Synthesis and Antimicrobial Evaluation of 2-(1H-1,2,3-Benzotriazol-1-yl)-N-Phenylacetamide Derivatives

 

C. M. Jamkhandi*, John Intru Disouza.

Department of Pharmacy JJT University Jhunjhunu Rajasthan India.

ABSTRACT:

2-(1H-1,2,3-benzotriazol-1-yl)-N-phenylacetamide derivatives find useful as anti-infective agents and substitution of bentriazole produces more potent anti-infective agents. Derivatives of benzotriazole substituted 2-(1H-1,2,3-benzotriazol-1-yl)-N-phenylacetamide are synthesized and anti microbial activities have been measured against Norfloxacine and Ketoconazole as standards drugs. It is found that the derivatives from 1a to Va are shown to produce good anti microbial actions against, S. Aureus, S. Pygens, B. Subtilis, E.coli, P. Aerigenosa, C Albicanse, A Niger. The all the derivatives show satisfactory anti-microbial activities.

 

 

INTRODUCTION:

Treatment of human infections is challenging from time immemorial to present day, as many new infections have taken birth and some old infections are resurfacing. Development of resistance to antibiotics and chemotherapeutic agents is observed in microorganisms. Due to these reasons there is need for continuous development of anti-infective agents. Synthetic compounds of derivatives of Benzotriazole have shown analgesic, antibacterial, antifungals activities^1-6 antifilarial activities⁷, and Benzotriazole also reported for anticonvulsant and anti-inflammatory⁸, antitumor⁹ activities, literature study reveals the antiviral activity¹⁰. The methods of synthesis of Benzotriazole derivatives with different techniques have been reported¹¹.

 

Present study is focused on Synthesis of 2-(1H-1,2,3-benzotriazol-1-yl)-N-phenylacetamide derivatives following published procedures to get possible potent anti-infective derivatives^12-15.

 

EXPERIMENTAL METHODS:

Procedure of Synthesis

Synthesis of Benzotriazole(a): 10.8 gm of O-phenylenediamine is added to mixture of 12g (11.5 ml) of glacial acetic acetic acid and 30 ml   of water, which is cooled to 15^oC, stir. Then solution of 7.5g of sodium nitrite in 15 ml water is added in portion. The temperature rises slowly to 85^oC and then cools slowly. When temperature is 45^oC the mixture is chilled at ice bath for 30 min. Pale brown solid separated by the filtration. The recrystallization is done using benzene as solvent.

 

Synthesis of ethyl 1H-benzotriazol-1-ylacetate(b): A mixture of Benzotriazole (0.1M), ethyl chloroacetate (0.1M) and 0.3g of K2CO3 in 60 ml of acetone was stirred for 10 hrs. The solvent was removed under reduced pressure. A solid mass was produced and then needle shaped brown crystals were obtained after recrystallization from the mixture of chloroform and ether (8:2%V/V).The yield obtained was 60% and M.P. was 40^oC.

 

Synthesis of 1H-benzotriazol-1-ylacetyl chloride(c): A 250-mL, three-necked flask, equipped with a magnetic stirbar, condenser, thermometer, and addition funnel, is charged with 10.0 g Benzotriazole and 34 mL of chloroform (CHCl₃). At 25°C, 22 mL (600 mmol) of thionyl chloride and 1 drop of dimethylformamide (DMF) are added, followed by heating the mixture at 68°C for 3 hr. After the initial suspension turns into a yellow solution, the heating source is removed and the acid chloride precipitates as a pale red solid. After cooling the reaction mixture to 25°C, the solid is collected via filtration using a Buchner funnel, washed with CHCl₃, and dried in a vacuum desiccator for 15 hr to give 5.12 g (90%) of as a white powder.

 

 Scheme-1:  For synthesis of 2-(1H-1,2,3-benzotriazol-1-yl)-N-phenylacetamide derivatives

 

 

Synthesis of 2-(1H-benzotriazol-1-yl)-N-(naphthalen-1-yl)acetamide(Ia): the compound (c) was treated with 1-aminonapthalien  in equimolar concentration and refluxed for 4 hrs in benzene solvent. Spectral data FTIR (KBr cm-1): 2924.92 (HC Aromatic), 1597.54 (-N=N str), 1675.15(-C=O). 1H-NMR (DMSO 1δ ppm): 7.1-7.5 (7H, d,Ar ),1.9 (NH-). m/z of m⁺  ion is 302.

 

Synthesis of 2-(1H-benzotriazol-1-yl)-N-(4-sulfamoylphenyl)acetamide (IIa): the compound (c) was treated with equimolar 4-aminobenzenesulfonamide and refluxed for 4 hrs in benzene solvent. Spectral data FTIR (KBr cm-1): 2924.92 (HC Aromatic), 1598.89 (-N=N str), 1653.15 (-C=O). 1H-NMR (DMSO 1δ ppm): 7.5 (4H, d,Ar),1.9 (NH-), 2.13 (s,2H,S0₂NH₂). m/z of m⁺  ion is 331.

