Three-dimensional Quantitative Structure Research Articles

Development of Imidazo[1,2-a]pyridines Containing Sulfonyl Piperazines as Potential Antivirals against Tomato Spotted Wilt Virus.

Mesoionic structures have become important advancements in recent agrochemical design. However, their potential beyond serving as excellent insecticides remains unexplored with limited reports available. Herein, a series of imidazo[1,2-a]pyridine mesoionics were developed by structurally incorporating sulfonyl piperazine moieties into imidazo[1,2-a]pyridines. Many of the obtained derivatives demonstrated bioactivity against tomato spotted wilt virus (TSWV) in bioassays. In particular, compound Z40, identified via three-dimensional quantitative structure activity relation models, displayed encouraging protective performance (half-maximal effect concentration = 252 μg/mL) compared to the positive controls ningnanmycin (332 μg/mL) and vanisulfane (523 μg/mL). Through defense enzyme assays, real-time quantitative polymerase chain reaction, and proteomics analysis, Z40 was identified as a plant immunomodulator that promotes defense enzyme activity and the mediates oxidative phosphorylation pathway, enabling plants to resist TSWV. We expect this study to help expand the possibilities of mesoionic compounds.

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.

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.

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.

Study on β-glucosidase activators by 3D-QSAR, molecular docking and molecular dynamics simulation

To investigate the conformational relationship and mechanism of action of β-glucosidase (BGL) activators, a theoretical study of three-dimensional quantitative structure activity relationship, molecular docking, molecular dynamics (MD) simulations, and binding free energy analysis were performed. The results indicate that comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models had good stability and predictive ability, with r2cv/ r2pred values of 0.540/0.998 and 0.654/0.993, respectively. The derived contour maps of steric, electrostatic, and hydrogen bond donor field further displayed the modified information of these activators. Molecular docking and MD were performed on calcium diascorbate (CaAS) and L-Ascorbyl 2,6-Dipalmitate (L-ADP), which have good activating ability. The study indicates a positive interaction between the activators and the enzyme, and this interaction does not cause irreversible negative effects on the conformation of BGL. The MD results show that the total binding free energies of CaAS and L-ADP with BGL were −19.837 kJ/mol and −37.798 kJ/mol, respectively, and the binding force of the activators with BGL was mainly derived from hydrophobic interaction and hydrogen bonding. This study offers important guidance for the efficient use of BGL and for the research and development of effective activators.

Strategic development and validation of Isoquinoline-Derived inhibitors targeting ROCK1 kinase

Rho-associated coiled-coil containing kinases (ROCKs) have emerged as pivotal downstream effectors of small guanosine triphosphatases. In recent years, isoquinoline derivatives have garnered substantial attention as potent inhibitors of ROCK1 (RKIs). To delve deeper into their pharmacological properties and to identify potential inhibitors, we conducted an in-depth exploration of a series of RKIs derived from isoquinoline derivatives. This exploration encompassed a multifaceted approach, combining three-dimensional quantitative structure–activity relationship modeling, induced fit docking, and virtual screening. Our comparative molecular field analysis model (q2 = 0.609, R2 = 0.991, ONC = 6, and r2pred = 0.973) and the most robust comparative molecular similarity indices analysis model (q2 = 0.712, R2 = 0.998, ONC = 7, and r2pred = 0.89) exhibited commendable predictive accuracy, bolstered by robust validation parameters. To gain deeper insights into the mechanism of action of isoquinoline-based RKIs, we harnessed precise docking techniques, including induced fit docking, structural interaction fingerprints, and binding pose metadynamics simulations. Employing the PRRR_2 pharmacophore, we meticulously screened Enamine's HLL-460 compound library, unearthing thousands of isoquinoline compounds that aligned with the desired profile. Subsequently, we identified three promising compounds (DS01, DS02, and DS03) through Glide docking, each assessed at varying precision levels. These compounds underwent comprehensive evaluation for their drug-like properties, leveraging QikProp and SwissADME, ultimately unveiling their potential as novel and efficacious RKIs. Furthermore, bolstered by molecular dynamics simulations and validated through activity assays, the bioactivity of the screened molecules DS02, and DS03 was corroborated. DS02 and DS03, previously unreported for their activity against ROCK1, delivered exceptionally promising results. This comprehensive study not only elucidates validated strategies for drug development but also imparts invaluable insights into the design of potent RKIs.

