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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 157-166

Schiff base ligands derived from 4-chloro-6-methylpyrimidin-2-amine: Chemical synthesis, bactericidal activity and molecular docking studies against targeted microbial pathogen


1 Department of Sciences, Amrita School of Arts and Sciences, Amrita Vishwa Vidyapeetham, Mysore Campus, Mysore, Karnataka, India
2 Division of Biotechnology and Bioinformatics, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
3 Department of Biotechnology, Davangere University, Davanagere, Karnataka, India
4 Division of Microbiology and Tissue Culture, School of Life Sciences, JSS Academy of Higher Education and Research, Mysore, Karnataka, India

Date of Submission29-Mar-2020
Date of Decision20-May-2020
Date of Acceptance07-Aug-2020
Date of Web Publication18-May-2021

Correspondence Address:
Dr. Chandrashekar Srinivasa
Division of Biotechnology and Bioinformatics, School of Life Sciences, JSS Academy of Higher Education and Research, Mysuru - 570 015, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_43_20

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  Abstract 


BACKGROUND: Schiff base is also known as imine or azomethine that typically contain nitrogen analog of an aldehyde or ketone in which the carbonyl group (C = O) has been replaced by an imine or azomethine group. In this study, we describe the synthesis of three Schiff base ligands, which are prepared by the condensation of 4-chloro-6-methyl pyrimidine-2-amine with various aromatic aldehydes and those synthesized compounds treated against various microbial pathogens, they were also supported by In silico approach.
MATERIALS AND METHODS: The synthesized compounds (L1-L3) were characterized by analytical and spectral techniques. In silico molecular docking, the analysis was carried out with the three Schiff base ligands against Gram-positive bacteria, Gram-negative bacterial and fungal outer membrane proteins to check for the binding affinity and molecular interactions.
RESULTS: All the synthesized compounds were treated against various microbial pathogens, and the obtained microbial inhibitor results were docked against the synthesized compounds to understand their best interaction studies. The results revealed that the ligands have considerably shown lower binding energy and good hydrogen bonding and hydrophobic interactions against various microorganisms.
CONCLUSION: All three Schiff base ligands compounds were examined In vitro for their antibacterial and antifungal potentials. Furthermore, the prepared compounds were exposed to in silico studies against selected bacterial proteins. Thus, the present study could be valuable in the discovery of new potent antimicrobial agents.

Keywords: Antimicrobial activity, molecular docking, Schiff bases ligands, spectral techniques


How to cite this article:
Prasad KS, Shivamallu C, Gopinath S M, Srinivasa C, Dharmashekara C, Sushma P, Jain AS, Ashwini P. Schiff base ligands derived from 4-chloro-6-methylpyrimidin-2-amine: Chemical synthesis, bactericidal activity and molecular docking studies against targeted microbial pathogen. Int J Health Allied Sci 2021;10:157-66

How to cite this URL:
Prasad KS, Shivamallu C, Gopinath S M, Srinivasa C, Dharmashekara C, Sushma P, Jain AS, Ashwini P. Schiff base ligands derived from 4-chloro-6-methylpyrimidin-2-amine: Chemical synthesis, bactericidal activity and molecular docking studies against targeted microbial pathogen. Int J Health Allied Sci [serial online] 2021 [cited 2021 Jun 18];10:157-66. Available from: https://www.ijhas.in/text.asp?2021/10/2/157/316296


