untitled European Journal of Chemistry 3 (3) (2012) 363‐366 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2012 EURJCHEM DOI:10.5155/eurjchem.3.3.363‐366.616 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis and characterization of 1'‐benzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐ dibenzimidazole derivatives and their antibacterial activity studies 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: 21 April 2012 Received in revised form: 20 May 2012 Accepted: 25 May 2012 Online: 30 September 2012 KEYWORDS A series of 1'‐benzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenzimidazole derivatives have been synthesized and characterized by FT‐IR, 1H NMR, MS and elemental analyses. Furthermore, these compounds were screened for anti‐bacterial study. Ampicillin is the drug used as a standard, for comparision with all the synthesized molecules. Ampicillin Bacillus subtilis Escherichia coli Spectroscopic study Antibacterial activity Benzimidazole derivatives 1. Introduction Benzimidazole and its derivatives are of great importance in medicinal chemistry because of their wide variety of biological and pharmacological applications [1, 2]. It is a fused heterocycle, containing a benzene ring attached with one face of the imidazole ring. It is the key structure in numerous compounds of therapeutic importance. Benzimidazole derivatives have been reported to have various bioactivities, including antiviral [3‐6], antihypertensive [7], antimicrobial [8,9], antioxidant [10], anti‐inflammatory [11] and anticancer [12–20] activities. There are several marketed benzimidazole based drugs, such as Astemizole (Janssen Pharmaceutica), Micardis (Boehringer Ingelheim), Omepraxole (Astra Zeneca) and Albendazole (Glaxo‐ SmithKline) [3].In particular, benzimidazole derivatives have been explored as anticancer inhibitors of Topoisomerase I [12], PARP‐1 [13,14], kinase Chk2 [15,16], Pgp and DNA synthesis [17], and tyrosine kinases [18‐20]. Nonetheless, to the best of our knowledge, although several benzimidazole series have been developed as tyrosine kinase inhibitors, the 2‐aryl benzimidazole series have not been explored as multi‐target EGFR, VEGFR‐2 and PDGFR inhibitors in published reports. Therefore we designed and synthesized the benzimidazole compounds. Their antimicrobial activities were evaluated, the main purpose of these compounds were to discover possible newantimicrobials. 2. Experimental 2.1. Materials and methods All solvents were dried and distilled according to standard methods before use. NMR spectra were recorded on a BRUKER‐ AV400 spectrometer in CDCl3 and tetramethylsilane (TMS; δ = 0.00 ppm) served as internal standards for 1H NMR. IR spectra were measured using a JASCO FT/IR‐4100 spectrophotometer. Mass spectra were measured with Micromass Q‐Tof (ESI). Column chromatography was conducted on Silica gel 60‐120 mesh (Merck) and thin‐layer chromatography was carried out using SILICA GEL GF‐254. The melting points (uncorrected) were measured on a SALACO apparatus. 