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Original Article
C Geetha Priya Loganathan*,1, Aidajinghun Syiemlieh2, Jaspershield Mawblei3, Deep Pandit4,

1C Geetha Priya Loganathan, Assistant Professor, RR College of Pharmacy, Department of Pharmaceutical Chemistry, Chikkabanavara, Bangalore.

2RR College of Pharmacy, Chhikabanavara, Bangalore, India.

3RR College of Pharmacy, Chhikabanavara, Bangalore, India.

4RR College of Pharmacy, Chhikabanavara, Bangalore, India.

*Corresponding Author:

C Geetha Priya Loganathan, Assistant Professor, RR College of Pharmacy, Department of Pharmaceutical Chemistry, Chikkabanavara, Bangalore., Email: geethavaishu2009@gmail.com
Received Date: 2022-10-20,
Accepted Date: 2022-12-08,
Published Date: 2023-03-31
Year: 2023, Volume: 13, Issue: 1, Page no. 15-23, DOI: 10.26463/rjps.13_1_6
Views: 814, Downloads: 25
Licensing Information:
CC BY NC 4.0 ICON
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0.
Abstract

Aim: The present study aimed to identify the potent 1,2,3-triazole derivatives for synthesis and also assess their anti-bacterial activity.

Methodology: In silico design of novel analogues was carried out for ten derivatives using Auto Dock Vina and compared with standard drug Ciprofloxacin. Swiss ADME software was used to analyze ‘Lipinski Rule of Five’ and drug likeness properties. Three derivatives which obeyed rule of five, having desired physicochemical properties and highest docking score were synthesized (PDB code: 2K35). The synthesis was carried out in two step process to determine their antibacterial activity. The synthesized compounds were structurally elucidated using Fourier-transform infrared spectroscopy (FTIR), Nuclear Magnetic Resonance (1H NMR), and Mass spectroscopy .

Results: Antibacterial activity of different compounds was observed by disc diffusion method against two organisms, E. coli and Streptococcus. Among the tested compounds, 4A showed significant antibacterial activity. Compounds 6A and 8A also exhibited appreciable antibacterial activity against E. coli while compound 6A showed appreciable antibacterial activity against Streptococcus.

Conclusion: According to data obtained from the present study, piperazine incorporated triazole derivatives were found to possess effective antibacterial activity. Further modifications of triazole based compounds at different positions to generate new molecules with potent anti-tumor activities will be described in future.

<p><strong>Aim: </strong>The present study aimed to identify the potent 1,2,3-triazole derivatives for synthesis and also assess their anti-bacterial activity.</p> <p><strong>Methodology:</strong> In silico design of novel analogues was carried out for ten derivatives using Auto Dock Vina and compared with standard drug Ciprofloxacin. Swiss ADME software was used to analyze &lsquo;Lipinski Rule of Five&rsquo; and drug likeness properties. Three derivatives which obeyed rule of five, having desired physicochemical properties and highest docking score were synthesized (PDB code: 2K35). The synthesis was carried out in two step process to determine their antibacterial activity. The synthesized compounds were structurally elucidated using Fourier-transform infrared spectroscopy (FTIR), Nuclear Magnetic Resonance (1H NMR), and Mass spectroscopy .</p> <p><strong>Results: </strong>Antibacterial activity of different compounds was observed by disc diffusion method against two organisms, <em>E. coli</em> and <em>Streptococcus</em>. Among the tested compounds, 4A showed significant antibacterial activity. Compounds 6A and 8A also exhibited appreciable antibacterial activity against <em>E. coli</em> while compound 6A showed appreciable antibacterial activity against <em>Streptococcus</em>.</p> <p><strong>Conclusion: </strong>According to data obtained from the present study, piperazine incorporated triazole derivatives were found to possess effective antibacterial activity. Further modifications of triazole based compounds at different positions to generate new molecules with potent anti-tumor activities will be described in future.</p>
Keywords
Benzotriazole, Amines, Antibacterial, Organisms
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Introduction

Mannich bases are of great importance in medicinal chemistry and can be used for the synthesis of numerous heterocyclic compounds with different biological activities such as, anti-microbial,1-4 anti HIV,5 antibacterial,6-8 anticancer,9-12 anti-proliferative,13,14 anti-tubercular,15,16 anti-oxidant,17 anthelmintic,18 antipsychotic,19 antimalarial.20 Mannich base is a beta-amino ketone.21,22 It is a type of nucleophilic addition reaction, which is formed by an amine, formaldehyde (or an aldehyde) and a carbon acid.23 The literature survey had demonstrated that Mannich bases are very reactive and therefore have been utilized for the development of nitrogen containing mixes. Furthermore, triazole can be found in a variety of natural goods, metabolic products of fungus and primitive marine creatures, etc. Because of their importance in industry, agriculture, and biological activity, we synthesized a group of compounds containing 1,2,3 -Triazole derivatives in coordination with piperazine associated with various primary aromatic amine (Table 1) moieties and evaluated their antibacterial potency (Table 2). In silico design studies were carried out for ten derivatives using software Auto Dock Vina (Table 3) (Fig 1-10), and compared with standard drug Ciprofloxacin. Three derivatives having highest docking score were synthesized (Table 4) and elucidated with FTIR,1H NMR, MASS and elemental analysis. Antibacterial activity was observed for the synthesized compounds by using disc diffusion method. Among these compounds, 4A showed significant anti-bacterial activity and compound 6A & 8A showed appreciable anti-bacterial activity against E. coli and 6A showed appreciable activity against Streptococcus. Absorption, distribution, metabolism, and excretion (ADME) properties and drug-likeness prediction was carried out using Swiss ADME (Table 5).

