Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays.

Mycobacterium tuberculosis is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. M. tuberculosis DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit M. tuberculosis GyrB ATPase activity from the Specs compound library. This approach yielded six compounds: four carbazole derivatives (1, 2, 3, and 8), the benzoindole derivative 11, and the indole derivative 14. Carbazole derivatives can be considered a new scaffold for M. tuberculosis DNA gyrase ATPase inhibitors. IC50 values of compounds 8, 11, and 14 (0.26, 0.56, and 0.08 µM, respectively) for inhibition of M. tuberculosis DNA gyrase ATPase activity are 5-fold, 2-fold, and 16-fold better than the known DNA gyrase ATPase inhibitor novobiocin. MIC values of these compounds against growth of M. tuberculosis H37Ra are 25.0, 3.1, and 6.2 µg/mL, respectively, superior to novobiocin (MIC > 100.0 µg/mL). Molecular dynamics simulations of models of docked GyrB:inhibitor complexes suggest that hydrogen bond interactions with GyrB Asp79 are crucial for high-affinity binding of compounds 8, 11, and 14 to M. tuberculosis GyrB for inhibition of ATPase activity. These data demonstrate that virtual screening can identify known and new scaffolds that inhibit both M. tuberculosis DNA gyrase ATPase activity in vitro and growth of M. tuberculosis bacteria.

Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity.

Mutations in DNA gyrase confer resistance to fluoroquinolones, second-line antibiotics for Mycobacterium tuberculosis infections. Identification of new agents that inhibit M. tuberculosis DNA gyrase ATPase activity is one strategy to overcome this. Here, bioisosteric designs using known inhibitors as templates were employed to define novel inhibitors of M. tuberculosis DNA gyrase ATPase activity. This yielded the modified compound R3-13 with improved drug-likeness compared to the template inhibitor that acted as a promising ATPase inhibitor against M. tuberculosis DNA gyrase. Utilization of compound R3-13 as a virtual screening template, supported by subsequent biological assays, identified seven further M. tuberculosis DNA gyrase ATPase inhibitors with IC50 values in the range of 0.42-3.59 µM. The most active compound 1 showed an IC50 value of 0.42 µM, 3-fold better than the comparator ATPase inhibitor novobiocin (1.27 µM). Compound 1 showed noncytotoxicity to Caco-2 cells at concentrations up to 76-fold higher than its IC50 value. Molecular dynamics simulations followed by decomposition energy calculations identified that compound 1 occupies the binding pocket utilized by the adenosine group of the ATP analogue AMPPNP in the M. tuberculosis DNA gyrase GyrB subunit. The most prominent contribution to the binding of compound 1 to M. tuberculosis GyrB subunit is made by residue Asp79, which forms two hydrogen bonds with the OH group of this compound and also participates in the binding of AMPPNP. Compound 1 represents a potential new scaffold for further exploration and optimization as a M. tuberculosis DNA gyrase ATPase inhibitor and candidate anti-tuberculosis agent.

Inhibition of Mycobacterium tuberculosis InhA by 3-nitropropanoic acid.

3-Nitropropanoic acid (3NP), a bioactive fungal natural product, was previously demonstrated to inhibit growth of Mycobacterium tuberculosis. Here we demonstrate that 3NP inhibits the 2-trans-enoyl-acyl carrier protein reductase (InhA) from Mycobacterium tuberculosis with an IC50 value of 71 µM, and present the crystal structure of the ternary InhA-NAD+ -3NP complex. The complex contains the InhA substrate-binding loop in an ordered, open conformation with Tyr158, a catalytically important residue whose orientation defines different InhA substrate/inhibitor complex conformations, in the "out" position. 3NP occupies a hydrophobic binding site adjacent to the NAD+ cofactor and close to that utilized by the diphenyl ether triclosan, but binds predominantly via electrostatic and water-mediated hydrogen-bonding interactions with the protein backbone and NAD+ cofactor. The identified mode of 3NP binding provides opportunities to improve inhibitory activity toward InhA.

Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis.

