. The pharmacophore model was described by three pharmacophoric features, taking advantage of both the bioactive pose of the antagonist and the receptor exclusion spheres. The results of the screening were implemented inside a 3D-QSAR model, correlating with the negative decadic logarithm of the inhibition rate of the ligands. After the validation of the obtained 3D-QSAR model, we designed a new series of compounds by introducing key modifications on the original scaffold. Again, we determined the compounds' binding poses after alignment to the pharmacophoric model, and we predicted their inhibition rates with the validated 3D-QSAR model. The obtained values resulted in being even more promising than parent compounds, demonstrating that ongoing research still leaves much room for improvement.

Novel mandelic acid derivatives containing piperazinyls as potential candidate fungicides against Monilinia fructicola: Design, synthesis and mechanism study

Brown rot of stone fruit, a disease caused by the ascomycete fungus Monilinia fructicola, has caused significant losses to the agricultural industry. In order to explore and discover potential fungicides against M. fructicola, thirty-one novel mandelic acid derivatives containing piperazine moieties were designed and synthesized based on the amide skeleton. Among them, target compound Z31 exhibited obvious in vitro antifungal activity with the EC50 value of 11.8 mg/L, and significant effects for the postharvest pears (79.4 % protective activity and 70.5 % curative activity) at a concentration of 200 mg/L. Antifungal activity for the target compounds was found to be significantly improved by the large steric hindrance of the R1 groups and the electronegative of the piperazines in the molecular structure, according to a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis. Further mechanism studies have demonstrated that the compound Z31 can disrupt cell membrane integrity, resulting in increased membrane permeability, release of intracellular electrolytes, and affect the normal growth of hyphae. Additional, morphological study also indicated that Z31 may disrupt the integrity of the membrane by inducing generate excess endogenous reactive oxygen species (ROS) and resulting in the peroxidation of cellular lipids, which was further verified by the detection of malondialdehyde (MDA) content. These studies have provided the basis for the creation of novel fungicides to prevent brown rot in stone fruits.

Synthetic Modification and Insecticidal Activity of 4-epi-cis-Dihydroagarofuran Derivatives.

To synthesize the fundamental framework of dihydroagarofuran, a novel strategy was devised for constructing the C-ring through a dearomatization reaction using 6-methoxy-1-tetralone as the initial substrate. Subsequently, the dihydroagarofuran skeleton was assembled via two consecutive Michael addition reactions. The conjugated diene and trans-dihydroagarofuran skeleton were modified. The insecticidal activities of 33 compounds against Mythimna separata were evaluated. Compounds 11-5 exhibited an LC50 value of 0.378 mg/mL. The activity exhibited a remarkable 29-fold increase compared to positive control Celangulin V, which was widely recognized as the most renowned natural dihydroagarofuran polyol ester insecticidal active compound. Docking experiments between synthetic compounds and target proteins revealed the shared binding sites with Celangulin V. Structure-activity relationship studies indicated that methyl groups at positions C4 and C10 significantly improved insecticidal activity, while ether groups with linear chains displayed enhanced activity; in particular, the allyl ether group demonstrated optimal efficacy. Furthermore, a three-dimensional quantitative structure-activity relationship model was established to investigate the correlation between the skeletal structure and activity. These research findings provide valuable insights for discovering and developing dihydroagarofuran-like compounds.

In silico degradation of fluoroquinolones by a microalgae-based constructed wetland system

Fluoroquinolone antibiotics (FQs) have been used worldwide due to their extended antimicrobial spectrum. However, the overuse of FQs leads to frequent detection in the environment and cannot be efficiently removed. Microalgae-based constructed wetland systems have been proven to be a relatively proper method to treat FQs, mainly by microalgae, plants, microorganisms, and sediments. To improve the removal efficiency of microalgae-constructed wetland, a systematic molecular design, screening, functional, and risk evaluation method was developed using three-dimensional quantitative structure–activity relationship models, molecular dynamics simulation, molecular docking, and TOPKAT approaches. Five designed ciprofloxacin alternatives with improved bactericidal effects and lower human health risks were found to be more easily degraded by microalgae (16.11–167.88 %), plants (6.72–58.86 %), microorganisms (9.10–15.02 %), and sediments (435.83 %–1763.51 %) compared with ciprofloxacin. According to the mechanism analysis, the removal effect of the FQs can be affected via changes in the number, bond energy, and molecular descriptors of favorable and unfavorable amino acids. To the best of our knowledge, this is the first comprehensive study of improving the microalgae, plants, microorganisms, and sediment removal efficiency of FQs in constructed wetlands, which provides theoretical support for the treatment of FQ pollution.

AI-based 3D-QSAR model of FDA-approved repurposed drugs for inhibiting sclerostin

