Safeners Research Articles

Pharmacophore Recombination Design, Synthesis, and Bioactivity of Ester-Substituted Pyrazole Purine Derivatives as Herbicide Safeners.

Mesosulfuron-methyl, an acetolactate synthase (ALS) inhibitor primarily applied to wheat and rye, can injure or even kill wheat crops. Herbicide safeners can improve the herbicide resistance of crops without reducing the herbicidal effect on targeted weed species. Herein, we present a series of pyrazole purine derivatives with the primary structure of the natural product cytokinin and commercialized safener mefenpyridyl, designed using the pharmacophore recombination method. The title compounds were synthesized and characterized using infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. A bioactivity assay proved that most of the target compounds can reduce the wheat phytotoxicity of mesosulfuron-methyl. Measurements of chlorophyll and glutathione contents, along with other enzyme activity assays, confirmed that compounds I-15 and I-13 exhibit higher safety activities compared with the mefenpyr-diethyl safener. Molecular structure comparisons demonstrated that I-15 is more readily absorbed and disseminated through the crop than the commercialized safener mefenpyr-diethyl. Molecular docking models and molecular dynamics simulations elucidated the protective mechanism of safeners; specifically, compound I-15 competitively binds to the ALS active site with mesosulfuron-methyl. The current study reveals the potential of pyrazole purine derivatives in the future discovery of novel herbicide safeners.

Developing fluorescence hyperspectral imaging methods for non-invasive detection of herbicide safeners action mechanism and effectiveness

Herbicide safeners are considered key agents for plant protection that reduce the harmful impacts of herbicides on crops and the environment in general, but traditional evaluation methods for their effectiveness are time-consuming and labor-intensive. In this study, a rapid and non-destructive method was proposed using chlorophyll fluorescence and hyperspectral imaging that combined with machine learning models. Besides, chemometric analysis was utilized to reveal the action mechanism between the wheat crop (Triticum aestivum L.) understudy and the herbicide isoproturon (ISO) and safener gibberellin acid (GA3). The results showed that ISO caused oxidative stress and disrupted the photosynthesis mechanism in wheat by hindering the electron transport pathway from primary acceptor quinone to secondary acceptor. Meanwhile, GA3 stimulated wheat to synthesize more glutathione (GSH) that accelerated the herbicide action metabolism. It's worth noting that excessive GA3 has decreased significantly the GSH and photosynthetic pigment concentrations, while the malondialdehyde concentration was significantly (p<0.05) increased. Additionally, competitive adaptive reweighted sampling proved the best performance when combined with partial least squares regression for predicting the phytochemical concentrations that characterized the effectiveness of GA3. In conclusion, the novelty of the current study came from the accurate real-time tracking method for GA3 action mechanism and its effectiveness on ISO toxicity. Where, that model holds great value for reducing the traditional methods' limitations in safener developments.

Italian Ryegrass Control Using a Capsule Suspension Formulation of S-metolachlor in Fenclorim-treated Wheat

Abstract Italian ryegrass control is one of the most significant limitations in wheat production in the U.S. today. Resistance to Herbicide Resistance Action Committee (HRAC)/Weed Science Society of America (WSSA) Groups 1, 2, and 9 in Arkansas have further complicated postemergence control, while residual herbicides still show effective weed control. One problem is the potential of HRAC/WSSA Group 15 herbicides to injure wheat when applied preemergence, indicating the need for a herbicide safener. A series of experiments were conducted in Fayetteville, AR, to evaluate crop tolerance and Italian ryegrass control using a capsule suspension formulation of S-metolachlor in conjunction with fenclorim-treated wheat. Experiments were conducted as a two-factor factorial with S-metolachlor applied at three rates (0.37, 0.74, and 1.12 kg ai ha-1) and a microencapsulated formulation of acetochlor at 1.05 kg ai ha-1, and three rates of a fenclorim seed treatment at 0, 0.5, and 2.0 g ai kg-1 of seed. Separate experiments utilized either a preemergence (PRE) or a delayed-preemergence (DPRE) application timing. In both experiments, S-metolachlor at 0.74 and 1.12 kg ai ha-1 provided 77 to 96% control of Italian ryegrass by preharvest, whereas acetochlor only provided 49 to 72% control. Visible wheat injury from PRE applications ranged from 7 to 49% for all treatments 21 d after treatment (DAT), with a reduction in injury when fenclorim-treated wheat was used for both the 0.74 and 1.12 kg ai ha-1 rate of S-metolachlor. In the DPRE experiments, wheat injury ranged from 5 to 16% 21 DAT with no noticeable safening from the presence of fenclorim at any herbicide rate. The results of these experiments indicate that a DPRE application using a CS formulation of S-metolachlor would be more favorable for producers to mitigate the potential for injury to wheat while providing Italian ryegrass control. Additionally, at the DPRE application timing, fenclorim is unnecessary for S-metolachlor to be safely applied at the rates evaluated.

