Thymol Derivatives Research Articles

Synthesis and antibacterial potential of novel thymol derivatives against methicillin-resistant Staphylococcus aureus and P. aeruginosa pathogenic bacteria.

The increasing threat of antibiotic resistance has created an urgent need for new antibacterial agents, particularly plant-based natural compounds and their derivatives. Thymol, a natural monoterpenoid phenolic compound derived from Monarda citriodora, is known for its aromatic and therapeutic properties, including antibacterial activity. This study focuses on synthesizing dihydropyrimidinone and dihydropyridine derivatives of thymol and exploring their antibacterial properties. The synthesized compounds were tested for their in vitro antibacterial potential against pathogenic microorganisms, specifically Pseudomonas aeruginosa (Gram-negative) and methicillin-resistant Staphylococcus aureus (MRSA) (Gram-positive). Among the synthesized derivatives, compound 3i (ethyl 4-(4-hydroxy-5-isopropyl-2-methylphenyl)-2-imino-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate) exhibited the most promising antibacterial activity, with minimum inhibitory concentration (MIC) values of 12.5µM against P. aeruginosa and 50.0µM against MRSA. Additionally, compound 3i demonstrated a synergistic effect when combined with vancomycin, enhancing its antibacterial efficacy. The optimum fractional inhibitory concentration index (FICI) observed was 0.10 and 0.5 for MRSA and P. aeruginosa, respectively, in combination with vancomycin. In silico analysis of the physiochemical properties of 3i indicated compliance with all drug-likeness rules. Furthermore, molecular docking studies revealed that compound 3i has a stronger binding affinity to the target protein than thymol, providing valuable insights into its potential mechanism of action.

Thymol-1,2,3-triazole derivatives: Network pharmacology, molecular simulations and synthesis targeting breast cancer

Cancer prevention has become a major focus of public health in the 21st century. Despite advancements in treatment, tackling cancer remains a significant challenge due to the different types of cancer. Breast cancer stands out as the leading cause of cancer-related deaths, highlighting its significant impact on female health worldwide. Monoterpenes, exemplified by thymol, exhibit notable potential in cancer treatment, owing to their pharmacological properties and mechanisms of action. Concurrently, 1,2,3-triazoles have garnered attention as promising entities for the development of anticancer agents, showcasing their efficacy and relevance in oncology research. This study describes the synthesis and characterization of a novel library of 1,2,3-triazole derivatives tethered to p-methoxythymol, a natural product. High-resolution mass spectrometry (HRMS) definitively confirmed the structures of the synthesized compounds, which were further elucidated by detailed analysis of their ¹H- and ¹³CNMR spectra. To predict the suitable target, network pharmacology was applied to the synthesized thymol derivatives, resulting in the identification of phosphatidylinositol-3-kinase (PIK3CA) as a key target. Furthermore, these thymol derivatives were screened for ADMET and molecular docking against the phosphatidylinositol-3-kinase (PIK3CA) target. Molecular dynamics simulations were conducted for the top two compounds over a duration of 100 ns to assess their stability. The RMSD (Root-Mean-Square Devia­tion) and RMSF (root-mean-square fluctuation) values for amino acid residues indicated structural integrity and stable protein-ligand interaction. Additionally, all designed compounds displayed favorable physicochemical properties and ADMET profiles, and two compounds, 4b and 4d, were found to be new lead molecules targeting PIK3CA

Development of amphipathic derivatives of thymol and carvacrol as potent broad-spectrum antibacterial agents

In the current study, to discover novel antibacterial agents, we designed and synthesized 72 carvacrol and thymol derivatives by biomimicking the structure and function of cationic antimicrobial peptides (AMPs). Many of the derivatives showed good antibacterial activity, and compound thy2I exhibited the most potent antibacterial activity with minimum inhibitory concentration (MIC) values ranging from 0.5 μg/mL to 8 μg/mL. Compound thy2I could kill both gram-positive and gram-negative bacteria via a membrane-targeting mechanism of action with a low frequency of resistance. In addition, thy2I had the advantages of good membrane selectivity, low toxicity in vitro and in vivo, and good plasma stability. The in vivo activity results revealed that thy2I exhibited a positive therapeutic effect in a mouse skin abscess model induced by Staphylococcus aureus ATCC29213. After thy2I treatment (10 mg/kg), the bacterial load of the S. aureus-infected abscesses was reduced by approximately 99.65 %. Our study suggests that thy2I may serve as an antibacterial lead for further clinical evaluation.

