untitled European Journal of Chemistry 3 (3) (2012) 359‐362 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2012 EURJCHEM DOI:10.5155/eurjchem.3.3.359‐362.607 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis of some novel benzimidazole derivatives and it’s biological evaluation Doddarasinakere Kempaiah Ravishankara and Paduvalahippe Gowdegowda Chandrashekara* Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore, 570005, India *Corresponding author at: Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore, 570005, India. Tel.: +91.0821.2342867; fax: +91.0821.2419239. E‐mail address: chanduchem@yahoo.com (P.G. Chandrashekara). COMMUNICATION INFORMATION ABSTRACT Received: 07 March 2012 Received in revised form: 04 April 2012 Accepted: 11 April 2012 Online: 30 September 2012 KEYWORDS A series of new benzimidazole derivatives have been synthesized by simple condensation reaction between benzimidazole derivatives and phenyl sulphonyl chloride derivatives. All these compounds were characterized by FT‐IR, 1H NMR, MS and elemental analysis. These compounds were screened for antibacterial and antioxidant activities, respectively. The antibacterial activities were compared with the standard drug such as chlorophenicol and antioxidant activities were compared with the ascorbic acid. Ester Tetrazole Sulphonation Benzimidazole Antioxidant activity Antimicrobial activity 1. Introduction Heterocyclic compounds have occupied a prominent place among various classes of organic compounds by virtue of their diverse biological activities. Hence the design, synthesis and production of new molecules for crop health and human welfare have taken center stage in recent years. Among the wide variety of heterocyclics that have been explored for developing pharmaceutically important role in medicinal chemistry [1]. Benzimidazole and its derivatives are of great importance in medicinal chemistry because of their wide variety of biological and pharmacological applications [1,2]. The literature survey shows several examples of compounds having a benzimidazole ring which exhibit remarkable bioactivity that could make them potentially useful in the treatment of cancer, and cardiovascular diseases [3]. The benzimidazole unit and it’s derivatives possess anticancer [4], antiinflammatory [5], antibacterial [6], antifungal [7], antidiabetic [8], and anti‐HIV activities [9]. On the basis of this observation we have synthesized benzimidazole derivatives as hitherto unreported analogues. Literature survey has also revealed the importance of benzimidazoles as antimicrobial and antioxidant agents [10‐ 14]. It has also been reported that certain substituted benzimidazole derivatives have a broad antimicrobial spectrum [11]. Motivated by this above‐mentioned facts herein is reported the synthesis and antimicrobial, anti oxidant activities of new benzimidazole series. 2. Experimental 2.1. Instrumentation All the reagents were purchased from Aldrich Chemicals Co, Loba Chemie. All the solvents and reagents used for the synthesis and analysis were of analytical grade. The progress of the reaction and the purity of the compounds were checked by thin layer chromatography (TLC). 