Balancing Growth and Defense: Nanoselenium and Melatonin in Tea (Camellia sinensis) Protection against Glufosinate.

Current crop stress resistance research suggests that the prominent stimulants nanoselenium (NSe) and melatonin (MT) might improve tea safety, quality, and stress resistance induced by the widely used nonselective herbicide glufosinate (GLU). Their biofortification effects on tea growth, antioxidant activity, and secondary metabolism pathways response to GLU remain unclear. Here, NSe, MT, and their combination NSe-MT effectively reduced 26.6-50.9% GLU and its metabolites in tea seedlings, balanced the photosystem, enhanced antioxidant defenses, and optimized reactive oxygen species scavenging mechanisms. Further, GLU-induced inhibition of glutamine synthetase (11.2-34.0%), ammonium toxicity (55.0-64.7%), and nitrogen metabolism disorders were alleviated. Stimulants exhibited different preferences in the accumulation of l-theanine (8.4-47%), gamma-aminobutyric acid (10.3-41.7%), and catechins (13.1-73.1%, excluding ECG), thereby influencing tea quality. Transcriptomic and metabolomic analyses validated that NSe-MT had a more pronounced impact on tender tea leaves than individual stimulant treatments. All stimulants reduced GLU-induced excessive jasmonic acid (29.8-50.5%) production and signaling responses, revealing their significance in crop physiological activities under herbicide or nitrogen stress. The reduction in aromatic amino acids helped mitigate GLU's interference with phenylpropanoid biosynthesis, leading to inhibited lignin production but enhanced nutritional flavonoid levels, such as catechins. NSe and NSe-MT demonstrated promising potential as herbicide safeners. These findings provided insights into GLU detoxification mechanisms in other nontarget crops as well.

Crystal structure and biological activity studies of two different types of herbicide safeners

Two heterocyclic compounds, imidazolidine-1,3-diylbis((5-methyl-3-phenylisoxazol-4-yl)methanone) (I) and (5-methylisoxazol-3-yl)(1-oxa-4-azaspiro[4.5]decan-4-yl)methanone (II), were characterized by X-rays. Compound I was crystallized in monoclinic system, space group Cc, a= 9.81000(12) Å, b= 15.21199(16) Å, c= 14.25369(17) Å, β= 90.3862 (12)degree, Z= 4, V= 2127.02(4) Å3, F(000) = 928.0, Dc= 1.382 Mg/m3, crystal size: 0.150 x 0.130 x 0.120 mm. Compound II was crystallized in the monoclinic system, space group P21/n, a = 5.6113(5) Å, b = 11.2280(10) Å, c = 20.675(2) Å, β = 95.543(10)degree, Z = 4, V = 1296.5(2) Å3, F(000) = 536.0, Dc = 1.282 Mg/m3, crystal size: 0.130 x 0.120 X 0.110 mm. Bioactivity assays showed that both compounds have good safety activity against nicosulfuron injury to corn, comparable to the commercial safener isoxadifen-ethyl. The molecular docking model indicated that two types of herbicide safeners competed with nicosulfuron for the acetolactate synthase active site and that this is the protective mechanism of safeners.. KEYWORDS :1,3-Disubstituted imidazolidine, Aryl-substituted formyloxazolidines, Single-crystal structure, Herbicide safener activity.