2.2. Synthesis 2.2.1. General procedure for the synthesis of 1'‐benzyl‐1,4'‐ dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenzimidazole derivatives (9) The compound 7, 1,7'‐dimethyl‐2'‐propyl‐1H,3'H‐2,5'‐ dibenzimidazole have been synthesized as per the procedure given in the reference [21]. The compound 1,7'‐dimethyl‐2'‐ propyl‐1H,3'H‐2,5'‐dibenzimidazole (1.0eq, 0.29g, 0.98mmol), substituted benzyl chloride (0.98mmol) and potassium carbonate (2.9mmol) in 15 mL of isopropyl alcohol was stirred with reflux for 4 hours. Completion of the reaction was monitored by TLC, finally the reaction mixture was distilled completely, then added water and extracted with dichloromethane, the dichloromethane was distilled completely to get crude product, which was purified by column chromatography using ethyl acetate and hexane as eluent, obtained the pure product with good yield (Scheme 1). 1'‐Benzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenzimida‐ zole (9a): Color: Light brown. Yield: 82% (0.22 g). M.p.: 102‐ 104 OC. FT‐IR (KBr, cm‐1): 1511 (aromatic CN stretch.), 1450 (aromatic CC stretch.), 2900 (alkane CH stretch), 3030 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.08‐ 1.12 (t, 3H, CH3), 1.65‐1.72 (m, 2H, CH2), 1.92 (s, 3H, ArCH3), 2.76‐2.81 (q, 2H, CH2), 3.95 (s, 3H, NCH3), 5.46 (s, 2H, ArCH2), 364 Ravishankara and Chandrashekara / European Journal of Chemistry 3 (3) (2012) 363‐366 Scheme 1 6.90‐7.25 (m, 7H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.73 (s, 1H, Ar). Anal. calcd. for C26H26N4: C, 79.16; H, 6.64; N, 14.20. Found: C, 79.09; H, 6.59; N, 14.16 %. MS (ESI, m/z): 395.70 (M+1). 1'‐3‐methylbenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐ dibenzimidazole (9b): Color: Brown. Yield: 77% (0.17 g). M.p.: 122‐124 OC. FT‐IR (KBr, cm‐1): 1495 (aromatic CN stretch.), 1445 (aromatic CC stretch.), 2855 (alkane CH stretch.), 3045 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 0.93‐ 1.11 (t, 3H, CH3), 1.62‐1.70 (m, 2H, CH2), 1.91 (s, 3H, ArCH3), 2.33 (s, 3H, ArCH3), 2.81‐2.86 (q, 2H, CH2), 3.96 (s, 3H, NCH3), 5.48 (s, 2H, ArCH2), 6.99‐7.29 (m, 7H, ArH), 7.68 (d, J = 8 Hz, 2H, ArH), 7.75(s, 1H, Ar). Anal. calcd. for C27H28N4: C, 79.38; H, 6.91; N, 13.71. Found: C, 79.31; H, 6.90; N, 13.68%. MS (ESI, m/z): 409.5 (M+1). 1'‐3‐Chlorobenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenz‐ imidazole (9c): Color: Light brown. Yield: 66% (0.16 g). M.p.: 92‐94 OC. FT‐IR (KBr, cm‐1): 750 (CCl stretch.), 1510 (aromatic CN stretch.), 1500 (aromatic CC stretch.), 3000 (alkane CH stretch.), 3137 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 0.96‐1.11 (t, 3H, CH3), 1.62‐1.73 (m, 2H, CH2), 1.93 (s, 3H, ArCH3), 2.71‐2.79 (q, 2H, CH2), 3.92 (s, 3H, NCH3), 5.45 (s, 2H, ArCH2), 7.28‐7.45 (m, 4H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.60‐7.68 (d, J = 8.2 Hz, 2H, ArH), 7.67‐7.72 (d, J = 8.2, 2H, ArH), 7.73 (s, 1H, Ar). Anal. calcd. for C26H25ClN4: C, 72.80; H, 5.87; N, 13.06. Found: C, 72.59; H, 5.70; N, 12.87%. MS (ESI, m/z): 429.82 (M+1). 1'‐4‐Fluorobenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenz‐ imidazole (9d): Color: Orange. Yield: 72% (0.19 g). M.p.: 111‐ 114 OC. FT‐IR (KBr, cm‐1): 1497 (aromatic CN stretch.), 1200 (CF stretch.), 1447 (aromatic CC stretch.), 2887 (alkane CH stretch.), 3107 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.08‐1.12 (t, 3H, CH3), 1.65‐1.72 (m, 2H, CH2), 1.92 (s, 3H, ArCH3), 2.76‐2.81 (q, 2H, CH2), 3.95 (s, 3H, NCH3), 5.46 (s, 2H, ArCH2), 6.90‐7.25 (m, 7H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.73 (s, 1H, Ar). Anal. calcd. for C26H25FN4: C, 75.70; H, 6.11; N, 13.58. Found: C, 75.62; H, 6.05; N, 13.49%. MS (ESI, m/z): 413.9 (M+1). 