1H NMR spectra were recorded on a BRUKER‐AV400 spectrometer in CDCl3 and tetramethylsilane (TMS; δ = 0.00 ppm) served as internal standards. IR spectra were measured using a JASCO FT/IR‐ 4100 spectrometer. Mass spectra were measured with Micromass Q‐Tof. CHNS were measure by the Elementar Vario EL III (Germany). Thin‐layer chromatography was carried out using SILICA GEL GF254. The melting points (uncorrected) were measured on a SALACO apparatus. 2.2. Synthesis 2.2.1. General procedure for the synthesis of 1‐(phenoxy carbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐(phenylsulfonyl)‐1H‐ tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐1H‐benzo[d]imidazole‐ 7‐carboxylate derivatives The compound 1‐(phenoxycarbonyloxy)ethyl 1‐((2'‐(1H‐ tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐2‐ethoxy‐1H‐benzo[d] imidazole‐7‐carboxylate was purchased from Pure Chem. Scientific Limited, USA. Mixture of 1‐(phenoxycarbonyl oxy)ethyl 1‐((2'‐(1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐2‐ ethoxy‐1H‐benzo[d]imidazole‐7‐carboxylate (0.2 g, 0.33 mmol), substituted phenyl sulfonyl chloride (0.36 mmol) and triethyl amine (0.66 mmol) in 10 mL of dichloromethane was stirred for 2 h at room temperature. After the completion of the reaction, 5 mL water was poured; the organic layer was extracted and distilled off completely to get product in good yield (Scheme 1). 1‐(Phenoxycarbonyloxy)ethyl‐2‐ethoxy‐1‐((2'‐(1‐(phenyl sulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl) methyl)‐1H‐benzo[d] imidazole‐7‐carboxylate (3a): Color: White. Yield: 80% (0.2 g). M.p.: 78‐80 oC. FT‐IR (KBr, cm‐1): 1690 (ketone CO stretch.), 1700 (ester CO stretch.), 3030 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.25‐1.32 (t, 3H, CH3), 1.43‐1.45 (d, 360 Ravishankara and Chandrashekara / European Journal of Chemistry 3 (3) (2012) 359‐362 Scheme 1 3H, CH3), 2.9‐3.0 (q, 2H, OCH2), 4.66 (s, 2H, NCH2), 5.59‐5.67 (m, 1H, CH), 6.81‐7.10 (m, J = 7.5 Hz, 2H, ArH), 7.12‐7.46 (m, 9H, ArH), 7.58‐7.88 (m, J = 8 Hz, 10H, ArH). Anal. calcd. for C39H32N6O8S: C, 62.89; H, 4.33; N, 11.28; S, 4.31. Found: C, 62.80; H, 4.29; N, 11.26; S, 4.30%. MS (m/z): (M+1) 745.79. 1‐(Phenoxycarbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐(2‐nitro phenylsulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐1H‐ benzo[d]imidazole‐7‐carboxylate (3b): Color: Yellow. Yield: 70% (0.18 g). M.p.: 132‐134 oC. FT‐IR (KBr, cm‐1): 1450 (NO2 stretch.), 1695 (ketone CO stretch.), 1710 (ester CO stretch.), 3040 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.21‐1.23 (t, 3H, CH3), 1.7‐2.0 (d, 3H, CH3), 3.18‐3.21 (q, 2H, OCH2), 4.63 (s, 2H, NCH2), 5.29‐5.47 (m, 1H, CH), 6.89‐7.10 (m, J = 7.2 Hz, 3H, ArH), 7.14‐7.48 (m, 12H, ArH), 8.28‐8.32 (m, 5H, ArH). Anal. calcd. for C39H31N7O10S: C, 59.31; H, 3.96; N, 12.41; S, 4.06. Found: C, 59.29; H, 3.98; N, 12.38; S, 4.01%. MS (m/z): (M+1) 790.91. 1‐(Phenoxycarbonyloxy)ethyl 1‐((2'‐(1‐(2,5‐dichlorophenyl sulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐2‐ethoxy‐1H‐ benzo[d]imidazole‐7‐carboxylate (3c): Color: White. Yield: 76% (0.20 g). M.p.: 92‐94 oC. FT‐IR (KBr, cm‐1): 1710 (ketone CO stretch.), 1729 (ester CO stretch.), 3039 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.23‐1.24 (t, 3H, CH3), 1.72‐ 2.02 (d, 3H, CH3), 3.17‐3.19 (q, 2H, OCH2), 4.66 (s, 2H, NCH2), 5.27‐5.31 (m, 1H, CH), 7.01‐7.12 (m, J = 7.2 Hz, 3H, ArH), 8.01‐ 8.11 (m, 7H, ArH), 8.18‐8.29 (m, 9H, ArH). Anal. calcd. for C39H30Cl2N6O8S: C, 57.57; H, 3.72; N, 10.33; S, 3.94. Found: C, 56.99; H, 3.70; N, 10.29; S, 3.89%. MS (m/z): (M+1) 814.22. 