Risk mitigation strategy and mechanism analysis of neonicotinoid pesticides on earthworms

Neonicotinoid insecticides (NNIs) are a new class of widely used insecticides with certain risks to non-target organisms, like earthworms. The gray correlation method was used to calculate the comprehensive risk effect value of acute toxicity (LC50) and bioaccumulation (logKow) of NNIs on earthworms. A comprehensive effects three-dimensional quantitative structure–activity relationship (3D-QSAR) model was constructed, using NNIs molecular structures and the comprehensive effect value as the independent and dependent variables, respectively. One of the representatives guadipyr (GUA) was selected as the template molecule for the molecular design and modification. A total of 63 NNIs alternatives were designed with a reduced comprehensive value higher than 10%, and as high as 42%. After screening, 15 NNIs alternatives were screened with decreased acute toxicity to earthworms, bioaccumulation effects and improved functional property. The calculated primary acute risk quotient of earthworms shows that the designed NNIs alternatives have lower earthworm risks (reduction of 70.48–99.99%). Results also found that the electronic, geometric and topological parameters of NNIs are the key descriptors that affect NNIs alternatives' toxicity. The number of hydrophobic interaction amino acid residues in NNIs molecules also contributes to the acute toxicity and the bioaccumulation of NNIs alternatives on earthworms. This study aims to design and screen functionally improved and environmentally friendly NNIs alternatives that have low risk to earthworms and provide theoretical methods and new ideas for the risk control and development of pesticides represented by NNIs.

3D-QSAR and ADMET studies of morpholino-pyrimidine inhibitors of DprE1 from Mycobacterium tuberculosis

DprE1 is involved in the synthesis of Mycobacterium tuberculosis cell wall and is a potent drug target for Tuberculosis (TB) treatment. The structure and dynamics of the loops L-I and L-II flanking the inhibitor binding site was studied using molecular dynamics (MD) simulation and MMPBSA in Amber v18. Docking and three-dimensional quantitative structure–activity relationship (3D-QSAR) of 55 Morpholino-pyrimidine (MP) inhibitors was carried out using Autodock v1.2.0 and Forge v10. ADMET analysis was done using SwissADME and pkCSM. All MP inhibitors docked in the DprE1 binding pocket, making contacts with L-II residues. MD studies showed that L-I and L-II unfold in the absence of the inhibitor but fold stably structure with reduced protein motions in the presence of MP-38, the highest affinity inhibitor. This was confirmed by k-means clustering and secondary structure analysis. L-II residues, L317, F320 and R325 contributed most towards the MMPBSA binding free energy of MP-38. A robust field-based 3D-QSAR model showed values of r2 train = 0.982, r2 test = 0.702 and q2 = 0.516. The MP inhibitor field points were broadly divided into negative electrostatics near the A, B rings and hydrophobic electrostatics near the D, E rings. Addition of negative groups at methanone position and ring B as well as addition of hydrophobic and bulky groups at ring E will improve activity. Highly active compounds 47, 49 and 50 of MP series exhibited highly favourable drug-like properties. SAR and ADMET insights attained from this model will help in the development of active DprE1 inhibitors in future. Communicated by Ramaswamy H. Sarma

Design of novel small molecules derived from styrylpyridine as potent HDAC1 inhibitors for the treatment of gastric cancer using 3D-QSAR, drug similarity, ADMET prediction, molecular docking, and molecular dynamics studies