Mycobacterium tuberculosis DNA gyrase manipulates the DNA topology using controlled breakage and religation of DNA driven by ATP hydrolysis. DNA gyrase has been validated as the enzyme target of fluoroquinolones (FQs), second-line antibiotics used for the treatment of multidrug-resistant tuberculosis. Mutations around the DNA gyrase DNA-binding site result in the emergence of FQ resistance in M. tuberculosis; inhibition of DNA gyrase ATPase activity is one strategy to overcome this. Here, virtual screening, subsequently validated by biological assays, was applied to select candidate inhibitors of the M. tuberculosis DNA gyrase ATPase activity from the Specs compound library (www.specs.net). Thirty compounds were identified and selected as hits for in vitro biological assays, of which two compounds, G24 and G26, inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concentration of 12.5 µg/mL. The two compounds inhibited DNA gyrase ATPase activity with IC50 values of 2.69 and 2.46 µM, respectively, suggesting this to be the likely basis of their antitubercular activity. Models of complexes of compounds G24 and G26 bound to the M. tuberculosis DNA gyrase ATP-binding site, generated by molecular dynamics simulations followed by pharmacophore mapping analysis, showed hydrophobic interactions of inhibitor hydrophobic headgroups and electrostatic and hydrogen bond interactions of the polar tails, which are likely to be important for their inhibition. Decreasing compound lipophilicity by increasing the polarity of these tails then presents a likely route to improving the solubility and activity. Thus, compounds G24 and G26 provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase.

Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity.

Mycobacterium tuberculosis protein kinase B (PknB) is essential to mycobacterial growth and has received considerable attention as an attractive target for novel anti-tuberculosis drug development. Here, virtual screening, validated by biological assays, was applied to select candidate inhibitors of M. tuberculosis PknB from the Specs compound library (www.specs.net). Fifteen compounds were identified as hits and selected for in vitro biological assays, of which three indoles (2, AE-848/42799159; 4, AH-262/34335013; 10, AP-124/40904362) inhibited growth of M. tuberculosis H37Rv with minimal inhibitory concentrations of 6.2, 12.5, and 6.2 µg/mL, respectively. Two compounds, 2 and 10, inhibited M. tuberculosis PknB activity in vitro, with IC50 values of 14.4 and 12.1 µM, respectively, suggesting this to be the likely basis of their anti-tubercular activity. In contrast, compound 4 displayed anti-tuberculosis activity against M. tuberculosis H37Rv but showed no inhibition of PknB activity (IC50 > 128 µM). We hypothesize that hydrolysis of its ethyl ester to a carboxylate moiety generates an active species that inhibits other M. tuberculosis enzymes. Molecular dynamics simulations of modeled complexes of compounds 2, 4, and 10 bound to M. tuberculosis PknB indicated that compound 4 has a lower affinity for M. tuberculosis PknB than compounds 2 and 10, as evidenced by higher calculated binding free energies, consistent with experiment. Compounds 2 and 10 therefore represent candidate inhibitors of M. tuberculosis PknB that provide attractive starting templates for optimization as anti-tubercular agents.

Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography.

The enoyl-acyl carrier protein reductase InhA of Mycobacterium tuberculosis is an attractive, validated target for antituberculosis drug development. Moreover, direct inhibitors of InhA remain effective against InhA variants with mutations associated with isoniazid resistance, offering the potential for activity against MDR isolates. Here, structure-based virtual screening supported by biological assays was applied to identify novel InhA inhibitors as potential antituberculosis agents. High-speed Glide SP docking was initially performed against two conformations of InhA differing in the orientation of the active site Tyr158. The resulting hits were filtered for drug-likeness based on Lipinski's rule and avoidance of PAINS-like properties and finally subjected to Glide XP docking to improve accuracy. Sixteen compounds were identified and selected for in vitro biological assays, of which two (compounds 1 and 7) showed MIC of 12.5 and 25 µg/mL against M. tuberculosis H37Rv, respectively. Inhibition assays against purified recombinant InhA determined IC50 values for these compounds of 0.38 and 0.22 µM, respectively. A crystal structure of the most potent compound, compound 7, bound to InhA revealed the inhibitor to occupy a hydrophobic pocket implicated in binding the aliphatic portions of InhA substrates but distant from the NADH cofactor, i.e., in a site distinct from those occupied by the great majority of known InhA inhibitors. This compound provides an attractive starting template for ligand optimization aimed at discovery of new and effective compounds against M. tuberculosis that act by targeting InhA.

