SYNTHESIS AND BIOLOGICAL EVALUATION OF BENZIMIDAZOLE DERIVATIVES AS ANTIMICROBIAL AGENTS

Objective: The present study aims to synthesize and biological evaluation of benzimidazole derivatives as antimicrobial agents. Methods: 2-Methylbenzimidazole react with ethyl-chloroacetate gives N 1 -Ethylacetate-2-methyl-benzimidazole (1), which on reaction with thiosemicarbazide gives N 1 -acetylthiosemicarbazide-2-methyl-benzimidazole (2). The compound (2) on dehydrative annulation by mineral acid gives N 1 -(2’-amino-5’-methylene)-1’,3’,4’-thiadiazole-2-methyl-benzimidazole(3), which on condensation with various aromatic and hetero aromatic aldehydes gives N 1 Results: The reaction sequence involves microwave-induced preparation of N -(2-substituted-Benzylidene-imino-5’-methylene)-1’, 3’, 4’-Thiadiazole]-2-methyl-benzimidazole(4a-4l). 1 -Ethylacetate-2-methyl-benzimidazole (1) from reaction of 2- methylbenzimidazole with ethyl-chloroacetate. Further reaction with thiosemicarbazide gives N 1 -acetylthiosemicarbazide-2-methyl-benzimidazole (2). The compound (2) on dehydrative annulation by sulfuric acid gives N 1 -(2’-amino-5’-methylene)-1’,3’,4’-thiadiazole-2-methyl-benzimidazole(3), which on condensation with various aromatic and hetero aromatic aldehydes gives N 1 -(2-substituted-Benzylidene-imino-5’-methylene)-1’, 3’, 4’-Thiadiazole]-2-methyl-benzimidazole(4a-4l). Which were characterized by IR and 1 Conclusion: All the synthesized compounds were screened for antimicrobial activity by cup plate method. Most of the derivatives showed good antimicrobial activity against Gram-Positive and Gram-negative bacteria. NMR spectral data.


INTRODUCTION
Benzimidazole is a heterocyclic aromatic organic compound. It is an important pharmacophore and a privileged structure in medicinal chemistry. This compound is bicyclic in nature which consist of fusion of benzene and imidazole. Benzimidazole derivatives were reported to possess analgesic and anti-inflammatory activity [1], antimicrobial [2,3], anticancer [4], anticonvulsant [5], antiviral [6], antioxidant [7], antihypertensive [8], anti-tubercular [9], anthelmintic [10],proton pump inhibitor activity [11]. In this present study benzimidazole derivatives of Schiff bases containing various aldehydes have been synthesized. These synthesized compounds were screened for antibacterial activity by cup plate method.

MATERIALS AND METHODS
Melting points of all synthesized compounds were determined in open capillary tubes and were uncorrected. The purity of the compounds was checked by TLC on pre-coated silica gel G plates and visualized in iodine vapour. The IR spectra were recorded on FT-IR 1800 (Perkin-Elmer)spectrophotometer by KBr pellets technique. 1 H NMR spectra were recorded on Jasco 4100 spectrophotometer using DMSO-d6 as solvent and TMS as internal standard.

Synthesis of N 1 -Ethylacetate-2-methyl-benzimidazole (1)
A mixture of 2-methyl-benzimidazole(0.30 mole, 39.60 g) and ethylchloroacetate (0.30 mole,36.74 g) with K2CO3(6.16 g) was added and mixed thoroughly. The reaction mixture was air dried and subjected to microwave irradiation for 3 min. The completion of reaction was monitored by thin layer chromatography. The reaction mixture was cooled and separated, solid extracted with ethanol to give the desired product as a colourless crystalline solid.

Synthesis of N 1
The N -Acetylthiosemicarbazide-2-methylbenzimidazole (2) using a pestle for uniform mixing. The mixture was kept inside a microwave irradiation for 10 min. The completion of the reaction was monitored by thin layer chromatography. The product was recrystallized using ethanol.

Synthesis of N 1 -(2'-amino-5'-methylene)-1', 3',4'-thiadiazole-2methyl-benzimidazole (3)
Equimolar solution of compound 2(0.10 mole, 26.30 g) dissolved in chloroform and concentrated H2SO4 (0.10 mole, 9.80 g) was added in to above solution at room temperature. This reaction mixture was subjected to microwave irradiation for 15 min. The sample was cooled in ice bath and irradiation was repeated several times. Completion of the reaction was monitored by TLC. The resulting product was neutralized with conc. Liq. ammonia. The final product was recrystallized from ethanol to give compound 3.

Antimicrobial activity
All synthesized benzimidazole derivatives 4a-4l were screened for in vitro antibacterial activity against strain of gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria using cup plate method (agar diffusion method) [12]. Ampicillin was used as standard drug for antibacterial activity. The solutions of 25, 50, 100 µg/ml concentration of synthesized benzimidazole derivatives and standard drug were used to evaluate antimicrobial potential. The result of antibacterial activity is shown in table 3.