Evaluating the Potential of Carbon Black for Safening of Herbicides in Soil

ABSTRACT Finely divided carbon char products offer a cost-effective method for the safening of herbicides in soil. In this investigation, two contrasting carbon char sources: Virgin Activated Charcoal (VAC) and Recovered Carbon Black (RCB) products were evaluated for safening of metsulfuron, sulfentrazone and pyroxasulfone herbicides in soil using sugar beet bioassay, and of rimsulfuron using perennial ryegrass bioassay. Plants were grown for seven days in WhirlPack® bags in soil with added carbon char product and added herbicide, and the root or shoot lengths were measured. The VAC was more efficacious in herbicide safening than the RCB. For the VAC, concentrations in soil (wt/wt) as low as 0.375% fully deactivated metsulfuron, sulfentrazone and pyroxasulfone, while for the RCB product a gradual degree of safening was observed, except for pyroxasulfone that was completely deactivated by both VAC and RCB. The VAC at concentrations of 3% and above fully deactivated rimsulfuron, while RCB did not. The two carbon char products examined in this study had different physical properties, of which the specific surface area (91 and 515 m2 g−1 for the RCB and VAC, respectively) and specific surface area of pores (75 and 247 m2 g−1 for RCB and VAC, respectively) showed the greatest difference. Higher surface area promoting greater sorption may explain more effective deactivation of herbicides by the VAC. To obtain the same degree of herbicide safening, more RCB would be required.

Herbicide safener isoxadifen-ethyl associated with increased Goss's wilt severity in corn (Zea mays).

Goss's bacterial wilt and leaf blight (Goss's wilt), caused by the bacterium Clavibacter nebraskensis, is a corn disease that has been a top ten yield-reducing disease in North America in the past 15 years. Isoxadifen-ethyl is an herbicide safener that effectively increases cytochrome P450 activity in corn which enhances a plant's metabolism of herbicide molecules. Recent research found a potential link between isoxadifen-ethyl and increased Goss's wilt severity. The application of isoxadifen-ethyl increased (P = 0.014-0.046) area under disease progress curve (AUDPC) by 19%, 7%, and 9% at three environments, independent of accompanying herbicide or herbicide application timing. However, no significant differences in incidence of systemic wilt or corn grain yield occurred among treatments at any environment. These data provide evidence for an association between isoxadifen-ethyl safener and Goss's wilt in corn. The reason for this association is unknown, but the safener may affect plant or pathogen physiological mechanisms. While the increased disease severity did not result in decreased grain yield in these experiments, an increase in pathogen inoculum due to higher disease severity could influence Goss' wilt epidemics in future years. © 2024 Society of Chemical Industry.

Design, Synthesis, and Biological Evaluation of Novel Purine Derivatives as Herbicide Safeners.

Mesosulfuron-methyl, an inhibitor of acetolactate synthase (ALS), has been extensively used in wheats. However, it can damage wheat (Triticum aestivum) and even lead to crop death. Herbicide safeners selectively shield crops from such damage without compromising weed control. To mitigate the phytotoxicity of mesosulfuron-methyl in crops, several purine derivatives were developed based on active substructure splicing. The synthesized title compounds underwent thorough characterization using infrared spectroscopy, 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry. We evaluated chlorophyll and glutathione contents as well as various enzyme activities to evaluate the safer activity of these compounds. Compounds III-3 and III-7 exhibited superior activity compared with the safener mefenpyr-diethyl. Molecular structure analysis, along with predictions of absorption, distribution, metabolism, excretion, and toxicity, indicated that compound III-7 shared pharmacokinetic traits with the commercial safener mefenpyr-diethyl. Molecular docking simulations revealed that compound III-7 competitively bound to the ALS active site with mesosulfuron-methyl, elucidating the protective mechanism of the safeners. Overall, this study highlights purine derivatives as potential candidates for novel safener development.

Herbicide Safeners: From Molecular Structure Design to Safener Activity.