Histone deacetylase (HDAC) dysregulation plays an important role in cancer progression and is an important therapeutic target for anticancer drug development. A series of molecules derived from styrylpyridine have HDAC inhibitory activity for the treatment of gastric cancer and could have great potential as drugs against gastric cancer.The objective of this work is to modify the styrylpyridine backbone in order to design new inhibitors with high activity and favorable pharmacokinetic properties for drug discovery. Based on the three-dimensional quantitative structure- activity study, robust and reliable comparative molecular field analysis and comparative molecular similarity index analysis models were developed and validated, then used to design seven new molecules and predict in silico their biological activity.As a result, the seven newly designed molecules have a higher biological activity than the synthesized template molecule N21. The designed molecules are submitted to tests for drug-like properties, pharmacokinetics properties, and molecular docking. These tests enabled us to select the two newly-designed molecules T5 and T6 as the best HDAC1 inhibitors, compared with the model molecule N21. Subsequently, molecular dynamics simulations were carried out to study the stability of styrylpyridine derivatives in the active site of HDAC1.The designed molecules T5 and T6 have the potential to be drugs for treating gastric cancer. The synthesis, in vitro and in vivo evaluation of the biological activity of newly designed molecules T5 and T6 are interesting proposal for the conception of new drugs to treat gastric cancer.

3D QSAR study on substituted 1, 2, 4 triazole derivatives as anticancer agents by kNN MFA approach

Background and objectivesResearchers have recently focused on the biological and synthetic effects of 1, 2, and 4-triazole fused heterocyclic molecules because they have tremendous medicinalvalue. The objective of the present study was to carry out the 3D QSAR evaluation on the substituted 1,2, and 4 triazole derivatives for anticancer potential using k-Nearest Neighbor-Molecular Field Analysis (kNN-MFA) method. MethodsUsing the molecular design suite, a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis was undertaken on a series of 4-amino-5-(pyridin3yl)-4H-1, 2, and 4-triazole-3-thiol anticancer drugs (Vlife MDS). This study used a genetic algorithm and a manual selection approach on 20 substituted 1, 2, and 4-triazole derivatives. Based on the genetic algorithm (GA), the 3D-QSAR model was generated. Statistical significance and predictive capacity were evaluated using internal and external validation. ResultsThe most significant model has a correlation coefficient of 0.9334 (squared correlation coefficient r2 = 0.8713), showing that biological activity and descriptors have a strong relationship. The model exhibited internal predictivity of 74.45 percent (q2 = 0.2129), external predictivity of 81.09 percent (pred r2 = 0.8417), and the smallest error term for the predictive correlation coefficient (pred r2se = 0.1255). The model revealed steric (S 1047––0.0780––0.0451S 927) and electrostatic (E 1002) data points that contribute remarkably to anticancer activity. A molecular field study demonstrates a link between the structural features of substituted triazole derivatives and their activities. ConclusionThe good-to-moderate anticancer potential of compounds confirms the significant pharmacological role of 1,2,4-triazole derivatives. These results could lead to the identification of potential chemical compounds with optimal anticancer activity and minimal side effects.

Molecular Docking Assessment of Cathinones as 5-HT2AR Ligands: Developing of Predictive Structure-Based Bioactive Conformations and Three-Dimensional Structure-Activity Relationships Models for Future Recognition of Abuse Drugs.

Commercially available cathinones are drugs of long-term abuse drugs whose pharmacology is fairly well understood. While their psychedelic effects are associated with 5-HT2AR, the enclosed study summarizes efforts to shed light on the pharmacodynamic profiles, not yet known at the receptor level, using molecular docking and three-dimensional quantitative structure-activity relationship (3-D QSAR) studies. The bioactive conformations of cathinones were modeled by AutoDock Vina and were used to build structure-based (SB) 3-D QSAR models using the Open3DQSAR engine. Graphical inspection of the results led to the depiction of a 3-D structure analysis-activity relationship (SAR) scheme that could be used as a guideline for molecular determinants by which any untested cathinone molecule can be predicted as a potential 5-HT2AR binder prior to experimental evaluation. The obtained models, which showed a good agreement with the chemical properties of co-crystallized 5-HT2AR ligands, proved to be valuable for future virtual screening campaigns to recognize unused cathinones and similar compounds, such as 5-HT2AR ligands, minimizing both time and financial resources for the characterization of their psychedelic effects.