  Introduction Top


Schiff bases, named for Hugo Schiff,[1] are obtained by the condensation of a primary amine with an aldehyde or a ketone under specific conditions. Structurally, a Schiff base (also known as imine or azomethine) is a nitrogen analog of an aldehyde or ketone in which the carbonyl group (C = O) has been replaced by an imine or azomethine group. It is due to this functional moieties, Schiff bases play a vital role in biological applications, including antibacterial,[2],[3],[4] antifungal,[5],[6], and antitumor activity.[7],[8] The imine group present in such compounds is critical to their biological activities.[9],[10] Further, Schiff base ligands are considered as “privileged ligands” because of their preparation and their coordination behavior with many different metals[11],[12],[13],[14] and stabilize them in various oxidation states. Moreover, Schiff bases have been used extensively as ligands in the field of coordination chemistry, some of the reasons are that the intramolecular hydrogen bonds between the (O) and the (N) atoms which play an important role in the formation of metal complexes and that Schiff base compounds show photochromism and thermochromism in the solid-state by proton transfer from the hydroxyl (O) to the imine (N) atoms.[15] Due to their multiple implications, the transition metal complexes with Schiff bases, as ligands, are of paramount scientific interest.[16] Schiff bases with donors (N, O, S, etc.) have structural similarities with natural biological systems and due to the presence of imine group, are utilized in elucidating the mechanism of transformation and insemination reaction in biological systems.[17],[18],[19] Moreover, it is well known that some drug activities, when administered as metal complexes, are being increased,[20] and several Schiff base complexes have also been shown to inhibit tumor growth.[21] The effect of the presence of various substituents in the phenyl rings of aromatic Schiff bases on their antimicrobial activity has been reported.[22]

Over the past decade, the synthesis of privileged classes of heterocyclic molecules has become one of the prime areas of research in synthetic organic chemistry.[23] These privileged structures have gained much attention, owing to their potential role as ligands, which are capable of binding multiple biological targets. Among the nitrogen-containing privileged class of molecules, substituted bromopyridines are considered as important therapeutic scaffolds.[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35] A vast number of bromopyridine derivatives have been synthesized for biological screening, and a variety of activities were observed. Several derivatives are being used clinically. A few of the many references for each activity are provided, such as antidepressants,[36] hypotensive activity,[37] analgesic[38] antithrombic,[39] anticoagulant,[40] antifibrillatory,[41] arteriosclerosis,[42] and anti-inflammatory activity.[43]

Therefore, in the present investigation, the author has made an effort to synthesize Schiff's base ligands of the cited derivatives and also characterized by employing infrared (IR), 1H-nuclear magnetic resonance (NMR) and mass spectral studies. Molecular docking is an alluring platform to comprehend drug biomolecular by placing a ligand into the favored restricting site of the objective explicit area of the protein receptor primarily in a noncovalent style to frame a steady perplexing of potential viability and greater specificity.[44],[45],[46]


  Materials and Methods Top


All the chemicals and solvents were of analytical R grade. 4-chloro-6-methylpyrimidin-2-amine was procured from Sigma-Aldrich, Bangalore, and used as received. The spectroscopic grade solvents were used as supplied by commercial sources without any further purification. Thin-layer chromatography (TLC) was performed using Silica Gel G (Merck Index) precoated plates, and the spots were visualized by exposure to iodine. All melting points were determined with a Büchi 530 melting point apparatus in open capillaries and are uncorrected. IR spectra were recorded in the range 4000–200 cm−11 on a JASCO FTIR-8400 spectrophotometer using Nujol mulls between polyethylene sheets. 1H-NMR spectra were obtained on a Varian AC 400 spectrometer. Electrospray Ionization-Mass Spectrometry (ESI-MS) was determined on the Varian 1200 L model mass spectrometer.

Chemical synthesis

6-chloro-2-((4-chlorobenzylidene) amino)-4-methylpyridin-3-ol



A volume of 25 mL methanolic solution of 4-chloro-6-methyl pyrimidine-2-amine (1.38 g, 10 mmol) was slowly added to a 15 mL of 4-chlorobenzaldehyde (1.12 g, 10 mmol in methanol). The reaction mixture was stirred for 30 min and then refluxed for 4 h. The completion of the reaction was monitored by TLC. The solvent was removed by distillation. The solid product obtained was recrystallized from ethanol to yield the final product, L1.