1‐(phenoxycarbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐(3‐nitro phenylsulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐1H‐ benzo[d]imidazole‐7‐carboxylate (3d): Color: White. Yield: 72% (0.19 g). M.p.: 98‐100 oC. FT‐IR (KBr, cm‐1): 1445 (NO2 stretch.), 1690 (ketone CO stretch.), 1700 (ester CO stretch.), 3039 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.18‐ 1.20 (t, 3H, CH3), 1.91‐2.01 (d, 3H, CH3), 3.13‐3.15 (q, 2H, OCH2), 4.78 (s, 2H, NCH2), 5.27‐5.29 (m, 1H, CH), 7.11‐7.12 (m, 3H, ArH), 8.11‐8.17 (m, 7H, ArH), 8.17‐8.28 (m, 10H, ArH). Anal. calcd. for C39H31N7O10S: C, 59.31; H, 3.96; N, 12.41; S, 4.06. Found: C, 59.22; H, 3.89; N, 12.39; S, 3.99%. MS (m/z): (M+1) 790.19. 1‐(Phenoxycarbonyloxy)ethyl 1‐((2'‐(1‐(4‐tert‐butylphenyl sulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐2‐ethoxy‐1H‐ benzo[d]imidazole‐7‐carboxylate (3e): Color: White. Yield: 86% (0.22 g). M.p.: 72‐74 oC. FT‐IR (KBr, cm‐1): 1700 (ketone CO stretch.), 1729 (ester CO stretch.), 3050 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.13‐1.18 (s, 9H, 3CH3), 1.19‐1.20 (t, 3H, CH3), 1.90‐2.01 (d, 3H, CH3), 3.14‐3.15 (q, 2H, OCH2), 4.79 (s, 2H, NCH2), 5.18‐5.20 (m, 1H, CH), 7.10‐7.12 (m, J = 7.4 Hz, 3H, ArH), 8.15‐8.20 (m, 8H, ArH), 8.20‐8.27 (m, 9H, ArH). Anal. calcd. for C43H40N6O8S: C, 64.49; H, 5.03; N, 10.49; S, 4.00. Found: C, 64.19; H, 4.99; N, 10.29; S, 3.87%. MS (m/z): (M+1) 801.73. 1‐(Phenoxycarbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐tosyl‐1H‐ tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐1H‐benzo[d]imidazole‐7‐ carboxylate (3f): Color: Yellow. Yield: 78% (0.19 g). m.p. 87‐89 oC. FT‐IR (KBr, cm‐1): 1690 (ketone CO stretch.), 1710 (ester CO stretch.), 3041 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.18‐1.20 (t, 3H, CH3), 1.88‐1.91 (d, 3H, CH3), 2.10 (s, 3H, ArCH3), 3.14‐3.15 (q, 2H, OCH2), 4.79 (s, 2H, NCH2), 5.17‐5.18 (m, 1H, CH), 7.11‐7.12 (m, J = 8.0 Hz, 3H, ArH), 8.11‐ 8.16 (m, 8H, ArH), 8.20‐8.25 (m, 9H, ArH). Anal. calcd. for C40H34N6O8S: C, 63.31; H, 4.52; N, 11.08; S, 4.23. Found: C, 63.11; H, 4.22; N, 10.87; S, 3.98%. MS (m/z): (M+1) 759.80. 1‐(Phenoxycarbonyloxy)ethyl 1‐((2'‐(1‐(4‐chlorophenyl sulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐2‐ethoxy‐1H‐ benzo[d]imidazole‐7‐carboxylate (3g): Color: White. Yield: 78% (0.16 g). M.p.: 138‐140 oC. FT‐IR (KBr, cm‐1): 1690 (ketone CO stretch.), 1710 (ester CO stretch.), 3041 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.21‐1.23 (t, 3H, CH3), 1.78‐ 1.79 (d, 3H, CH3), 3.78‐3.80 (q, 2H, OCH2), 4.82 (s, 2H, NCH2), 5.16‐5.17 (m, 1H, CH), 7.10‐7.12 (m, J = 8.0 Hz, 3H, ArH), 8.11‐ 8.15 (m, 7H, ArH), 8.20‐8.25 (m, 10H, ArH). Anal. calcd. for C39H31ClN6O8S: C, 60.11; H, 4.01; N, 10.79; S, 4.12. Found: C, 60.07; H, 3.71; N, 10.29; S, 3.82%. MS (m/z): (M+1) 780.18. 