Design of novel anti-cancer agents targeting COX-2 inhibitors based on computational studies

The overexpression of cyclooxygenase-2 (COX-2) was clearly associated with carcinogenesis, and COX-2 as a possible target has long been exploited for cancer therapy. A group of 29 derivatives of 1, 5-diarylpyrazole was used to study its structural requirements using three-dimensional quantitative structure–activity relationship (3D-QSAR), the density functional theory method, molecular docking, and molecular dynamics. Four 3D-QSAR models were developed, and the predictive capability of the four selected models was also successfully tested using different validation methods. The contribution contours of the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models effectively illustrate the relationships between the various chemical characteristics and their biological activities. Using the density functional theory method with the 6-31G (d, p) basis set and the Becke, 3-parameter, Lee-Yang-Parr (B3LYP) function to evaluate chemical reactivity properties, the results obtained from energy gaps of 3.431, 3.446, and 2.727 ev for molecules numbers 21, 22, and 23 indicate that these three molecules have good chemical stability and reactivity and select the most reactive regions in the three molecules studied. Molecular docking results revealed that the active sites of the COX-2 protein (PDB code: 3PGH) were residues ARG222, THR212, HIS386, HIS207, TYR148, and ASP382, in which the most active ligands and now ligands can inhibit the COX-2 enzyme. Based on the various results obtained by molecular modeling, four new compounds (N1, N2, N3, and N4) were proposed with significant predicted activity by different 3D-QSAR models. A molecular docking study and molecular dynamics simulations of the proposed new molecules (N1 and N2) and the most active molecule over 100 ns revealed that all three molecules establish multiple hydrogen interactions with several residues and also exhibit frequent stability throughout the simulation period. As a result, it is strongly recommended to consider the two newly proposed molecules, N1 and N4, as promising candidates for novel anti-cancer agents specifically designed to target COX-2 inhibition.

3D-QSAR and Molecular Docking Studies of Novel GPR52 Agonists

To study the three-dimensional quantitative structure–activity relationship (3D-QSAR) of a series of GPR52 agonists, comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were used to establish 3D-QSAR models. The cross-validation coefficient ([Formula: see text]), non-cross validation coefficient ([Formula: see text]) and standard error of estimate (SEE) of the constructed CoMFA model were 0.679, 0.981 and 0.058, respectively. While those for the CoMSIA model were 0.661, 0.846 and 0.110, respectively. The internal and external validation parameters showed that the constructed 3D-QSAR models had good prediction ability and significant statistical reliability. According to the information provided by 3D-QSAR analysis, new compounds were designed, and the molecular docking together with absorption, distribution, metabolism, exclusion, toxicity (ADMET) prediction results showed that the new compounds had good GPR52 agonistic activity.

Deciphering the toxicity mechanism of haloquinolines on Chlorella pyrenoidosa using QSAR and metabolomics approaches

The hazardous potential of haloquinolines (HQLs) is becoming an issue of great concern due to its wide and long-term usage in many personal care products. We examined the growth inhibition, structure-activity relationship, and toxicity mechanism of 33 HQLs on Chlorella pyrenoidosa using the 72-h algal growth inhibition assay, three-dimensional quantitative structure–activity relationship (3D-QSAR), and metabolomics. We found that the IC50 (half maximal inhibitory concentration) values for 33 compounds ranged from 4.52 to > 150 mg·L−1, most tested compounds were toxic (1 mg·L−1 < IC50 < 10 mg·L−1) or harmful (10 mg·L−1 < IC50 < 100 mg·L−1) for the aquatic ecosystem. Hydrophobic properties of HQLs dominate their toxicity. Halogen atoms with large volume appear at the 2, 3, 4, 5, 6, and 7-positions of the quinoline ring to significantly increase the toxicity. In algal cells, HQLs can block diverse carbohydrates, lipids, and amino acid metabolism pathways, thereby resulting in energy usage, osmotic pressure regulation, membrane integrity, oxidative stress disorder, thus fatally damaging algal cells. Therefore, our results provide insight into the toxicity mechanism and ecological risk of HQLs.