Discovery of novel piperidine-containing thymol derivatives as potent antifungal agents for crop protection.

Plant fungal diseases pose a significant threat to crop production. The extensive use of chemical pesticides has led to growing environmental safety risks and pesticide resistance of various plant pathogens. Therefore, it is an urgent task to explore novel eco-friendly fungicidal agents with high efficacy to combat fungal infection. In this study, we rationally designed a series of novel thymol derivatives by incorporation of the sulfonamide moiety and evaluated their biological activities against plant pathogenic fungi. The bioassay results underscored the remarkable in vitro antifungal activity of compounds 5m and 5t against Phytophthora capsici (P. capsici), with EC50 values of 8.420 and 8.414 μg/mL, respectively. Their efficacies were superior to that of widely used commercial fungicides azoxystrobin (AZO, 20.649 μg/mL) and cabendazim (CAB, 251.625 μg/mL). Furthermore, compound 5v exhibited excellent in vitro antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum), with an EC50 value of 12.829 μg/mL, significantly outperforming AZO (63.629 μg/mL). In vivo bioassays demonstrated the impactful activity of compound 5v against S. sclerotiorum, achieving over 98% curative and protective efficacies at the concentration of 200 μg/mL. Further mechanistic investigations unveiled that compound 5v induced mycelial shrinkage and collapse in S. sclerotiorum, resulting in organelle damage and the accumulation of antioxidant enzyme activity. The significant antifungal efficacy of the prepared thymol derivatives shall encourage further exploration of compound 5v as a promising candidate to develop novel fungicides for crop protection. © 2024 Society of Chemical Industry.

Validation of the traditional antimicrobial use of the Iranian medicinal plant Thymus daenensis Celak through phytochemical characterization of its bioactive constituents

Thymus daenensis Celak (Lamiaceae family), known as denaian thyme, is an Iranian endemic plant, commonly used for its carminative, expectorant, antibacterial and antifungal properties. Previous studies report the chemical profile of the essential oil of T. daenensis aerial parts, but little is known about its non volatile constituents. Herein, phytochemical and biological investigation of the polar extract of T. daenensis aerial parts to provide further insight into traditional use of this plant has been accomplished. High-performance liquid chromatography coupled to linear ion-trap and orbitrap high-resolution mass spectrometry (LC-ESI/LTQOrbitrap/MS/MS) analysis of MeOH extract was performed to guide the isolation of specialized metabolites and successive characterization by NMR analysis. MeOH extract displayed antioxidant activity evaluated by DPPH (EC50 = 48.99 ± 1.47 μg/mL) and TEAC assay (1.37 mg/mL). Successively, the biofilm inhibitory activity of extract and isolated compounds against mature biofilms of Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Listeria monocytogenes, and Staphylococcus aureus, and their influence on the metabolism of sessile bacterial cells were evaluated. Two previously unreported thymol derivatives have been identified. The biofilm inhibitory activity of isolated compounds highlighted a promising antimicrobial action for the tested compounds. In particular, vanillic acid, (3S,5R,6R,7E,9S)-megastigm-7-ene-3,5,6,9-tetrol 3-O-β-D-glucopyranoside, thymoquinol-2-O-β-D-glucopyranoside and the never reported compound daenol resulted capable of exerting inhibitory activity vs all pathogenic strains. All compounds tested at a concentration of 10 μg/mL inhibited the metabolism of the sessile cells of E. coli at a percentage ranging between 37.7% and 77.39%, and of L.monocytogenes at a percentage ranging between 21.79% and 71.17%.

Chemical Constituents and Their Bioactivities of Plants from the Genus Eupatorium (2015-Present).

The genus Eupatorium belongs to the Asteraceae (Compositae) family and has multiple properties, such as invasiveness and toxicity, and is used in folk medicine. The last review on the chemical constituents of this genus and their biological activities was published in 2015. The present review provides an overview of 192 natural products discovered from 2015 to the present. These products include 63 sesquiterpenoids, 53 benzofuran derivatives, 39 thymol derivatives, 15 fatty acids, 7 diterpenoids, 5 monoterpenoids, 4 acetophenones, and 6 other compounds. We also characterized their respective chemical structures and cytotoxic, antifungal, insecticidal, antibacterial, anti-inflammatory, and antinociceptive activities.