1‐(Phenoxycarbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐(3‐(trifluoro methyl) phenylsulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐ 1H‐benzo[d]imidazole‐7‐carboxylate (3h): Color: White. Yield: 78% (0.15 g). M.p.: 63‐65 oC. FT‐IR (KBr, cm‐1): 1695 (ketone CO stretch.), 1725 (ester CO stretch.), 3052 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.22‐1.23 (t, 3H, CH3), 1.69‐1.71 (d, 3H, CH3), 3.79‐3.81 (q, 2H, OCH2), 4.79 (s, 2H, NCH2), 5.28‐5.29 (m, 1H, CH), 7.16‐7.18 (m, J = 6.9 Hz, 3H, ArH), 8.16‐8.18 (m, 7H, ArH), 8.19‐8.22 (m, 10H, ArH). Anal. calcd. for C40H31F3N6O8S: C, 59.11; H, 3.84; N, 10.34; S, 3.95%. Found: C, 58.91; H, 3.69; N, 10.31; S, 3.43. MS (m/z): (M+1) 813.15. 1‐(Phenoxycarbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐(4‐fluoro phenylsulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐1H‐ benzo[d]imidazole‐7‐carboxylate (3i): Color: White. Yield: 78% (0.19 g). M.p.: 80‐82 oC. Ravishankara and Chandrashekara / European Journal of Chemistry 3 (3) (2012) 359‐362 361 Table 1. Antibacterial activity of synthesized compounds *. Compound Bacillus subtilis Klebsiellapneumoniae Xanthomonasvesicatoria Bacillus cereus Shigellaflexneri Salmonella Typhi 5 mg 10 mg 5 mg 10 mg 5 mg 10 mg 5 mg 10 mg 5 mg 10 mg 5 mg 10 mg 3a ‐ ‐ 11 10 ‐ ‐ 10 ‐ 14 ‐ ‐ ‐ 3b 10 ‐ 14 10 12 ‐ ‐ ‐ 15 14 ‐ ‐ 3c ‐ ‐ 10 ‐ ‐ 10 11 12 10 ‐ ‐ ‐ 3d 12 ‐ ‐ ‐ 10 10 16 ‐ 17 ‐ ‐ ‐ 3e 18 ‐ 10 ‐ 18 ‐ ‐ ‐ ‐ ‐ ‐ ‐ 3f 10 ‐ 22 ‐ 19 ‐ 10 ‐ ‐ ‐ ‐ ‐ 3g 10 ‐ 16 11 10 ‐ ‐ ‐ 10 ‐ ‐ ‐ 3h ‐ ‐ 10 10 ‐ ‐ 17 ‐ 19 ‐ ‐ ‐ 3i ‐ ‐ 11 10 ‐ ‐ 10 ‐ ‐ ‐ ‐ ‐ 3j ‐ ‐ 10 14 ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ Chloramphenicol 31 ‐ 37 36 30 ‐ 37 33 36 ‐ ‐ ‐ * Positive control zone is 30 to 40 mm; Standard drug: Chloramphenicol; ‘‐‘ = Not active. FT‐IR (KBr, cm‐1): 1692 (ketone CO stretch.), 1723 (ester CO stretch.), 3049 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.26‐1.28 (t, 3H, CH3), 1.68‐1.70 (d, 3H, CH3), 3.77‐3.78 (q, 2H, OCH2), 4.88 (s, 2H, NCH2), 5.27‐5.28 (m, 1H, CH), 6.98‐7.10 (m, 3H, ArH), 8.00‐8.31 (m, 7H, ArH), 8.42‐8.51 (m, 10H, ArH). Anal. calcd. for C39H31FN6O8S: C, 61.41; H, 4.10; N, 11.02; S, 4.20. Found: C, 61.11; H, 3.91; N, 10.78; S, 4.10%. MS (m/z): (M+1) 763.67. 1‐(Phenoxycarbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐(2‐fluoro phenylsulfonyl)‐1H‐tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐1H‐ benzo[d]imidazole‐7‐carboxylate (3j): Color: White. Yield: 72% (0.18 g). M.p.: 118‐120 oC. FT‐IR (KBr, cm‐1): 1691 (ketone CO stretch.), 1719 (ester CO stretch.), 3039 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.19‐1.21 (t, 3H, CH3), 1.44‐ 1.46 (d, 3H, CH3), 3.1‐3.2 (q, 2H, OCH2), 4.78 (s, 2H, NCH2), 5.55‐ 5.59 (m, 1H, CH), 7.11‐7.13 (m, 2H, ArH), 7.12‐7.38 (m, 8H, ArH), 8.98‐9.16 (m, 10H, ArH). Anal. calcd. for C39H31FN6O8S: C, 61.41; H, 4.10; N, 11.02; S, 4.20. Found: C, 61.11; H, 3.97; N, 10.80; S, 4.11%. MS (m/z): (M+1) 763.28. 2.3. Biological evaluation ‐ antibacterial and antioxidant activity studies 2.3.1. Antibacterial activity Antibacterial tests were carried out by disc diffusion method using 100 µL of suspension containing 106 cells/mL of bacteria. The discs (6 mm diameter) were impregnated with 5 mg and 10 mg/mL of each compound and placed on the inoculated nutrient agar. Then, the inoculated plates were incubated at 37±0.1 oC at 24 h. One antibacterial drug, chloramphenicol, also is used as positive control. Antibacterial activity was evaluated by measuring the zone of inhibition against the test organisms. 