1'‐3,4‐Difluorobenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐ dibenzimidazole (9e): Color: Light brown. Yield: 86% (0.22 g). M.p.: 127‐130 OC. FT‐IR (KBr, cm‐1): 1510 (aromatic CN stretch.), 1225 (CF stretch.), 1501 (aromatic CC stretch.), 3006 (alkane CH stretch.), 2999 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.11‐1.13 (t, 3H, CH3), 1.68‐1.73 (m, 2H, CH2), 1.93 (s, 3H, ArCH3), 2.75‐2.80 (q, 2H, CH2), 3.95 (s, 3H, NCH3), 5.45 (s, 2H, ArCH2), 7.01‐7.62 (m, 9H, ArH). Anal. calcd. for C26H24F2N4: C, 72.54; H, 5.62; N, 13.01. Found: C, 72.49; H, 5.59; N, 12.88%. MS (ESI, m/z): 431.49 (M+1). Ravishankara and Chandrashekara / European Journal of Chemistry 3 (3) (2012) 363‐366 365 Table 1. Antimicrobial studies of compounds 9a‐j. Compound Zone of Inhibition (mm)* Escherichia coli Bacillus subtilis 400 µg 800 µg 400 µg 800 µg 9a 11 19 13 19 9b 11 16 ‐ 10 9c ‐ 9 ‐ 9 9d ‐ 9 ‐ ‐ 9e ‐ 10 ‐ 11 9f 9 13 ‐ 12 9g 13 18 10 16 9h 12 23 15 21 9i 13 18 13 19 9j 9 10 ‐ ‐ Ampicillin 30 32 ‐ 31 *: Inhibition zones including cup borer (8.5 mm) diameter; Positive control zone is 30 to 35 mm in 200 µg; ‘‐‘ = Not active. 1'‐3‐Nitrobenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenz‐ imidazole (9f): Color: Yellow. Yield: 77% (0.20 g). M.p.: 87‐89 OC. FT‐IR (KBr, cm‐1): 1492 (aromatic CN stretch.), 1150 (CO stretch.), 1385 (NO stretch.), 1456 (aromatic CC stretch.), 3030 (alkane CH stretch.), 3107 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.12‐1.16 (t, 3H, CH3), 1.63‐1.68 (m, 2H, CH2), 1.93 (s, 3H, ArCH3), 2.77‐2.82 (q, 2H, CH2), 3.95 (s, 3H, NCH3), 5.46 (s, 2H, ArCH2), 6.89‐7.23 (m, 7H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.74 (s, 1H, ArH). Anal. calcd. for C26H25N5O2: C, 71.05; H, 5.73; N, 15.93. Found: C, 70.93; H, 5.69; N, 15.87%. MS (ESI, m/z): 440.32 (M+1). 1'‐4‐Chlorobenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenz‐ imidazole (9g): Color: Brown red. Yield: 79% (0.26 g). M.p.: 118‐120 OC. FT‐IR (KBr, cm‐1): 745 (CCl stretch.), 1520 (aromatic CN stretch.), 1555 (aromatic CC stretch.), 2999 (alkane CH stretch.), 3122 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.09‐1.13 (t, 3H, CH3), 1.64‐1.72 (m, 2H, CH2), 1.94 (s, 3H, ArCH3), 2.76‐2.80 (q, 2H, CH2), 3.95 (s, 3H, NCH3), 5.46 (s, 2H, ArCH2), 6.98‐7.25 (m, 4H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.72 (d, J = 8 Hz, 2H, Ar), 7.74 (s, 1H, Ar), 7.78 (s, 1H, Ar). Anal. calcd. for C26H25ClN4: C, 72.80; H, 5.87; N, 13.06. Found: C, 72.79; H, 5.81; N, 12.90%. MS (ESI, m/z): 429.95 (M+1). 1'‐3‐Methoxybenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐ dibenzimidazole (9h): Color: Orange. Yield: 69% (0.15 g). M.p.: 137‐139 OC. FT‐IR (KBr, cm‐1): 755 (CCl stretch.), 1490 (aromatic CN stretch.), 1550 (aromatic CC stretch.), 2987 (alkane CH stretch.), 3100 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.08‐1.12 (t, 3H, CH3), 1.64‐1.68 (m, 2H, CH2), 1.93 (s, 3H, ArCH3), 2.74‐2.83 (q, 2H, CH2), 3.83 (s, 3H, OCH3), 3.94 (s, 3H, NCH3), 5.45 (s, 2H, ArCH2), 6.89‐7.23 (m, 7H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.74 (s, 1H, ArH). Anal. calcd. For C27H28N4O: C, 76.39; H, 6.65;N, 13.20. Found: C, 76.28; H, 6.60; N, 13.11%. MS (ESI, m/z): 425.37 (M+1). 