Yield: 69%; mp: 136°C; FT-IR (nujol, ν/cm−1): 3079, 2988, 2353 (C-H), 1655 (C = N), 1H-NMR (400 MHz, DMSO-d6) δ: 1.76 (s, CH3, 3H), 8.62 (s, CH, 1H,-N = CH-), 7.74-7.29 (m, Ar-H, 7H, Aromatic protons); Mass (m/z): 266 (M+, 92%).

2-((4-bromobenzylidene) amino)-6-chloro-4-methylpyridin-3-ol



In a round bottom flask, a mixture of 4-chloro-6-methyl pyrimidine-2-amine (1.38 g, 10 mmol in 25 mL methanol) and 4-bromobenzaldehyde (1.01 g, 10 mmol in 15 mL methanol) was heated under reflux for 4 h with initial stirring of 30 min. The product obtained was concentrated under vacuum, filtered off, and recrystallized from ethanol to give the final product, L2.

Yield: 67%; mp: 178°C; FT-IR (nujol, ν/cm−1): 3074, 2928, 2157(Ar-C-H), 1614 (C = N); 1H-NMR (400 MHz, d6-dimethylsulfoxide [DMSO-d6]) δ: 1.76 (s, CH3, 3H), 8.19 (s, CH, 1H,-N = CH-), 7.48–7.73 (m, Ar-H, 8H, Aromatic protons); Mass (m/z): 310 (M+, 87%).

6-chloro-2-((4-hydroxybenzylidene) amino)-4-methylpyridin-3-ol



An equimolar quantity of a methanolic solution of both 4-chloro-6-methyl pyrimidine-2-amine (1.38 g, 10 mmol in 25 mL methanol) and 4-hydroxybenzaldehyde (1.24 g, 15 mL of 10 mmol) was stirred for 30 min and refluxed for 4 h. The solvent was removed under vacuum and the solid product obtained was filtered, dried and crystallized from ethanol, L3.

Yield 69%; mp 224°C; FT-IR (nujol, ν/cm-1) 3069, 2984, 2906 (Ar-C-H), 1593 (C = N), 3458 (O-H); 1H-NMR (400 MHz, DMSO-d6) δ 1.76 (s, CH3, 3H), 8.81 (s, CH, 1H,-N = CH-), 10.12 (s, OH, 1H), 7.48-7.12 (m, Ar-H, 7H, Aromatic protons); Mass (m/z) 247 (M+, 67%).

Antimicrobial activity

Even though pharmacological industries have produced several new antibiotics in the last three decades, resistance to these drugs by microorganisms has increased. In general, bacteria have the genetic ability to transmit and acquire resistance to drugs, which are utilized as therapeutic agents.[47] From 1980–1990, Montelli and Levy[48] have documented a high incidence of resistant microorganisms in clinical microbiology in Brazil. This fact has also been verified in other clinics around all over the world. To contribute to the field of bioinorganic chemistry, consequently, the compounds synthesized have been evaluated for their antibacterial and antifungal actions.

Schiff bases are reported to show a variety of biological activities like antibacterial[49] and antifungal.[50]

The antimicrobial activity of a drug or a test compound is evaluated by a wide range of techniques. In any technique, the principle is the preparation of a concentration gradient of the drug/test compound in a nutrient medium and the observation of growth of the organism taking place when the medium is seeded with test organism and incubated. There is one important method employed for antimicrobial sensitivity testing of a compound, namely the disc diffusion technique. This technique has been followed in the present investigation.

The in vitro antimicrobial screening effects of the synthesized compounds were evaluated against four bacteria, namely Bacillus Subtilis,  Escherichia More Details coli, Staphylococcus aureus and Ralstonia olanacearum and three fungi namely Aspergillus niger, Aspergillus flavus, and Alternaria solani by disc diffusion method using nutrient agar medium for antibacterial studies and potato dextrose agar medium for antifungal studies.[49],[50],[51]