Coumarin Probe for Selective Detection of Fluoride Ions in Aqueous Solution and Its Bioimaging in Live Cells.

We have synthesized novel coumarin-based fluorescent chemosensors for detection of fluoride ions in aqueous solution. The detection mechanism relied on a fluoride-mediated desilylation triggering fluorogenic reaction and a strong interaction between fluoride and the silicon center. In this work, the hydroxyl-decorated coumarins containing oxysilyl moiety have been synthesized through the aldehyde-functionalized coumarins. The optical responses toward fluoride, as well as aqueous stability studies of both aldehyde and hydroxyl functionalized coumarins, have been investigated. Due to the highest fluorescence enhancement upon the addition of fluoride and good stability in aqueous solution, the hydroxyl-decorated coumarin connected with the bulky tert-butyldiphenyloxysilyl group (-OSitBuPh2) has been selected for further investigation of its potential as a fluoride sensor. This hydroxyl-decorated coumarin can selectively sense fluoride ions in aqueous media (contain 0.8% MeCN) with desirable response times (40 min). The limit of detection of this compound was determined as 0.043 ppm, satisfying the standard fluoride level (0.7 ppm) in drinking water recommended by U.S. Department of Health and Human Services. The application of this silyl-capped coumarin derivative for fluoride analysis in collected water samples displayed satisfactory analytical accuracy (<5% error). Finally, this compound was successfully employed in fluorescence bioimaging of fluoride ions in human liver cancer cells, indicating its excellent cell permeability, ability to retain inside the living cells, and good stability under physiological conditions.

Synthesis of two subunits of the macrolide domain of the immunosuppressive agent sanglifehrin a and assembly of a macrolactone precursor. application of masamune anti-aldol condensation.

Asymmetric anti-aldol coupling of a norephedrine-derived ester with an α-chiral aldehyde was used to synthesize a carboxylic acid representing the C13-C19 segment of the macrocyclic domain present in the immunosuppressive agent sanglifehrin A. Felkin addition set configuration at the C14-C17 stereotetrad in this unit in which hydroxyl functions at C15 and C17 were masked as an internal ketal. The carboxyl group of this segment was coupled to the N-terminus of the tripeptide portion (C1-N12) of sanglifehrin A macrolactone to assemble the C1-C19 domain. Synthesis of the C20-C25 subunit of sanglifehrin A containing a (23S) alcohol was completed via asymmetric allylation of (E)-3-iodo-2-methylprop-2-enal followed by oxidative cleavage of the terminal vinyl appendage and a Takai olefination with pinacol dichloromethylboronate. Esterification of this alcohol with a C1-C19 carboxylic acid furnished an open C1-C25 macrolactone precursor, but this substance failed to undergo macrocyclization via intramolecular Suzuki-Miyaura coupling.

Synthesis of the tripeptide domain of sanglifehrins using asymmetric phase-transfer catalysis.

The tripeptide (S)-valinyl-(S)-m-hydroxyphenylalanyl-(3S)-piperazate common to immunosuppressant sanglifehrins was synthesized from the constituent amino acid residues in nine steps and 42% overall yield. A key construction was the installation of (S) absolute configuration in m-hydroxyphenylalanine using asymmetric phase-transfer catalysis in the presence of N-(1-naphthyl)cinchonidinium bromide. Cbz-protected (S)-valine was first coupled to the amino group of (S)-m-triisopropylsilyloxyphenylalanine tert-butyl ester, and the resulting dipeptide after ester cleavage was linked to (3S)-methyl piperazate.

Structure-based drug design of novel M. tuberculosis InhA inhibitors based on fragment molecular orbital calculations.