The synthesis of highly nonplanar oxidovanadium(IV) porphyrins as robust catalysts for oxidative bromination of phenols in aqueous medium

Two new complexes, oxidovanadium(IV) 2,3,5,10,12,13,15,20-octaphenyl-7,8,17,18-tetrabromoporphyrin V(IV)O(OPP)Br4 (2), and oxidovanadium(IV) 2,3,5,10,12,13,15,20-octaphenyl-7,8,17,18-tetrachloroporphyrin V(IV)O(OPP)Cl4 (3) starting from oxidovanadium(IV) 2,3,5,10,12,13,15,20-octaphenylporphyrin V(IV)O(OPP) (1) have been prepared in good yields and characterized by various spectroscopic techniques. The single-crystal and DFT-optimized structures of these porphyrins showed a highly nonplanar saddle-shape conformation of the porphyrin macrocycle. In the cyclic voltammograms, the first ring oxidation potential and the first ring reduction potential of V(IV)O(OPP)Br4 (2) and V(IV)O(OPP)Cl4 (3) showed anodic shift as compared to V(IV)O(OPP) (1), indicating the electron-deficient nature of both the porphyrins. The oxidation state of vanadium in the synthesized complexes as +4 was confirmed by EPR spectroscopy, and these porphyrins exhibited axially compressed [Formula: see text] configuration. These porphyrins were utilized as catalysts for the oxidative bromination of thymol and other phenol derivatives with excellent conversion ([Formula: see text] 99.9%), good selectivity, and high TOF value (86869 h[Formula: see text].

Bioactive monoterpenoids and acetophenones from the aerial parts of Eupatorium fortunei

Thirty-nine thymol and acetophenone derivatives, including eight pairs of enantiomers, were isolated from the aerial parts of Eupatorium fortunei. Their structures were assigned by detailed analyses of spectroscopic data and NMR calculations based on density functional theory, with 18 ones (1a/1b−14) being previously undescribed compounds. While the absolute configurations of 1a/1b, 2a/2b, 4, 6a/6b, 7, 11a/11b and 15a/15b−18a/18b were established by calculations of electronic circular dichroism data, that of 14 was determined by modified Mosher's method. Compounds 1a/1b and 2a/2b represent a previously unreported type of monoterpenoid dimers via an amide linkage, and compound 3 is a monoterpene-phenylpropanoid hybrid connected through an ester bond. Among the known molecules, the formerly mis-assigned structures of 15a/15b and 22 were revised, and pure natural enantiomers of 16a/16b−18a/18b were reported for the first time. Selective compounds showed antiradical and NO production inhibitory activities in the preliminary biological screening. Compound 31 was further demonstrated to alleviate oxidative stress by activating Nrf2 signaling pathway.

Characterization of the effects of thymol derivatives on colorectal cancer spheroids.

Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies with a high mortality rate. In the last few years, attention has been focused on substances of natural origin with anticancer activity. One such substance is thymol and its derivatives, which have been shown to have an antitumor effect also against CRC cells. In our study, we focused on determining the biological and antibacterial effects of thymol and thymol derivatives. Analyses were performed on a 3D model of human colon carcinoma cell lines (HCT-116 and HT-29) - spheroids. The cytotoxic (MTT assay) and genotoxic effect (comet assay) of thymol and derivatives: acetic acid thymol ester and thymol ß-D-glucoside were determined. ROS levels (ROS-Glo™ H2O2 Assay) and total antioxidant status (Randox TAS Assay) were also monitored. Last but not least, we also detected the effect of the derivatives using a disk diffusion assay and determined the number of colonies on the plates on selected bacteria such as Lacticaseibacillus rhamnosus, Lactiplantibacillus plantarum, Lacticaseibacillus paracasei, Lactobacillus brevis, Lactobacillus pentosus and Weizmannia coagulans. The derivatives did not show a significant inhibitory effect on the growth of LAB bacteria (lactic acid bacteria) in contrast to thymol. Overall, thymol derivatives are cytotoxic, genotoxic and increase ROS levels. Among the derivatives tested, acetic acid thymol ester (IC50 ~ 0.2 μg/ml) was more effective. The second derivative tested (thymol β-D-glucoside) was effective at higher concentrations than thymol. Our research confirmed that thymol derivatives have a toxic effect on the 3D model of intestinal tumor cells, while they do not have a toxic effect on selected intestinal bacteria. Thus, they could bring new significance to the prevention or treatment of CRC.