Herbicide safeners, highly effective antidotes, find widespread application in fields for alleviating the phytotoxicity of herbicides to crops. Designing new herbicide safeners remains a notable issue in pesticide research. This review focuses on discussing and summarizing the structure-activity relationships, molecular structures, physicochemical properties, and molecular docking of herbicide safeners in order to explore how different structures affect the safener activities of target compounds. It also provides insights into the application prospects of computer-aided drug design for designing and synthesizing new safeners in the future.

Selective herbicide safening in dicot plants: a case study in Arabidopsis.

Safeners are agrochemicals co-applied with herbicides that facilitate selective control of weeds by protecting monocot crops from chemical injury through enhancing the expression of detoxifying enzymes such as glutathione transferases (GSTs). Even though the application of safeners causes the induction of genes encoding GSTs in model dicots such as Arabidopsis thaliana, safeners do not protect broadleaf crops from herbicide injury. In this study, we proposed that the localized induction of Arabidopsis GSTs and the fundamental differences in their detoxifying activity between dicot and monocot species, underpin the failure of safeners to protect Arabidopsis from herbicide toxicity. Using the herbicide safener, isoxadifen-ethyl, we showed that three tau (U) family GSTs namely AtGSTU7, AtGSTU19 and AtGSTU24 were induced with different magnitude by isoxadifen treatment in root and rosette tissues. The higher magnitude of inducibility of these AtGSTUs in the root tissues coincided with the enhanced metabolism of flufenacet, a herbicide that is active in root tissue, protecting Arabidopsis plants from chemical injury. Assay of the recombinant enzyme activities and the significant reduction in flufenacet metabolism determined in the T-DNA insertion mutant of AtGSTU7 (gstu7) in Arabidopsis plants identified an important function for AtGSTU7 protein in flufenacet detoxification. In-silico structural modeling of AtGSTU7, suggested the unique high activity of this enzyme toward flufenacet was due to a less constrained active site compared to AtGSTU19 and AtGSTU24. We demonstrate here that it is possible to induce herbicide detoxification in dicotyledonous plants by safener treatment, albeit with this activity being restricted to very specific combinations of herbicide chemistry, and the localized induction of enzymes with specific detoxifying activities.

Synergistic effects of herbicide safener on tembotrione behavior in irrigated Inceptisols, weed obstruction and maize productivity

Synergistic effects of herbicide safener on tembotrione behavior in irrigated Inceptisols, weed obstruction and maize productivity

Efficacy and mechanism of cyprosulfamide in alleviating the phytotoxicity of clomazone residue on maize seedling.

The residues of clomazone (Clo) can lead to phytotoxic symptoms such as foliar bleaching, reduced plant height, and decreased maize yields. Herbicide safener represent one of the most economically efficient strategies for mitigating herbicide-induced damage. In this study, various seed treatments were implemented, including the immersion of maize seeds in water (CK), immersion in Cyprosulfamide (CSA), soil supplemented with clomazone (ClO) and CSA+ClO, evaluated physiological indicators, chlorophyll content, and qRT-PCR analyses of the maize plants were evaluated under the different treatments. The objective of this study was to investigate the impact of CSA on mitigating residual damage caused by Clo on maize and elucidate its mechanism. Compared to the CK, treatment with Clo resulted in significant inhibition of maize plant height, fresh weight, chlorophyll content, and carotenoid levels by 19.0%, 29.9%, 92.5%, and 86.3% respectively. On the other hand, under CSA+Clo treatment, milder inhibition was observed with reductions of only 9.4% in plant height and 7.2% in fresh weight, as well as decreases of 35.7% and 21.8% respectively in chlorophyll and carotenoid contents. The findings revealed that the application of CSA effectively mitigated the inhibitory effects of Clo residues on maize plant height, fresh weight, carotenoids and chlorophyll content. Additionally, the combination of CSA and Clo reduced MDA levels by 13.4%, increased SOD activity by 9.7% and GST activity by 26.7%, while elevating GSSG content by 31.3% compared to Clo alone, ultimately mitigating oxidative damage in maize plants. qRT-PCR analysis showed that the expression of five P450 genes (CYP72A5, CYP81A4, CYP81Q32, CYP81A9, CYP81A36), nine GST genes (GST30, GST31, GSTIV, GSTVI, GST21, GST7, GST37, GST25, IN2-1), and two UGT genes (UGT76C2, UGT83A1) significantly high increased by 6.74-, 10.27-, 4.98-, 10.56-, 25.67-, 16.70-, 46.92-,7.53-, 5.10-, 238.82-, 143.50-, 4.58-, 31.51-, 39.3-, 4.20-, 10.47-fold after CSA+Clo treatment compared to that in the Clo treatment. The pre-treatment of CSA led to the upregulation of five P450 genes, nine GST genes, and two UGT genes, which may be associated with the metabolism of Clo in maize. Overall, this study suggests that CSA could be effectively mitigates Clo residual damage by up-regulating detoxification-related genes, enhancing chlorophyll content and activities of antioxidant enzymes.