2-trans enoyl-acyl carrier protein reductase (InhA) is a promising target for developing novel chemotherapy agents for tuberculosis, and their inhibitory effects on InhA activity were widely investigated by the physicochemical experiments. However, the reason for the wide range of their inhibitory effects induced by similar agents was not explained by only the difference in their chemical structures. In our previous molecular simulations, a series of heteroaryl benzamide derivatives were selected as candidate inhibitors against InhA, and their binding properties with InhA were investigated to propose novel derivatives with higher binding affinity to InhA. In the present study, we extended the simulations for a series of 4-hydroxy-2-pyridone derivatives to search widely for more potent inhibitors against InhA. Using ab initio fragment molecular orbital (FMO) calculations, we elucidated the specific interactions between InhA residues and the derivatives at an electronic level and highlighted key interactions between InhA and the derivatives. The FMO results clearly indicated that the most potent inhibitor has strong hydrogen bonds with the backbones of Tyr158, Thr196, and NADH of InhA. This finding may provide informative structural concepts for designing novel 4-hydroxy-2-pyridone derivatives with higher binding affinity to InhA. Our previous and present molecular simulations could provide important guidelines for the rational design of more potent InhA inhibitors.

Elucidating specific interactions for designing novel pyrrolamide derivatives as potential GyrB inhibitors based on ab initio fragment molecular orbital calculations.

Tuberculosis (TB), the second leading infectious killer, causes serious public health problems worldwide. To develop novel anti-TB agents, many biochemical studies have targeted the subunit B of DNA gyrase (GyrB), which captures a second DNA segment and responses for ATP hydrolysis. Here, we investigated specific interactions between GyrB residues and existing pyrrolamide derivatives at an electronic level using ab initio fragment molecular orbital (FMO) calculations and designed potent inhibitors against GyrB. The evaluated binding affinities between GyrB and pyrrolamides were confirmed to be consistent with the IC50 values obtained from previous experiments. Thus, we employed the most potent pyrrolamide (compound 1) as a lead compound and proposed novel pyrrolamide derivatives. The specific interactions between GyrB and these derivatives were investigated using molecular mechanic optimizations and FMO calculations. The results revealed that our proposed derivatives had strong hydrogen bonds with Asp79 and Arg141 and exhibited electrostatic interactions with Glu56 and Ile84 of GyrB. In addition, the binding affinity between GyrB and compound 1 was enhanced significantly by the replacement at the R3 site of compound 1. The present results may provide structural concepts for the rational design of potent GyrB inhibitors as anti-TB agents.Communicated by Ramaswamy H. Sarma.

Spirooxazine-Based Dual-Sensing Probe for Colorimetric Detection of Cu2+ and Fe3+ and Its Application in Drinking Water and Rice Quality Monitoring.

A spirooxazine derivative, PheSPO (3,3-dimethyl-1-phenethylspiro[indoline-2,3'-naphtho[2,1-b][1,4]oxazine]), as a dual-sensing probe for Cu2+ and Fe3+ was synthesized, and its structure was confirmed by 1H NMR, 13C NMR, HRMS, and single-crystal X-ray diffraction. The results reveal that the PheSPO probe is selective to both Cu2+ and Fe3+ through distinct colorimetric responses in acetonitrile. The sensing performance of PheSPO toward Cu2+ was investigated, and upon addition of Cu2+, an instant change in color from colorless to bright yellow with a strong absorption band at 467 nm was observed. Due to a dual-sensing behavior, PheSPO also exhibits a unique response toward Fe3+ that can be discovered from a color change from colorless to red at an absorption wavelength of 514 nm. Based on spectroscopic analyses and density functional theory calculations, the 1:1 stoichiometric complexation of PheSPO with the targeted metal ions was proposed and the binding constants of 1.95 × 103 M-1 for Cu2+ and 1.29 × 103 M-1 for Fe3+ were obtained. In addition, the detection limits of PheSPO for Cu2+ and Fe3+ were 0.94 and 2.01 µM, respectively. To verify its applicability in real samples, PheSPO was further explored for quantitative determination of both Cu2+ and Fe3+ in spiked drinking water. The results showed that the recoveries of Cu2+ and Fe3+ examined using the PheSPO probe were found comparable to those obtained from atomic absorption spectroscopy. Moreover, the PheSPO strip test was developed, and its utilization for qualitative detection of Fe3+ in real rice samples was demonstrated.