Novel 1,2,3,4-tetrahydroisoquinoline-based Schiff bases as laccase inhibitors: Synthesis and biological activity, 3D-QSAR, and molecular docking studies

Laccase is considered a potential target in the field of agricultural fungicides. To promote the discovery and development of compounds with laccase inhibitory activity, herein, taking reported laccase inhibitor 4-chlorocinnamaldehyde thiosemicarbazide (PMDD-5Y) as the lead compound, two series of 29 novel Schiff-base compounds were designed and synthesized by introducing natural structural unit 1,2,3,4-tetrahydroisoquinoline for the first time. All the synthesized compounds had good antifungal activities against several phytopathogenic fungi in vitro. Among them, compound 4k exhibited prominent biological activities against Valsa mali (EC50 = 5.37 µg/mL), Rhizoctonia solani (EC50 = 3.51 µg/mL), and laccase (IC50 = 0.047 mmol/L), and, thus, could be a promising candidate for a novel chemical fungicide targeting laccase. Furthermore, the structure-activity relationship of the compounds were studied using three-dimensional quantitative structure–activity relationships, molecular docking, and density functional theory calculations. The experimental results preliminarily suggested that the active hydrogen on the nitrogen atom, which acts as a positively charged region, can form key interactions with the laccase target. This may be a key factor in influencing the biological activity.

Design, Synthesis, Antibacterial Evaluation, Three-Dimensional Quantitative Structure-Activity Relationship, and Mechanism of Novel Quinazolinone Derivatives.

Plant bacterial illnesses are common and cause dramatic damage to agricultural goods all over the world, yet there are few efficient bactericides to alleviate them at present. To discover novel antibacterial agents, two series of quinazolinone derivatives with novel structures were synthesized and their bioactivity against plant bacteria was tested. Combining CoMFA model search and the antibacterial bioactivity assay, D32 was identified as a potent antibacterial inhibitor against Xanthomonas oryzae pv. Oryzae (Xoo), with an EC50 value of 1.5 μg/mL, much better in inhibitory capacity compared to bismerthiazol (BT) and thiodiazole copper (TC) (31.9 and 74.2 μg/mL). The activities of compound D32 against rice bacterial leaf blight in vivo were 46.7% (protective activities) and 43.9% (curative activities), better than commercial drug thiodiazole copper (29.3% protective activities and 30.6% curative activities). Flow cytometry, proteomics, reactive oxygen species, and key defense enzymes were used to further investigate the relevant mechanisms of action of D32. The identification of D32 as an antibacterial inhibitor and revelation of its recognition mechanism not only open the possibility of developing new therapeutic strategies for treatment of Xoo but also provide clues for elucidation of the acting mechanism of quinazolinone derivative D32, which is a possible clinical candidate worth in-depth study.

Design, Synthesis, Herbicidal Activity, and Structure-Activity Relationship Study of Novel 6-(5-Aryl-Substituted-1-Pyrazolyl)-2-Picolinic Acid as Potential Herbicides.

Picolinic acid and picolinate compounds are a remarkable class of synthetic auxin herbicides. In recent years, two new picolinate compounds, halauxifen-methyl (ArylexTM active) and florpyrauxifen-benzyl (RinskorTM active), have been launched as novel herbicides. Using their structural skeleton as a template, 33 4-amino-3,5-dicholor-6-(5-aryl-substituted-1-pytazolyl)-2-picolinic acid compounds were designed and synthesized for the discovery of compounds with potent herbicidal activity. The compounds were tested for inhibitory activity against the growth of Arabidopsis thaliana roots, and the results demonstrated that the IC50 value of compound V-7 was 45 times lower than that of the halauxifen-methyl commercial herbicide. Molecular docking analyses revealed that compound V-7 docked with the receptor auxin-signaling F-box protein 5 (AFB5) more intensively than picloram. An adaptive three-dimensional quantitative structure-activity relationship model was constructed from these IC50 values to guide the next step of the synthetic strategy. Herbicidal tests of the new compounds indicated that compound V-8 exhibited better post-emergence herbicidal activity than picloram at a dosage of 300 gha-1, and it was also safe for corn, wheat, and sorghum at this dosage. These results demonstrated that 6-(5-aryl-substituted-1-pyrazolyl)-2-picolinic acid compounds could be used as potential lead structures in the discovery of novel synthetic auxin herbicides.