Protective mechanisms of neral as a plant-derived safener against fenoxaprop-p-ethyl injury in rice.

The use of herbicide safeners effectively minimises crop damage while maintaining the full efficacy of herbicides. The present study aimed to assess the potential protective effects of neral (NR) as a safener, in order to mitigate injury caused by fenoxaprop-p-ethyl (FE) on rice. The alleviating effect of NR was similar to that of the safener isoxadifen-ethyl (IE). The root elongation of rice was significantly promoted under the FE + NR and FE + IE treatments, as compared to the FE treatment. The transcriptome analysis further suggested that the effects of NR treatment on plant metabolic pathways differed from those of IE treatment. In total, 895 and 47 up-differentially expressed genes induced by NR (NR-inducible genes) and IE (IE-inducible genes) were identified. NR-inducible genes were mainly enriched in phytohormone synthesis and signalling response, including 'response to brassinosteroid', 'response to jasmonic acid', 'response to ethylene', 'brassinosteroid metabolic process', 'brassinosteroid biosynthesis' and 'plant hormone signal transduction'. In contrast, IE-inducible genes were predominantly enriched in glutathione metabolism. The activity of glutathione S-transferase was found to be increased after IE treatment, whereas no significant increase was observed following NR treatment. Moreover, several transcription factor genes, such as those encoding AP2/ERF-ERF and (basic helix-loop-helix) bHLH were found to be significantly induced by NR treatment. This is the first report of the utilisation of NR as an herbicide safener. The results of this study suggest the toxicity of FE to rice is mitigated by NR through a distinct mechanism compared to IE. © 2023 Society of Chemical Industry.

Integrating transcriptome and physiological analyses to elucidate the molecular responses of sorghum to fluxofenim and metolachlor herbicide

Integrating transcriptome and physiological analyses to elucidate the molecular responses of sorghum to fluxofenim and metolachlor herbicide

Soil enzyme activities, physiological indicators, agronomic traits and yield of common buckwheat under herbicide combined with safeners

In the pursuit of green agricultural development, alleviating the harmful effects of herbicides is critical. Herbicide safeners have been identified as an effective solution to safeguard crops without compromising the herbicidal efficacy. However, the impact of combined applications of herbicide and safeners on the physiological characteristics, growth, yield of common buckwheat, and soil enzyme activities remains unclear. Therefore, a two-year (2021 and 2022) field experiment was conducted in the Loess Plateau region of Northwest China under seven treatments: herbicide metolachlor application alone (H1); herbicide metolachlor combined with gibberellin (H1S1); herbicide metolachlor combined with brassinolide (H1S2); herbicide metolachlor combined with naian (H1S3); herbicide metolachlor combined with jiecaotong (H1S4); manual weeding (CK1) and spraying the same volume of water (CK2). The results indicated that H1S3 minimized herbicide toxicity while sustaining the herbicide control efficacy. H1S2 treatment significantly increased the chlorophyll content (SPAD value), superoxide dismutase (SOD), peroxidase (POD) activities, and decreased the malondialdehyde (MDA) content of the leaves compared to H1 treatment. Additionally, the safeners helped restore the biochemical homeostasis of the soil by preventing the inhibition of invertase and urease activities and increasing soil catalase activity. Furthermore, H1S2 promotion of dry matter accumulation, alleviation of herbicide inhibition on plant height, stem diameter, grainnumber per plant and thousand-grain weight resulted in a significant increase in grain yield (14.36 % in 2021 and 27.78 % in 2022) compared to other safener treatments. Overall, this study demonstrates that brassinolide as a safener can effectively mitigate the negative effects of herbicide on the growth and development of common buckwheat while also improving grain yield. These findings provide valuable technical guidance for sustainable and intensive production of common buckwheat in the Loess Plateau of Northwest China.