Molecular docking

Ligand preparation

The structures of Schiff base ligands were sketched using ChemSketch software.[52] The two-dimensional structures were converted into three-dimensional (3D) structures using OpenBabel software by the addition of hydrogens and generation of 3D coordinates. The input files were given in. cml format and the output files was saved in. Protein Data Bank (PDB) format. These ligand files formed using OpenBabel software was further geometrically optimized using ArgusLab [Figure 1].
Figure 1: Three-dimensional structures of Schiff base ligands

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Protein preparation

In the present study, the Schiff base ligands were checked for the antimicrobial activity against two Gram-positive (E. coli[53] and Ralstonia solanacearum[54]), two Gram-negative bacteria (B. subtilis[55] and S. aureus[56]), and three fungi (A. niger,[57] A. flavus,[58] and A. solani[59]). The protein crystal structures of E. coli, R. solanacearum, B. subtilis, S. aureus, A. niger, and A. flavu organisms were downloaded from the PDB,[60] whereas the protein structure of the A. solani was modeled using the Swiss model web-server and these proteins were considered as the macromolecules for the further molecular docking studies with the Schiff base ligands [Figure 2], [Figure 3] ,[Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]. The target binding site residues for each of the downloaded and modeled proteins were taken from the Galaxy Web online web portal.
Figure 2: Structures of Schiff base ligands

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Figure 3: Infrared spectrum of compound 7

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Figure 4: Crystal structure of Gram-positive bacterial receptor Escherichia coli (Protein Data Bank ID: 6HZQ)

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Figure 5: The three Schiff base ligands (a-c) showing interactions with the Escherichia coli receptor

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Figure 6: Crystal structure of gram-positive bacterial receptor Ralstonia solanacearum (Protein Data Bank ID: 3TOT)

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Figure 7: The three Schiff base ligands (a-c) showing interactions with the Ralstonia solanacearum receptor forming Hydrogen bonds and non-bonded interactions

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Figure 8: Crystal structure of Gram-negative bacterial receptor Bacillus Subtilis (Protein Data Bank ID: 5MVR)

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Docking interaction

All the proteins were docked with the 3D structures of the Schiff base ligands using PyRx software. The protein and ligand input files were given in. PDB format and grid box was set to maximum to get the best orientation with the lowest binding affinity. [61]

Molecular docking visualization

The docked conformations were then visualized using PyMOL 2.4 [62] the molecular visualization software which is an open-source foundation distributed and maintained by Schrodinger to determine hydrogen bonds, bond length, and hydrophobic interactions between the Schiff base ligands and the proteins of two Gram-positive, two Gram-negative bacteria and three Fungi.[63],[64]

Molecular docking interactions of all the seven proteins with Schiff base ligands were visualized using PyMol software. The binding sites are labeled and represented as ribbon structures that show hydrogen bonds and nonbonded interactions with the Schiff base ligands.


  Results and Discussion Top


General methods for synthesis and characterization

The Schiff base ligands were synthesized by the condensation of 5-bromopyridin-2-amine with different aromatic aldehydes in 1:1 molar proportion in methanol. The Schiff bases were soluble in methanol, ethanol, DMSO, acetone, and insoluble in water. The compounds were purified by repeated recrystallization from ethanol and then dried. The structures of the Schiff bases are confirmed by physical and spectral data and are given in [Figure 9].
Figure 9: The three Schiff base ligands (a-c) showing interactions with the acillus Subtilis receptor forming hydrogen bonds and nonbonded interactions

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Infrared spectra

The IR spectra of the ligands under investigation were recorded by nujol method on JASCO FT-IR spectrophotometer in the frequency range of 4000-400 cm−1. The important diagnostic bands in the IR spectra were assigned, and the bands positions are compiled in the synthesis part. IR spectrum of L3 is shown as representative spectrum in [Figure 10]. The significant stretching vibrations observed in the region between 1510 and 1640 cm−1 is due to the imine (C = N) group. Further, the aromatic stretching was observed at around 1428 cm−1. The broadband noticed at 3415 cm−1 is attributed to the hydroxyl group stretching.
Figure 10: Crystal structure of Gram-negative bacterial receptor S.aureus (Protein Data Bank ID: 6D9T)