Thymol and carvacrol derivatives as anticancer agents; synthesis, in vitro activity, and computational analysis of biological targets.

Various thymol and carvacrol derivatives have been synthesized to test the anticancer activity potential. Computational methods including network pharmacology and molecular docking approaches were utilized to identify and assess the potential biological targets relating to cancer. Amongst the synthesized derivatives the ethoxy-cyclohexyl analogues were consistently the most active against a panel of 10 different cancer cell lines covering a variety of origins. Biological target predictions revealed the AKT1 protein to be a core and central target of the most active compounds. Molecular docking identified a binding pocket within this protein in which the most active compounds bind. The incorporation of computational analysis methods and conventional structure-activity approaches identified analogues of thymol and carvacrol with the highest anticancer potential, and analyzed their possible biological targets in a comprehensive manner.

The chemical composition of the aerial parts essential oil of Pulicaria odora (L.) Rchb. growing in Sicily (Italy)

The genus Pulicaria Gaertn. (Asteraceae) comprises more than ninety-two species as annual or perennial herbs or small shrubs, distributed in Africa, Europe, and Asia, and concentrated mainly in the Mediterranean region. Several species have been used in the traditional medicine of many countries. In the present study the chemical composition of the essential oil from aerial parts of Pulicaria odora (L.) Rchb., present in the Mediterranean region and collected in Sicily, was analysed by GC-MS. No papers have been previously published on the essential oil of the aerial part of this species. The result showed the presence of large quantity of carbonyl compounds (25.29%), oxygenated sesquiterpenes (23.28%) and thymol derivatives (16.76%). Chemical considerations with respect of other oils of Pulicaria taxa were carried out.

Chemical constituents from Eupatorium fortunei and their anti-inflammatory evaluation by in silico and experimental approaches

The well-known aromatic and medicinal plant Eupatorium fortunei Turcz. is widely cultivated in China, and previous studies on its bioactive constituents mainly focus on the essential oil ingredients especially thymol derivatives. However, reports on other type of constituents and the potential application are lacking. In the present project, an intensive chemical fractionation on the aerial part extract of E. fortunei led to the isolation and identification of a series of fatty acid derivatives (lipids, 1a/1b-19) including seven pairs of previously undescribed enantiomers (1a/1b-7a/7b), as well as a lignan (brachangobinan A (BBA), 20) and two monoterpenes (8S/8R-9-hydroxythymol, 21a/21b). A preliminary biological evaluation of these compounds in a NO production inhibitory assay model demonstrated compound BBA as the most active one. Network pharmacology analysis was used to predict and explore the possible anti-inflammatory targets and mechanism of BBA, which revealed some potential inflammation-related proteins and signaling pathways. Further experimental investigations validated that the anti-inflammatory effect of BBA could be achieved by suppressing pro-inflammatory factors and blocking the activation of NF-κB signaling pathway. Taken together, our work shows that E. fortunei can serve as a potential resource of lipids and anti-inflammatory agents.

Formicidal Potential of Thymol Derivatives: Adverse Effects on the Survival and Behavior of Acromyrmex balzani