In silico multiscale drug design to discover key structural features of potential JAK2 inhibitors.

Background: JAK2 inhibitors have been proposed as a new therapeutic option for thalassemia therapy. The objective of this study was to discover the key structural features for improving 2-aminopyrimidine derivatives as potential JAK2 inhibitors. Materials & methods: Quantitative structure-activity relationship (QSAR) approaches (hologram QSAR and comparative molecular similarity indices analysis), molecular dynamics simulations, binding energy calculations and pharmacokinetic predictions were employed. Results: Reliable QSAR models, binding mode and binding interactions of JAK2 inhibitors were obtained and these obtained results were used as the key information for rational design of highly potent JAK2 inhibitors. Conclusion: The concept of new potential JAK2 inhibitors integrated from the obtained results was proved, producing two newly designed compounds, D01 and D02, with potential for use as JAK2 inhibitors.

In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions.

Serine/threonine protein kinase B (PknB) is essential to Mycobacterium tuberculosis (M. tuberculosis) cell division and metabolism and a potential anti-tuberculosis drug target. Here we apply Hologram Quantitative Structure Activity Relationship (HQSAR) and three-dimensional QSAR (Comparative Molecular Similarity Indices Analysis (CoMSIA)) methods to investigate structural requirements for PknB inhibition by a series of previously described quinazoline derivatives. PknB binding of quinazolines was evaluated by molecular dynamics (MD) simulations of the catalytic domain and binding energies calculated by Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) methods. Evaluation of a training set against experimental data showed both HQSAR and CoMSIA models to reliably predict quinazoline binding to PknB, and identified the quinazoline core and overall hydrophobicity as the major contributors to affinity. Calculated binding energies also agreed with experiment, and MD simulations identified hydrogen bonds to Glu93 and Val95, and hydrophobic interactions with Gly18, Phe19, Gly20, Val25, Thr99 and Met155, as crucial to PknB binding. Based on these results, additional quinazolines were designed and evaluated in silico, with HQSAR and CoMSIA models identifying sixteen compounds, with predicted PknB binding superior to the template, whose activity spectra and physicochemical, pharmacokinetic, and anti-M. tuberculosis properties were assessed. Compound, D060, bearing additional ortho- and meta-methyl groups on its R2 substituent, was superior to template regarding PknB inhibition and % caseum fraction unbound, and equivalent in other aspects, although predictions identified hepatotoxicity as a likely issue with the quinazoline series. These data provide a structural basis for rational design of quinazoline derivatives with more potent PknB inhibitory activity as candidate anti-tuberculosis agents.

Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction.

Aim: In silico screening approaches were performed to discover novel InhA inhibitors. Methods: Candidate InhA inhibitors were obtained from the combination of virtual screening and pharmacokinetic prediction. In addition, molecular mechanics Poisson-Boltzmann surface area, molecular mechanics Generalized Born surface area and WaterSwap methods were performed to investigate the binding interactions and binding energy of candidate compounds. Results: Four candidate compounds with suitable physicochemical, pharmacokinetic and antibacterial properties are proposed. The crucial interactions of the candidate compounds were H-bond, pi-pi and sigma-pi interactions observed in the InhA binding site. The binding affinity of these compounds was improved by hydrophobic interactions with hydrophobic side chains in the InhA pocket. Conclusion: The four newly identified InhA inhibitors reported in this study could serve as promising hit compounds against Mycobacterium tuberculosis and may be considered for further experimental studies.

A model of modified meta-iodobenzylguanidine conjugated gold nanoparticles for neuroblastoma treatment.