BACKGROUND: Wnt activation promotes bone formation and prevents bone loss. The Wnt pathway antagonist sclerostin and additional anti-sclerostin antibodies were discovered as a result of the development of the monoclonal antibody romosozumab. These monoclonal antibodies greatly increase the risk of cardiac arrest. Three-dimensional quantitative structure-activity relationships (3D-QSAR) predicts biological activities of ligands based on their three-dimensional features by employing powerful chemometric investigations such as artificial neural networks (ANNs) and partial least squares (PLS). OBJECTIVE: In this study, ligand-receptor interactions were investigated using 3D-QSAR Comparative molecular field analysis (CoMFA). Estimates of steric and electrostatic characteristics in CoMFA are made using Lennard-Jones and Coulomb potentials. METHODS: To identify the conditions necessary for the activity of these molecules, fifty Food and Drug Administration (FDA)-approved medications were chosen for 3D-QSAR investigations and done by CoMFA. For QSAR analysis, there are numerous tools available. This study employed Open 3D-QSAR for analysis due to its simplicity of use and capacity to produce trustworthy results. Four tools were used for the analysis on this platform: Py-MolEdit, Py-ConfSearch, and Py-CoMFA. RESULTS: Maps that were generated were used to determine the screen’s r2 (Coefficient of Multiple Determinations) value and q2 (correlation coefficient). These numbers must be fewer than 1, suggesting a good, trustworthy model. Cross-validated (q2) 0.532 and conventional (r2) correlation values of 0.969 made the CoMFA model statistically significant. The model showed that hydroxamic acid inhibitors are significantly more sensitive to the steric field than the electrostatic field (70%) (30%). This hypothesis states that steric (43.1%), electrostatic (26.4%), and hydrophobic (20.3%) qualities were important in the design of sclerostin inhibitors. CONCLUSION: With 3D-QSAR and CoMFA, statistically meaningful models were constructed to predict ligand inhibitory effects. The test set demonstrated the model’s robustness. This research may aid in the development of more effective sclerostin inhibitors that are synthesised using FDA-approved medications.

Quantification- and structural-taste intensity of umami peptides from Agrocybe aegerita through quantitative structure-activity relationship

Agrocybe aegerita, one of the edible mushroom varieties, is popular among consumers for its umami taste. Umami peptides, including EV, EG, EY, ENG, ECG, DEL, DDL, PEG, PEEL, DGPL, and EDCS are the main umami compounds in A. aegerita. In this study, when the concentration of these 11 umami peptides was 5 mg/mL, the corresponding relative umami intensity (measured by MSG concentration) ranged from 4.457 to 5.240 mg/mL, with DDL being the highest. All umami peptides exhibited better umami taste under neutral and weakly acidic conditions (pH 6-7). EY and ENG, with a higher umami intensity at 70 °C, were more suitable for a wide application in thermally processed foods. Additionally, the relationship between the structure and strength of umami peptides was explored using a three-dimensional quantitative structure-activity relationship model with an R2 of 0.987. Overall, umami peptides in A. aegerita possess strong potential for application in food processing.

Homologous Design and Three-Dimensional Quantitative Structure-Activity Relationship Study of Acaricidal 2,4-Diphenyloxazolines Containing Different Heteroatoms and Alkyl Chains.

In order to speculate the three-dimensional structure of the potential binding pocket of the chitin synthase inhibitor, a series of 2,4-diphenyloxazoline derivatives with different lengths of alkyl chains and heteroatoms were designed and synthesized by a homologous strategy. The bioassay results indicate that both the length of the alkyl chains and the type of substituents can affect the acaricidal activity against mite eggs. Compounds containing chloropropyl, alkoxyalkyl, and para-substituted phenoxyalkyl or phenylthioalkyl groups exhibit good activity, while those containing steric hindrance substituents or carbonyl substituents on the benzene ring exhibit reduced activity. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study showed that there may be a narrow hydrophobic region deep in the pocket, and the steric effect plays a more important role than the electrostatic effect. The current work will provide assistance for future molecular design and target binding research.

Design, synthesis and bactericidal activity of novel coumarin derivatives containing pyridinium salts

Coumarin is a natural product known for its diverse biological activities. While its antifungal properties in agricultural chemistry have been extensively studied, there is limited research on its antibacterial potential. In this study, we developed several novel coumarin derivatives by combining coumarin with pyridinium salt through molecular hybridization and chemical synthesis. Our findings reveal that most of these derivatives exhibit promising antibacterial activity. Among them, derivative A25 has been identified as the most effective compound based on three-dimensional quantitative structure-activity relationships. It demonstrates significant in vitro and in vivo activity against Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas oryzae pv. oryzicola (Xoc), and Xanthomonas campestris pv. citri (Xac), outperforming the commercially available thiediazole copper. Initial investigations into its mechanism of action suggest that A25 disrupts the cell membranes of Xoc and Xoo, thereby inhibiting bacterial growth. Additionally, A25 enhances the activity of defense enzymes in rice and modulates the expression of proteins related to the pyruvate metabolism pathway. This dual action contributes to rice's resistance against bacterial infestation. We anticipate that this study will serve as a foundation for the development of coumarin-based bactericides.

Design, Synthesis, and 3D-QASR of 2-Ar-1,2,3-triazole Derivatives Containing Hydrazide as Potential Fungicides.

A series of novel 2-Ar-1,2,3-triazole derivatives were designed and synthesized based on our previously discovered active compound 6d against Rhizoctonia solani. Most of these compounds exhibited good antifungal activity against R. solani at a concentration of 25 μg/mL. Based on the results of biological activity, we established a three-dimensional quantitative structure-activity relationship (3D-QSAR) model that guided the synthesis of compound 7y. Compound 7y exhibited superior activity against R. solani (EC50 = 0.47 μg/mL) compared to the positive controls hymexazol (EC50 = 12.80 μg/mL) and tebuconazole (EC50 = 0.87 μg/mL). Furthermore, compound 7y demonstrated better protective activity than the aforementioned two commercial fungicides in both detached leaf assays and greenhouse experiments, achieving 56.21% and 65.75% protective efficacy, respectively, at a concentration of 100 μg/mL. The ergosterol content was determined and molecular docking was performed to explore the mechanism of these active molecules. DFT calculation and MEP analysis were performed to illustrate the results of this study. These results suggest that compound 7y could serve as a novel 2-Ar-1,2,3-triazole lead compound for controlling R. solani.