Molecular Docking24-30

Before the docking analysis, ligands were prepared from the optimized compounds and saved in pdb file format by using Spartan. Fourteen ligands were created from the optimized compounds and saved in pdb file format before the docking analysis. The protein bank's 3D compound of the Hydramacin-1 protein was downloaded (with pdb ID: 2K35). The discovery studio visualizer was used to help prepare the enzyme for docking analysis. Hydrogen was introduced throughout the preparation process. The pbd file-stored crystal compound was cleaned of the water molecule, heteroatoms, and co-ligands.

Using Autodock Vina, the Pyrex software assisted in docking the ligands to the active site. Using chimeric software, it was also possible to reformat the complexes (ligand-receptor) following a successful docking technique for further research. The interactions between the complexes were studied using pyMOL and the Discovery Studio Visualizer.

Scheme  

Material and Methods

All melting points were calculated without correction in capillary tubes using a Thieles device. On a Bruker 400 MHz spectrometer, 1H nuclear magnetic resonance spectra were captured. Tetramethylsilane (TMS) was employed in this spectrometer as an internal standard and Dimethyl sulfoxide (DMSO) d6 as a solvent. On a PerkinElmer Spectra One FTIR spectrometer, KBr pellets' FTIR spectrum were captured. The Agilent 1100 series LC/MSD and API-ES/APCI ionization mode were used to run the mass spectra. All of the chemicals utilized in this study were bought from Vasa chemicals, a business supplier in Malleshwaram, Bangalore.

Plan of the Work

Synthesis of 1-(4-nitrophenyl) piperazin-1-yl) methyl)-1 H -benzo(d)(1,2,3)-triazole (Compound A)

Benzotriazole (0.01 Mol) was dissolved in ethanol, and added to para nitro Benzaldehyde (0.05 Mol), and Piperazine (0.01 Mol) until the mixture completely dissolved. The reaction mixture was heated to reflux for 8 hr at  room temperature (27°C). The precipitate was filtered and recrystallized with suitable solvent (DMF- Dimethylformamide & Ethanol). The reaction was confirmed by chromatography.

Synthesis of N- (4-(1H - benzo(d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) -2,4-dimethylaniline (Compound 4A)

The mixture of compound A (0.01 Mol) was dissolved in ethanol, and added to formaldehyde (0.05 Mol), and 2,4 dimethyl aniline (0.01 Mol) until the mixture completely dissolved. The reaction mixture was heated to reflux for 8 hr at room temperature (27°C). The precipitate was filtered and recrystallized with suitable solvent (DMF & Ethanol). The reaction was confirmed by chromatography. The synthesized compounds were structurally elucidated using FTIR, 1H NMR, and MASS.

Synthesis of N- (4-(1H - benzo(d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) -2,6-dimethylaniline (Compound 6A)

The mixture of compound A (0.01 Mol) was dissolved in ethanol, and added to formaldehyde (0.05 Mol), 2,6 dimethylaniline (0.01 Mol) until the mixture completely dissolved. The reaction mixture was heated to reflux for 8 hr at room temperature (27°C). The precipitate was filtered and recrystallized with suitable solvent (DMF & Ethanol). The reaction was confirmed by chromatography. The synthesized compounds were structurally elucidated using FTIR, 1H NMR, and MASS. Synthesis of N- (4-(1H - benzo(d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) 4-Nitroaniline (Compound 8A) The mixture of compound A (0.01 Mol) was dissolved in ethanol, and added to formaldehyde (0.05 Mol), 4-nitroaniline (0.01 Mol) until the mixture completely dissolved. The reaction mixture was heated to reflux for 8 hr at room temperature (27°C). The precipitate was filtered and recrystallized with suitable solvent (DMF & Ethanol). The reaction was confirmed by chromatography. The synthesized compounds were structurally elucidated using FTIR, 1H NMR, and MASS.

Characterized by IR, NMR, Mass Spectra

4A: Yellow Colour, Molecular formula C26H29N7O2, IR - bending CH-aromatic 81, (CH3 )1454, (NO) 1513, (N=N) 1598, (NH) 1627 cm-1, Elemental Analysis (C,66.22;H,6.20;N,20.79;0,6.79). 1H NMR 6.991 (m,H),7.066(d,H),7.076(d,H),1.000, (s,3H) 2.292(s,3H),2.317(s,3H),2.493 (s,3H),2.497(s,3H),Mass 196 Base peak , 471.32, ( M+) 315.24 (M++1).