Leaf-cutting ants are important pests of agricultural and forest crops. Currently, few insecticides are registered for the control of these insects. Natural bioactive molecules can serve as models for the synthesis of new insecticidal compounds. Such ant killer products must be sustainable and efficient, considering not only lethal effects, but also sublethal effects, which can interfere with behavior and communication between colony members. In this study, we analyzed the toxicity of the monoterpene thymol and its derivatives, as well as the sublethal effects of these compounds on the behavior of the leaf-cutting ant Acromyrmex balzani. These effects were compared with the conventional synthetic insecticide deltamethrin. Although deltamethrin showed higher toxicity (LD50 = 0.87 × 10−5 µg/mg), all other tested compounds increased ant mortality, with thymyl chloroacetate being the most toxic derivative (LD50 = 1.41 µg/mg), followed by thymol (LD50 = 2.23 µg/mg). These three most toxic compounds interfered differentially in the behavior of ants. Thymyl chloroacetate caused increased self-cleaning and reduced allogrooming, which may be related to an attempt to avoid contamination between nestmates. In general, thymol caused greater avoidance among ants, reduced walking speed and caused disorientation in workers. On the other hand, thymyl chloroacetate (LD30) considerably increased the walking speed of the group, without changing the orientation of the individuals. Such changes may interfere with basic activities such as foraging and altering colony cohesion via different mechanisms. Thus, despite the desirable effects of deltamethrin on ant control, this insecticide is highly toxic and should be discontinued soon. Our results show that thymol and its structural modification in thymyl chloroacetate may represent potential ant killers to be used in the management of A. balzani.

Characterization of thymol derivatives from Eupatorium fortunei Turcz. aerial parts

From the aerial parts of Eupatorium fortunei, four thymol derivatives (1-4) were isolated and structurally elucidated by NMR and mass spectroscopic methods. Of which, a new dimeric thymol derivative (1) was characterized and its absolute configuration was established by electronic circular dichroism quantum method. In addition, the 1D and 2D NMR as well as HR-ESI mass spectral data of 2 were provided for the first time. Compounds 2-4 were evaluated for their inhibitory activity against α-glucosidase and acetylcholinesterase enzymes. All tested compounds showed weak inhibition at the concentration range of 1–256 μg/mL in both enzymatic assays.

Constituents of Pulicaria inuloides and Cytotoxic Activities of Two Methoxylated Flavonols.

Plants of the genus Pulicaria are known for providing traditional medicines, spices, herbal teas, and insect deterrents. Pulicaria inuloides (Poir.). DC. is one of the less chemically studied species within the genus. Hydroalcoholic extracts from roots and aerial parts of P. inuloides were analyzed using the UHPLC-PAD-MSn technique and revealed the presence of six caffeoylquinic and eleven caffeoylhexaric conjugates together with hydroxykaempferol dimethyl ether and quercetagetin trimethyl ether. Moreover, constituents of chloroform extract from the whole P. inuloides plants were isolated and identified by spectroscopic methods. One new and four known caryophyllene derivatives, three thymol derivatives, and four polymethoxylated flavonols were found in the analyzed extract. The structure of the new compound was established by spectroscopic methods (HRESIMS, 1H NMR, 13C NMR, COSY, HSQC, HMBC, NOESY). The cytotoxicity of 6-Hydroxykaempferol 3,7-dimethyl ether and quercetagetin 3,7,3’-trimethyl ether (chrysosplenol C), which are major flavonols isolated from the plant, were tested on prostate epithelial cells (PNT2), prostate cancer cells (DU145 and PC3), human keratinocytes (HaCaT), and melanoma cells (HTB140 and A375). Both flavonols demonstrated moderate cytotoxic activity against PC3 cells (IC50 = 59.5 µM and 46.6 µM, respectively). The remaining cell lines were less affected (IC50 > 150 µM).

Photoredox-catalyzed 1,2-oxo-alkylation of vinyl arenes with 1,3-diketones: an approach to 1,4-dicarbonyls via C-C activation.

A mild and inexpensive approach to synthesising a series of 1,4-diketones in moderate to excellent yields via 1,2-oxo alkylation has been developed using fluorescein as a photocatalyst and air as an oxidant. The key features include (i) varied substrate scope (39 examples); (ii) good functional group tolerance; (iii) unsymmetrical 1,4-dicarbonyls; (iv) late-stage functionalization of thymol and ibuprofen derivatives; and (v) the synthetic expansion to 5- and 6-membered N-, O- and S-containing heterocycles.

Two new thymol derivatives from Eupatorium fortunei

Two new thymol derivatives (1–2) were isolated from the aerial parts of Eupatorium fortunei. Their structures were elucidated on the basis of comprehensive spectroscopic data analysis as 8,9-dehydrothymol-3-O-β-glucoside (1), and 9-(acetyloxy)thymol-3-yl (3-methylbut-2-enoate) (2). All isolates were evaluated for cytotoxic activities with IC50 values greater than 50 μM in vitro against MCF-7, HeLa, A549, and Hep G-2 cancer cells.