2.3.2. Antioxidant activity The DPPH assay was done by using solution of each compound made in methanol was added to 95 µL of DPPH solution (0.2 mM/mL methanol) and mixed vigorously. The mixture was incubated in dark at room temperature for 30 min. Absorbance was measured at 517 nm using an Elisa reader. Ascorbic acid was used as positive control. The level of percentage inhibition of DPPH• by each compound was calculated according to the Equation 1. % Radical scavenging = [(AC ‐ A)/AC] X 100 (1) where AC is the absorbance of the control and A is the absorbance of sample. Percentage scavenging was also evaluated in ascorbic acid equivalence. 3. Results and discussion We have synthesized a series of 1‐(phenoxy carbonyloxy)ethyl 2‐ethoxy‐1‐((2'‐(1‐(phenylsulfonyl)‐1H‐ tetrazol‐5‐yl) biphenyl‐4‐yl)methyl)‐1H‐benzo[d]imidazole‐7‐ carboxylate derivatives using a known procedure and obtained products with good yield. The structures of all the synthesized compounds were characterized by spectroscopic data, and allowed these molecules for study of antibacterial and antioxidant activities (Table 1 and 2). Benzimidazole derivatives shows a very good anti bacterial activities [10‐14], we are comparing the synthesized new benzimidazole derivatives to the marketed chlorophenicol [15] which shows very good anti bacterial activity, here we are synthesizing the newly substituted benzimidazole derivatives for the studies of antibacterial activities by comparison with the drug molecule. In this studies compound 3f shows good bacterial activity, in which the tertiary butyl group is the electron releasing group, which is attached to the para position. The compound 3i shows least antibacterial activity, in which the fluoro group is attached to the para position, which is the electron withdrawing group. The remaining molecules showing the moderate activity. The synthesized compounds were tested for anti oxidant activities by evaluation with ascorbic acid [16,17]. In antioxidant studies the compound 3h shows the good antioxidant activity, in which the trifluoro methyl group is attached to the meta position which is highly electron withdrawing. Compound 3a shows the least antioxidant activity, which does not having any substitution. Table 2. Antioxidant activity of synthesized compounds. Sample Antioxidant percentage, 5 mg/mL 3a 14 3b 22 3c 21 3d 16 3e 16 3f 16 3g 31 3h 55 3i 24 3j 18 Ascorbic acid 90 4. Conclusion The structure proposed of the synthesized compound is well supported by spectroscopic data. From the data of antibacterial activity and antioxidant activity, it may be concluded that all the synthesized compounds possess good to moderate activity. Acknowledgements Our work was financially supported by Sri Mahadeshwara Government First Grade College, Kollegal. 362 Ravishankara and Chandrashekara / European Journal of Chemistry 3 (3) (2012) 359‐362 References [1]. Goker, H.; Kus, C.; Abbasoglu, U. Arch. Pharm. 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