Review on the Discovery of Novel Natural Herbicide Safeners.

The phytotoxicity of herbicides on crops is a major dilemma in agricultural production. Fortunately, the emergence of herbicide safeners is an excellent solution to this challenge, selectively enhancing the performance of herbicides in controlling weeds while reducing the phytotoxicity to crops. But owing to their potential toxicity, only a tiny proportion of safeners are commercially available. Natural products as safeners have been extensively explored, which are generally safe to mammals and cause little pollution to the environment. They are typically endogenous signal molecules or phytohormones, which are generally difficult to extract and synthesize, and exhibit relatively lower activity than commercial products. Therefore, it is necessary to adopt rational design approaches to modify the structure of natural safeners. This paper reviews the application, safener effects, structural characteristics, and modifications of natural safeners and provides insights on the discovery of natural products as potential safeners in the future.

Design, Synthesis, and Structure-Activity Relationship of Novel Aryl-Substituted Formyl Oxazolidine Derivatives as Herbicide Safeners.

Nicosulfuron is the leading herbicide in the global sulfonylurea (SU) herbicide market; it was jointly developed by DuPont and Ishihara. Recently, the widespread use of nicosulfuron has led to increasingly prominent agricultural production hazards, such as environmental harm and influence on subsequent crops. The use of herbicide safeners can significantly alleviate herbicide injury to protect crop plants and expand the application scope of existing herbicides. A series of novel aryl-substituted formyl oxazolidine derivatives were designed using the active group combination method. Title compounds were synthesized using an efficient one-pot method and characterized by infrared (IR) spectrometry, 1H and 13C nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS). The chemical structure of compound V-25 was further identified by X-ray single crystallography. The bioactivity assay and structure-activity relationship proved that nicosulfuron phytotoxicity to maize could be reduced by most title compounds. The glutathione S-transferase (GST) activity and acetolactate synthase (ALS) in vivo were determined, and compound V-12 showed inspiring activity comparable to that of the commercial safener isoxadifen-ethyl. The molecular docking model indicated that compound V-12 competed with nicosulfuron for the acetolactate synthase active site and that this is the protective mechanism of safeners. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions demonstrated that compound V-12 exhibited superior pharmacokinetic properties to the commercialized safener isoxadifen-ethyl. The target compound V-12 shows strong herbicide safener activity in maize; thus, it may be a potential candidate compound that can help further protect maize from herbicide damage.

Decatungstate‐Photocatalyzed Functionalization of α‐Imino Esters for the Preparation of Unnatural α‐Amino Acid Derivatives

AbstractA library of unnatural α‐amino acid derivatives has been prepared via the hydrofunctionalization of the C=N bond in a set of compounds belonging to the family of α‐imino esters. The devised methodology capitalizes on the use of tetrabutylammonium decatungstate as the photocatalyst to generate C‐centered radicals from aliphatic and aromatic aldehydes, cyclic and acyclic oxygenated compounds and even cycloalkanes, via a hydrogen atom transfer (HAT) step. The best performance was observed when α‐hydrazono esters were employed in the role of radical traps, which delivered the corresponding (protected) α‐hydrazino acids as products. The versatility of the protocol was further demonstrated by the possibility to functionalize the herbicide safener isoxadifen‐ethyl.

Design, Synthesis, and Bioactivity of Novel Ester-Substituted Cyclohexenone Derivatives as Safeners.