Potential Fungicide Candidates: A Dual Action Mode Study of Novel Pyrazole-4-carboxamides against Gibberella zeae

Pyrazole carboxamides are a class of traditional succinate dehydrogenase inhibitors (SDHIs) that have developed into a variety of commercialized fungicides. In the present work, a series of novel 1,5-disubstituted-1H-pyrazole-4-carboxamide derivatives were designed and synthesized based on the active backbone of 5-trifluoromethyl-1H-4-pyrazole carboxamide. Bioassay results indicated that some target compounds exhibited excellent in vitro antifungal activities against six phytopathogenic fungi. Notably, the EC50 values of Y47 against Gibberella zeae, Nigrospora oryzae, Thanatephorus cucumeris, and Verticillium dahliae were 5.2, 9.2, 12.8, and 17.6 mg/L, respectively. The in vivo protective and curative activities of Y47 at 100 mg/L against G. zeae on maize were 50.7 and 44.2%, respectively. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis revealed that the large steric hindrance and electronegative groups on the 5-position of the pyrazole ring were important for the activity. The IC50 value of Y47 against succinate dehydrogenase (SDH) was 7.7 mg/L, superior to fluopyram (24.7 mg/L), which was consistent with the docking results. Morphological studies with fluorescence microscopy (FM) and scanning electron microscopy (SEM) found that Y47 could affect the membrane integrity of mycelium by inducing endogenous reactive oxygen species (ROS) production and causing peroxidation of cellular lipids, which was further verified by the malondialdehyde (MDA) content. Antifungal mechanism analysis demonstrated that the target compound Y47 not only had significant SDH inhibition activity but could also affect the membrane integrity of mycelium, exhibiting obvious dual action modes. This research provides a novel approach to the development of traditional SDHIs and their derivatives.

Exposure to high-performance benzotriazole ultraviolet stabilizers: Advance in toxicological effects, environmental behaviors and remediation mechanism using in-silica methods

Benzotriazole ultraviolet stabilizers (BUVSs), as light stabilizers, have attracted widespread attention because of their easy migration in the environment and their acute toxicity and biological toxicity effects, such as immunotoxicity and hepatotoxicity. Accordingly, the treatment and remediation mechanisms of high-performance, environmentally friendly, and low human health risk BUVS substitutes were analyzed. Firstly, the weights and the comprehensive effect (CE) values of migration and toxicity of BUVSs were determined by Topsis assisted by the coefficient of variation (CV) method. From this, a three-dimensional quantitative structure activity relationship (3D-QSAR) model based on the CE values of the 13 BUVSs was constructed. Secondly, EPI software was used to predict the functionality and environmental friendliness of BUVS substitutes, and a partial least squares regression machine learning (ML-PLSR) model was used to analyze the mechanism. Then, ADMET (absorption, distribution, metabolism, excretion, toxicity), TOPKAT, and exposure dose models were used to evaluate the ecological and human health risks of BUVSs and their substitutes. Finally, the key charge information affecting the UV-326 substitutes was deduced by time dependent density functional theory (TDDFT). Using UV-326 as an example, 15 UV-326 substitutes with reduced CE values were designed (reductions of 2.61%–23.18%). Compared with ML-PLSR models of acute toxicity, immunotoxicity, and hepatotoxicity, it was found that the decrease of DM and Qyy values and the increase of Qzz value could further decrease the toxicity of the UV-326 substitutes. Ecological and human health risk assessment showed that the exposure risks of the six UV-326 substitutes were within acceptable limits. TDDFT showed that the change of electron distribution and electron excitation type were the key factors affecting the performance of the UV-326 substitutes, and a charge transfer excitation type was more conducive to obtaining high-performance, environmentally friendly UV-326 substitutes. This study aims to alleviate the toxic damage to the ecological environment and human health caused by BUVS exposure.