6A: Slighty Yellowish colour, Molecular formula C26H29N7O2, IR (CH)-bending 737, 1443, (NO) 1520 (N=N) 1603, (NH) 1644 cm-1. Elemental Analysis (C,66.22; H,6.20;N,20.79;0,6.79). 1H NMR 2.067, (s,3H)2.500, (s,3H)2.486, (s,3H)6.937, (m,H)6.957, (m,H)6.976, (m,H)7.071, (m,H),7.089(m,H), Mass 215.03 Base peak 459.57(M+ ) 8A: Yellow colour. Molecular formula C24H24N8O4, IR (CH) bending 736, (CH3) 1923, (NO) 1597 (N=N) 1661, (NH) 1582, cm-1. Elemental Analysis (C,59.01;H ,4.95;N,22.94;0,13.10). 1 H NMR 6.602, (m, H), 6.581, (m, H),6.674, (m, H),6.810, (m, H),7.583, (m,H),7.938, (m,H),7.958(m,H), Mass(161.09 Base peak 484.60(M+)

Anti-Bacterial Activity

The antibacterial activity of synthesized compounds 4A, 6A, 8A was done using disc diffusion method against that following organisms as directed by Ellen J Boron.

E. coli              -  Gram negative

Streptococcus  -  Gram positive

Test Sample

4A - N- (4-(1H - benzo(d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) -2,4-dimethylaniline

6A- N- (4-(1H - benzo(d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) -2,6-dimethylaniline

8A- N- (4-(1H - benzo(d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) 4-nitroaniline

Preparation of Media

Ciprofloxacin was employed as a standard for Escherichia coli and Streptococcus utilizing test samples 4A, 6A, and 8A in the concentrations of 50 mg/mL in a suitable solvent and 100 mg/mL in dimethyl sulfoxide as the solvent.

Preparation of Nutrient

Agar Agar (3.3%), Peptone (0.5%), Sodium chloride (0.5%), Beef extract (0.5%), Distilled water (qs), and pH-adjusted (7.2-7.4). Following this, 5 mL of the media were distributed into culture tubes and autoclaved to sanitize. \

Disc Diffusion Method

Escherichia coli and Streptococcus suspension (Figure 11 and 12) was added to sterile nutritional agar at 45 degrees Celsius, transferred to sterile petri dishes, and allowed to harden. Five-millimeter diameter sterile discs made of Whatmann filter paper sanitized in isopropyl alcohol were placed on the surface of agar plates after dipping in the solutions containing compound sample, standard, and blank. To reduce the impact of time variations between the applications of various solutions, the plates were left hanging at room temperature for an hour as a pre-incubation diffusion period. The plates were then incubated for 18 hours at 37°C, while antibacterial activity was monitored. In plates where the zone of inhibition was visible, the diameter of the zone of inhibition was measured.

Results and Discussion

The triazole derivatives were synthesized and screened for antibacterial activity and confirmed by IR and 1H NMR and Mass.

4A - N- (4-( 1H – benzo (d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) -2,4-dimethylaniline

6A- N- (4-( 1H – benzo (d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) -2,6-dimethylaniline

8A- N- (4-(1H – benzo (d) 1,2,3-triazole-1-yl) (4-nitrophenyl) piperazin-1-yl) methyl) -4 -nitroaniline

The melting points of all the synthetic compounds were discovered in open capillary tubes, and measurements were taken as-is. The results of the elemental analysis are discussed in their own section. By using elemental analysis, the calculated values and actual values of the elements were more closely matched.

Anti-bacterial Activity

The synthesized compounds were screened for their antibacterial activity against Escherichia coli and Streptococcus. The results showed that against E. coli, the compound 4A showed significant antibacterial activity and compound 6A & 8A showed appreciable antibacterial activity. When tested against Streptococcus, compound 6A also showed appreciable anti-bacterial activity when compared to standard Ciprofloxacin.

ADME Studies (Table 5)

Drug-likeness and ADME characteristics Swiss ADME, a free web tool for assessing ADME characteristics and drug-likeness of compounds, was used to anticipate the presence of a few selected antibacterial agents among the data set.

Conclusion

When compared to regular ciprofloxacin, piperazine-incorporated triazole derivatives were found to have effective anti-bacterial activity, according to the results obtained in the current investigation. These triazole analogues could be considered as helpful templates for future research concerning the anti-cancer activity based on the above findings.

Conflict of interest

None

Acknowledgement

The Management, Director, Principal, and Faculty of R. R. College of Pharmacy in Chikkabanavaram, Bangalore, are gratefully acknowledged by the writers for providing the necessary input for this work.

Supporting File
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