Tembotrione, a 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor, has been widely used in many types of plants. Tembotrione has been reported for its likelihood of causing injury and plant death to certain corn hybrids. Safeners are co-applied with herbicides to protect certain crops without compromising weed control efficacy. Alternatively, herbicide safeners may effectively improve herbicide selectivity. To address tembotrione-induced Zea mays injury, a series of novel ester-substituted cyclohexenone derivatives were designed using the fragment splicing method. In total, 35 title compounds were synthesized via acylation reactions. All the compounds were characterized using infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The configuration of compound II-15 was confirmed using single-crystal X-ray diffraction. The bioactivity assay proved that tembotrione phytotoxicity to maize could be reduced by most title compounds. In particular, compound II-14 exhibited the highest activity against tembotrione. The molecular structure comparisons as well as absorption, distribution, metabolism, excretion, and toxicity predictions demonstrated that compound II-14 exhibited pharmacokinetic properties similar to those of the commercial safener isoxadifen-ethyl. The molecular docking model indicated that compound II-14 could prevent tembotrione from reaching or acting with Z. mays HPPD (PDB: 1SP8). Molecular dynamics simulations showed that compound II-14 maintained satisfactory stability with Z. mays HPPD. This research revealed that ester-substituted cyclohexenone derivatives can be developed as potential candidates for discovering novel herbicide safeners in the future.

New 6'-Amino-5'-cyano-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-pyridine]-3'-carboxamides: Synthesis, Reactions, Molecular Docking Studies and Biological Activity.

The purpose of this work was to prepare new isatin- and monothiomalondiamide-based indole derivatives, as well as to study the properties of the new compounds. The four-component reaction of 5-R-isatins (R = H, CH3), malononitrile, monothiomalonamide (3-amino-3-thioxo- propanamide) and triethylamine in hot EtOH yields a mixture of isomeric triethylammonium 6'-amino-3'-(aminocarbonyl)-5'-cyano-2-oxo-1,2-dihydro-1'H- and 6'-amino-3'-(aminocarbonyl)- 5'-cyano-2-oxo-1,2-dihydro-3'H-spiro[indole-3,4'-pyridine]-2'-thiolates. The reactivity and structure of the products was studied. We found that oxidation of spiro[indole-3,4'-pyridine]-2'-thiolates with DMSO-HCl system produced only acidification products, diastereomeric 6'-amino-5'-cyano-5-methyl-2-oxo-2'-thioxo-1,2,2',3'-tetrahydro-1'H-spiro-[indole-3,4'-pyridine]- 3'-carboxamides, instead of the expected isothiazolopyridines. The alkylation of the prepared spiro[indole-3,4'-pyridine]-2'-thiolates upon treatment with N-aryl α-chloroacetamides and α-bromoacetophenones proceeds in a regioselective way at the sulfur atom. In the case of α-bromoacetophenones, ring-chain tautomerism was observed for the S-alkylation products. According to NMR data, the compounds consist of a mixture of stereoisomers of 2'-amino-6'-[(2-aryl-2-oxoethyl)thio]-3'-cyano-2-oxo-1'H-spiro[indoline-3,4'-pyridine]-5'-carboxamides and 5'-amino-3'-aryl-6'-cyano-3'-hydroxy-2-oxo-2',3'-dihydrospiro[indoline-3,7'-thiazolo[3,2-a]pyridine]-8'-carboxamides in various ratios. The structure of the synthesized compounds was confirmed by IR spectroscopy, HRMS, 1H and 13C DEPTQ NMR studies and the results of 2D NMR experiments (1H-13C HSQC, 1H-13C HMBC). Molecular docking studies were performed to investigate suitable binding modes of some new compounds with respect to the transcriptional regulator protein PqsR of Pseudomonas aeruginosa. The docking studies revealed that the compounds have affinity for the bacterial regulator protein PqsR of Pseudomonas aeruginosa with a binding energy in the range of -5.8 to -8.2 kcal/mol. In addition, one of the new compounds, 2'-amino-3'-cyano-5-methyl-2-oxo-6'-{[2-oxo-2-(p-tolylamino)ethyl]thio}-1'H-spiro-[indoline-3,4'-pyridine]-5'-carboxamide, showed in vitro moderate antibacterial effect against Pseudomonas aeruginosa and good antioxidant properties in a test with 1,1-diphenyl-2-picrylhydrazyl radical. Finally, three of the new compounds were recognized as moderately active herbicide safeners with respect to herbicide 2,4-D in the laboratory experiments on sunflower seedlings.