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1H-nuclear magnetic resonance spectra and mass spectra

A review of the literature revealed that NMR spectroscopy has been proven to be useful in establishing the nature and structure of many Schiff bases, as well as their metal complexes in solution. The NMR spectra of Schiff bases were recorded in DMSO solution, using tetramethylsilane as an internal standard on VARIAN-400 NMR spectrometer. Chemical shifts were reported as δ-values in parts per million (ppm) relative to Si(CH3)4 as relative reference (δ = 0 ppm) and to the solvent as an internal reference. The singlet observed at δ =1.76 ppm is due to the methyl group attached to the aromatic ring. The imine proton signal (-CH = N-) was observed at δ = 8.81 ppm. The OH proton singlet signal was noticed δ = 10.12 ppm. The mass spectrum was recorded on electron ionization mode on VARIAN-1200 L model spectrometer. The mass spectra of ligands are compiled in the synthetic part.

Antimicrobial activity

In the present study, the antimicrobial activity of the Schiff base ligands was evaluated against two Gram-positive (E. coli and R. solanacearum), two Gram-negative bacteria (B. subtilis and S. aureus) and three fungi (A. niger, A. flavus, and A. solani). Standard antibiotics, namely Chloramphenicol and standard antifungal drug Fluconazole were used for comparison with antibacterial and antifungal activities shown by compounds [Table 1]. All the ligands possessed good antibacterial activity against Gram-positive bacteria (E. coli and R. solanacearum) and antifungal activity against A. niger and A. solani. However, the ligands exerted moderate to poor activity against B. subtilis, S. aureus, and A. flavus. Keeping in view, the rising problems of antimicrobial resistance, these chemical compounds may be used for formulating as novel chemotherapeutic agents.
Table 1: Antimicrobial activity of Schiff base ligands L1-L3

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Molecular docking interactions

Molecular docking interactions of Gram-positive bacteria E. coli and R. solanacearum receptor with Schiff base ligands were visualized using PyMol software [Figure 11] and [Figure 12]. The binding sites are labeled and represented as ribbon structures that show hydrogen bonds and nonbonded interactions with the Schiff base ligands.
Figure 11: The three Schiff base ligands (a-c) showing interactions with the Staphylococcus aureus receptor forming hydrogen bonds and nonbonded interactions

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Figure 12: Crystal structure of Fungi receptor Aspergillus niger (Protein Data Bank ID: 6IGY)

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The L1 interacts with TYR-419 and THR-497 residues and forms three Hydrogen bonds with the E. coli receptor and the other residues depict the formation of nonbonded interactions [Figure 11]a. Similarly, L2 and L3 forms four hydrogen bonds with THR-497, LYS-499, TYR-418 [Figure 11]b and three hydrogen bonds with ASN-361, LYS-319, TYR-419 [Figure 11]c residues, respectively.

The L1 interacts with VAL-51 residue and forms two Hydrogen bonds with the R. solanacearum receptor and the other residues depict the formation of nonbonded interactions [Figure 12]a. Similarly, L2 and L3 forms three hydrogen bonds with LYS-50, VAL-51 [Figure 12]b and five hydrogen bonds with ARG-66, ASP-100, SER-459 [Figure 12]c residues respectively.

Molecular docking interactions of Gram-negative bacteria B. subtilis and S. aureus receptors with Schiff base ligands were visualized using PyMol software [Figure 13] and [Figure 14]. The binding sites are labeled and represented as ribbon structures that show hydrogen bonds and nonbonded interactions with the Schiff base ligands.
Figure 13: The three Schiff base ligands (a-c) showing interactions with the Aspergillus niger receptor forming Hydrogen bonds and non-bonded interactions

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Figure 14: Crystal structure of Fungi receptor Aspergillus flavus (Protein Data Bank ID: 6DRS)

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The L1 interacts with GLY-38, THR-43, and ARG-132 residues and forms four Hydrogen bonds with the B. subtilis receptor and the other residues depict the formation of nonbonded interactions [Figure 1]a. Similarly, L2 and L3 forms three hydrogen bonds with ASP-130 [Figure 13]b and ASP-132 and three hydrogen bonds with THR-14, THR-43, and ASP-132 [Figure 13]c residues, respectively.