1'‐3,4‐Dichlorobenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐ dibenzimidazole (9i):Color: Yellow. Yield: 75% (0.19 g). M.p.: 120‐122 OC. FT‐IR (KBr, cm‐1): 799 (CCl stretch.), 1492 (aromatic CN stretch.), 1399 (aromatic CC stretch.), 2899 (alkane CH stretch.), 3037 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.08‐1.12 (t, 3H, CH3), 1.67‐1.73 (m, 2H, CH2), 1.89 (s, 3H, ArCH3), 2.74‐2.76 (q, 2H, CH2), 3.93 (s, 3H, NCH3), 5.44 (s, 2H, ArCH2), 7.01‐7.64 (m, 9H, ArH). Anal. calcd. for C26H24Cl2N4: C, 67.39; H, 5.22; N, 12.09. Found: C, 67.31; H, 5.21; N, 11.98%. MS (ESI, m/z): 464.48 (M+1). 1'‐3‐Fluorobenzyl‐1,4'‐dimethyl‐2'propyl‐1H,1'H‐2,6'‐dibenz‐ imidazole(9j): Color: Orange. Yield: 72% (0.28 g).M.p.: 108‐110 OC. FT‐IR (KBr, cm‐1): 1515 (aromatic CN stretch.), 1400 (CF stretch.), 1555 (aromatic CC stretch.), 2899 (alkane CH stretch.), 3128 (aromatic CH stretch.). 1H NMR (400 MHz, CDCl3, δ, ppm): 1.99‐1.12 (t, 3H, CH3), 1.67‐1.74 (m, 2H, CH2), 1.94 (s, 3H, ArCH3), 2.72‐2.78 (q, 2H, CH2), 3.93 (s, 3H, NCH3), 5.44 (s, 2H, ArCH2), 7.28‐7.45 (m, 4H, ArH), 7.59 (d, J = 8 Hz, 2H, ArH), 7.60‐7.68 (d, J = 8.2 Hz, 2H, ArH), 7.73(s, 1H, Ar). Anal. calcd. for C26H25FN4: C, 75.70; H, 6.11; N, 13.58. Found: C, 75.61; H, 6.07; N, 13.49%. MS (ESI, m/z): 413.50 (M+1). 2.3. Biological evaluation 2.3.1. Antibacterial Activity The screening of the compounds 9a‐jfor antibacterial action is performed by Well diffusion method [22] with modification in concentration of prepared compounds. The synthesized compounds were tested against one strain of gram +ve bacteria (Bacillus subtilis), and gram–ve bacteria (Escherichia coli). 25 mL of nutrient agar medium was poured into petri plate and after cooling; agar plates were swabbed with 100 µL of bacterial suspension containing 106 cells/mL. Wells were made in the seeded plates with the help of a cup‐ borer (8.5 mm) and 20 µL, 40 µL (10 mg/1mL) of each test compound dissolved in DMSO was loaded into the wells. Ampicillin and DMSO as positive control and negative control respectively were used as for all the test compounds. 3. Results and discussion We have synthesized a series of 1'‐benzyl‐1,4'‐dimethyl‐ 2'propyl‐1H,1'H‐2,6'‐dibenzimidazole derivatives by using a known procedure and obtained products with good yield. The structures of all the synthesized compounds were characterized by spectroscopic data, and subjected these molecules for study of antibacterial activities (Table 1). Benzimidazole derivatives have shown very good antibacterial activities, we compared the synthesized new benzimidazole derivatives with the ampicillin which is a known antibacterial drug [22]. In the present study compound 9h shows good bacterial activity, in which the methoxy group is attached, which is electron releasing group, The compound 9a shows a next highest antibacterial activity, none of electron withdrawing and electron releasing group is attached. The remaining molecules showed moderate antibacterial activity. 4. Conclusion We have synthesized 1'‐benzyl‐1,4'‐dimethyl‐2'propyl‐ 1H,1'H‐2,6'‐dibenzimidazole derivatives and structure propo‐ sed to the synthesized compound is well supported by spectroscopic data. From the data of antibacterial activity, it may be concluded that all the synthesized compounds showed good to moderate activity. 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