 

Synthesis of 2-(1H-benzotriazol-1-yl)-N-(4-hydroxyphenyl)acetamide (IIIa): the compound (c) was treated with equimolar 4-aminophenol and refluxed for 4 hrs in benzene solvent. Spectral data FTIR (KBr cm-1): 2854.33 (HC Aromatic), 1593.03 (-N=N str), 1416.50 (-C-N str), 3337.73 (-NH- str) . 1H-NMR (DMSO 1δ ppm): 7.1-6.6 (4H, d,Ar ),1.9 (NH-). m/z of m⁺  ion is 268.

 

Synthesis of 2-(1H-benzotriazol-1-yl)-N-(4-nitrophenyl)acetamide (IVa): the compound (c) was treated with equimolar 4-nitroaniline and refluxed for 4 hrs in benzene solvent. Spectral data FTIR (KBr cm-1): 2852.95 (HC Aromatic), 1602.45 (-N=N str), 1301.75  (-C-N str), 3355.07  (-NH- str) . 1H-NMR (DMSO 1δ ppm): 7.1-6.7 (4H, d,Ar ). m/z of m⁺  ion is 296.

 

Synthesis of 4-[(1H-benzotriazol-1-ylacetyl)amino] benzoic acid (Va): the compound (c) was treated with equimolar 4-aminobenzoic acid and refluxed for 4 hrs in benzene solvent. Spectral data FTIR (KBr cm-1): 2924.00 (HC Aromatic), 1610.40 (-N=N str), 1704.78  (-C=O), 1317.98  (-C-N- str) . 1H-NMR (DMSO 1δ ppm): 7.4-7.1 (4H, d,Ar ). m/z of m⁺  ion is 297.

 

The melting points of the synthesized derivatives were determined by open capillary (LABHOSP) and were uncorrected. The purity of the compounds was checked using pre coated TLC plates (MERCK, 60F) using Benzene:chloroform: methanol (8:4:2) solvent system. The developed chromatographic plates were visualized under UV at 254nm. IR spectra were recorded using KBr on Shimadzu FTIR model 8400 spectrophotometer and Agilent Technologies CARY 630 FTIR,1H NMR spectra in DMSO on a BRUKER FT-NMR instrument using TMS as internal standard. Fluorimetric determination was carried out using Elico Fluorimeter, model CL-53.

 

Synthetic Scheme for benzotriazole substituted N-Phenyl acetamide derivative (Scheme-1).

 

Antimicrobial Activity:

The synthesized compounds were screened for antibacterial and antifungal activity (Fig 1 and 2). The cup plate method was adopted for screening and Norfloxacine and Ketaconazole used as standard drugs in concentration of 1µg/ml. The bacterial strains of B. subtilis, S. aureus, E. coli, and S. typhi were used for antibacterial activity. For antifungal activity A. niger and C. albicanus strains were used. The MICs and MBCs were determined. Overnight broth cultures were used in all MIC determinations. Agar dilution MICs were determined by using agar plates with an incorporated standard drug dilutions and samples with incubation at 37°C and were defined as the lowest antibiotic concentrations completely inhibiting growth. Broth dilution MICs were determined with overnight broth cultures of the strains to be tested.

 

Table 1: Physical properties of the Benzotriazole derivatives(Ia to Va)

Derivative	Mol. Weight	Derivative Name	R	%Yield	MP
Ia	C18H14N4O	2-(1H-benzotriazol-1-yl)-N-(naphthalen-1-yl)acetamide		65	243 oC
IIa	C14H13N5O3S	2-(1H-benzotriazol-1-yl)-N-(4-sulfamoylphenyl)acetamide		76	130 oC
IIIa	C14H12N4O	2-(1H-benzotriazol-1-yl)-N-(4-hydroxyphenyl)acetamide		65	223 oC
Iva	C14H11N5O3	2-(1H-benzotriazol-1-yl)-N-(4-nitrophenyl)acetamide		68	260 oC
Va	C15H12N4O3	4-[(1H-benzotriazol-1-ylacetyl)amino]benzoic acid		64	220 oC

 

Figure 1: Graphical representation Antimicrobial activity.

 

Figure 2: Graphical representation Antifungal activity

 

 

 

RESULTS AND DISCUSSION:

The derivatives synthesized are characterized by the physical properties (Table 1), chemical properties, spectral data like IR, NMR and Mass spectra.

 

CONCLUSION:

The synthesized derivatives are like I a to Va showed comparable Zone of inhibition with standards and have good antibacterial and antifungal activities.

 

ACKNOWLEDGEMENTS:

Authors are thankful to Shri. G. D. Patil Secretary Shree Warana Vibhag Shikshan Mandal Warananagar for providing laboratories facilities. Authors are thankful to Mrs. Dr. U. S. Chougule, Mr. Shaikh and Mr Krishnath Paymal, CFC and Chemistry Dept of Shivaji University for kind assistance in microbial and spectral data.

 

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Received on 03.07.2012       Modified on 28.07.2012

Accepted on 29.07.2012      © RJPT All right reserved