The L1 interacts with HIS-118 and SER-281 residues and forms three hydrogen bonds with the S. aureus receptor, and the other residues depict the formation of nonbonded interactions [Figure 14]a. Similarly, L2 and L2 forms three hydrogen bonds with HIS-118 and SER-281 [Figure 14]b and three hydrogen bonds with HIS-118 and ASN-171 [Figure 14]c residues respectively.

Molecular docking interactions of Fungi A. niger [Figure 15], A. flavus [Figure 16] and A. solani [Figure 17] receptors with Schiff base ligands were visualized using PyMol software. The binding sites are labeled and represented as ribbon structures that show hydrogen bonds and nonbonded interactions with the Schiff base ligands.

The L1 interacts with TRP-149 and ASP-218 residues and forms three Hydrogen bonds with the A. niger receptor and the other residues depict the formation of nonbonded interactions [Figure 15]a. Similarly, L2 and L3 forms three hydrogen bonds with GLU-149 and ASP-218 [Figure 15]b and three hydrogen bonds with GLU-149 and ASP-218 [Figure 15]c residues respectively.
Figure 15: The three Schiff base ligands (a-c) showing interactions with the Aspergillus flavus receptor forming Hydrogen bonds and nonbonded interactions

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Figure 16: Crystal structure of Fungi receptor Alternaria solani

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Figure 17: The three Schiff base ligands (a-c) showing interactions with the Alternaria solani receptor forming Hydrogen bonds and non-bonded interactions

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The L1 interacts with THR-66 residue and forms two Hydrogen bonds with the A. flavus receptor and the other residues depict the formation of nonbonded interactions [Figure 16]a. Similarly, L2 and L3 forms two hydrogen bonds with THR-66 [Figure 16]b and six hydrogen bonds with ILE-26, GLY-30, THR-66 and THR-197 [Figure 16]c residues respectively.

The L1 interacts with SER-79 residue and forms one hydrogen bond with the A. flavus receptor and the other residues depict the formation of nonbonded interactions [Figure 17]a. Similarly, L2 and L3 forms one hydrogen bond with SER-79 [Figure 17]b and three hydrogen bonds with ALA-13 and SER-79 [Figure 17]c residues respectively.


  Conclusions Top


The work has approached the synthetic and biological activities of these wonder molecules, bromopyridine imino derivatives. The preparation procedure follows in this work for the synthesis of title compounds that offers a reduction in reaction time, operation simplicity, cleaner reaction, and easy work-up. All these Schiff base ligands are insoluble in water but soluble in organic solvents, Dimethylformamide (DMF), DMSO, CH3Cl and THF. Elemental analyses confirm the chemical composition of the synthesized compounds while FT-IR and1H-NMR spectroscopy confirms the functional groups, particularly-HC = N and O-H groups, of the compounds. All spectroscopic analysis confirmed the proposed structures for these compounds. Antibacterial data have shown that the synthesized compounds have significant biological activity against the tested microorganisms. From the molecular docking studies, it can be concluded that the Schiff base ligands have considerably shown lower binding energy and good hydrogen bonding and hydrophobic interactions against the receptors of two Gram-positive (E. coli and R. solanacearum), two Gram-negative bacteria (1s and S. aureus), and three fungi (A. niger, A. flavus and A. solani) microorganisms.

Acknowledgments

Authors acknowledge the support and infrastructure provided by the JSS Academy of Higher Education and Research, Mysuru, India. KSP thankfully acknowledge the Director, Amrita Vishwa Vidyapeetham, Mysuru Campus, Mysuru for infrastructure support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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