Iodine-131 meta-iodobenzylguanidine (131I-mIBG) has been utilized as a standard treatment to minimize adverse side effects by targeting therapies to bind to the norepinephrine transporter (NET) expressed on 90% of neuroblastoma cells. However, only a minority of patients who receive 131I-mIBG radiotherapy have clinical responses, and these are usually not curative. In this study, novel ligand-conjugated gold nanoparticles (GNPs) based on mIBG were synthesized and evaluated biologically with neuroblastoma cells in vitro. To induce specific internalization to the tumor cells and utilize it as a model for radioenhancement, 127I-modified mIBG was successfully synthesized and grafted covalently to the surface of carboxylated PEG-GNPs. 49.28% of the novel mIBG derivative was grafted on carboxylated PEG-GNPs. The particles were stable and not toxic to the normal fibroblast cell line, L929, even at the highest concentration tested (1013 NPs per mL) at 24, 48, and 72 h. Moreover, the cellular uptake of the model was decreased significantly in the presence of a NET inhibitor, suggesting that there was specific internalization into neuroblastoma cells line (SH-SY5Y) via the NET. Therefore, this model provides useful guidance toward the design of gold nanomaterials to enhance the efficiency of 131I-mIBG treatment in neuroblastoma patients. However, the investigation of radio-therapeutic efficiency after radioisotope 131I substitution will be further conducted in a radiation safety laboratory using an animal model.

Coumarin-Caged Compounds of 1-Naphthaleneacetic Acid as Light-Responsive Controlled-Release Plant Root Stimulators.

Six coumarin-caged compounds of 1-naphthaleneacetic acid (NAA) comprising different substituents on the coumarin moiety were synthesized and evaluated for their photophysical and chemical properties as light-responsive controlled-release plant root stimulators. The 1H NMR and HPLC techniques were used to verify the release of NAA from the caged compounds. After irradiation at 365 nm, the caged compounds exhibited the fastest release rate at t1/2 of 6.7 days and the slowest release rate at t1/2 of 73.7 days. Caged compounds at high concentrations (10-5 and 10-6 M) significantly stimulate secondary root germination while free NAA at the same level is toxic and leads to inhibition of secondary root germination. The cytotoxicity of the caged compounds against fibroblasts and vero cells were evaluated, and the results suggested that, at 10-5-10-6 M, caged compounds exhibited no significant cytotoxicity to the cells. Thus, the caged compounds of NAA in this study could be of great benefit as efficient agrochemicals.

Recent Progress in the Development of HIV-1 Entry Inhibitors: From Small Molecules to Potent Anti-HIV Agents.

Viral entry, the first process in the reproduction of viruses, primarily involves attachment of the viral envelope proteins to membranes of the host cell. The crucial components that play an important role in viral entry include viral surface glycoprotein gp120, viral transmembrane glycoprotein gp41, host cell glycoprotein (CD4), and host cell chemokine receptors (CCR5 and CXCR4). Inhibition of the multiple molecular interactions of these components can restrain viruses, such as HIV-1, from fusion with the host cell, blocking them from reproducing. This review article specifically focuses on the recent progress in the development of small-molecule HIV-1 entry inhibitors and incorporates important aspects of their structural modification that lead to the discovery of new molecular scaffolds with more potency.

Synthesis of Copper-Chelates Derived from Amino Acids and Evaluation of Their Efficacy as Copper Source and Growth Stimulator for Lactuca sativa in Nutrient Solution Culture.

Five tetradentate ligands were synthesized from l-amino acids and utilized for the synthesis of Cu(II)-chelates 1-5. The efficacy of Cu(II)-chelates as copper (Cu) source and growth stimulator in hydroponic cultivation was evaluated with Lactuca sativa. Their stability test was performed at pH 4-10. The results suggested that Cu(II)-chelate 3 is the most pH tolerant complex. Levels of Cu, Zn, and Fe accumulated in plants supplied with Cu(II)-chelates were compared with those supplied with CuSO4 at the same Cu concentration of 8.0 µM. The results showed that Cu(II)-chelate 3 significantly enhanced Cu, Zn, and Fe content in shoot by 35, 15, and 48%, respectively. Application of Cu(II)-chelate 3 also improved plant dry matter yield by 54%. According to the results, Cu(II)-chelate 3 demonstrated the highest stimulating effect on plant growth and plant mineral accumulation so that it can be used as an alternative to CuSO4 for supplying Cu in nutrient solutions and enhancing the plant growth.