Catalytic electro-oxidation of hydrazine by thymol based-modified glassy carbon electrode

In the present, thymol based new organic compounds (4A, 4B and 4C) are designed and synthesized via Steglich Esterification Reactions and Pd-catalyst Sonogashira Coupling Reactions. After isolation and characterization, thymol based hybrid molecules are used for hydrazine (N2H4) electrooxidation reactions as anode catalysts. A variety of metal based anode catalyst have been reported in literature, but this study may be the first study for thymole based hybrid molecules as an anode catalyst in fuel cells. The performance of hybrid molecules was investigated via cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) in hydrazine solution. Hybrid 2-isopropyl-5-methylphenyl-4-oxo-4-(5-(p-tolylethynyl)thiophen-2-yl)butanoate (4C) gives the highest performance as 3.66 mAcm−2 (17.24 mAmg−1). Our results displayed that natural products like thymol derivatives may be new generation anode catalyst for fuel cells, and they may be alternative for expensive Pd and Pt based metal anode catalyst.

Obtaining substituted phenol derivatives with potential antimicrobial activity

Objectives. With the growing resistance of pathogenic microorganisms to antibiotics, the development of new antimicrobial drugs offering specific mechanisms of action becomes an urgent task. Only few antimicrobials offer a broad spectrum of activity against gram-positive and gram-negative bacteria, molds, and yeasts. In this regard, the purpose of the work was to develop methods for synthesizing biologically active derivatives of alkyl-substituted phenols (reactions at the hydroxy group) to study their biological effect.Methods. The synthesis of imidazole acetates of substituted phenols was carried out in two stages. At the first stage, the chloroacetyl derivative of the selected compounds was obtained, to which imidazole was then added. O-acylation reactions at the first stage of the synthesis were carried out under varying conditions. The first version of the synthesis was carried out using chloroacetyl chloride as an acylating agent together with a high-boiling solvent. In the second variant, chloroacetic anhydride was used, along with an attempt to replace the solvent with a low-boiling one. A thymol methoxy derivative was additionally synthesized by a known method using methyl iodide and varying the reaction parameters.Results. The parameters of chloroacetylation and methoxylation of aromatic alcohols were optimized with rational selection of solvents and the ratio of reagents in the reactions. Synthesized thymol (2-isopropyl-5-methylphenol) and propofol (2,6-isopropylphenol) derivatives contained imidazole as an additional pharmacophore with affinity for microorganism cell membrane proteins. A thymol methoxy derivative comprising an aromatic ether exhibiting increased hydrophobicity was also obtained. The synthesized compounds were characterized by NMR spectroscopy.Conclusions. Chloroacetyl derivatives of aromatic alcohols can be effectively synthesized by cooling the reaction mixture using an excess quantity of an acylating agent and increasing the reaction time (compared to literature data). The yield of thymol chloroacetate was 75%, while that of propofol chloroacetate was 30%. This can be explained by the sterically hindered reaction of the propofol alcohol group, which has isopropyl substituents at the second and sixth positions of the benzene ring.

Thymol and its Derivatives for Management of Phytopathogenic fungi of Maize

Background: Thymol is a bioactive compound having many pharmacological activities. Objective: The present study was carried out to evaluate the fungi toxic effects of thymol and derivatives against phytopathogenic fungi of maize. Method: Thymol was derivatized to get formylated thymol, Mannich bases, and imine derivatives. All the synthesized thymol derivatives were characterized by their physical and spectral properties. Synthesized thymol derivatives were screened for their in vitro antifungal effects using poisoned food technique against three maize pathogenic fungi, namely Fusarium moniliforme, Rhizoctonia solani and Dreschlera maydis. Results: Thymol and formylated thymol showed promising results for control of D. maydis with ED50 values less than standard carbendazim and comparable to standard mancozeb. These two compounds were further evaluated for control of D. maydis causative maydis leaf blight disease on maize plants grown in the field during the Kharif season (June to October) 2018. Conclusion: Thymol exhibited significant control of maydis leaf blight disease of maize and emerged as a potential alternative to synthetic fungicides used in cereal crops.