Organic Chemistry: Current Research

Organic Chemistry: Current Research
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Research Article - (2016) Volume 5, Issue 1

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Synthesis and Antimicrobial Activity of New Synthesized Benzimidazole Derivatives and their Acyclic Nucleoside Analogues

Hamada H Amer1,2*, SM El-Kousy3, WM Salama3 and A H-H Sheleby2
1Chemistry Department, Faculty of Medical and Applied Science, Turabbah Campus, Taif University, Saudi Arabia
2Faculty of Veterinary Medicine, Sadat City University, Sadat City, Menoufia, Egypt
3Chemistry Department, Faculty of Science, El-Menoufia University, Egypt
*Corresponding Author: Hamada H Amer, Assistant Professor, Chemistry Department, Faculty of Medical and Applied Science, Taif University, Saudi Arabia, Tel: 00966537348857 Email:

Abstract

New benzimidazole derivatives and their N-substituted acyclic nucleoside analogues were prepared. The synthesized compounds were tested for their antimicrobial activity against Escherichia coli, Staphylococcus aureus, Micrococcus, Salmonella typhi and Salmonella para typhi. The synthesized compounds were tested also against fungi species such as Aspergillus flavus, Aspergillus fumigates, Aspergillus ochraceus and Candida albicans. Most of tested compounds exhibited moderate to high antimicrobial activity while few compounds were found to exhibit little or no activity against the tested microorganisms.

Keywords: Benzimidazole derivatives; Sugar hydrazones; Acyclic nucleosides; Antimicrobial activity

Introduction

Imidazoles are common scaffolds in highly significant biomolecules, including biotin, the essential amino acid histidine, histamine, the pilocarpine alkaloids [1] and other alkaloids, which have been shown to exhibit interesting biological activities such as antimicrobial, anticryptococcal, inhibition of nitric oxide synthase and cytotoxic activities [2]. Imidazole derivatives have also been found to possess many pharmacological properties and are widely implicated in biochemical processes. Members of this class of diazoles are known to possess NO synthase inhibition [3], antibiotic [4], antifungal [5-8] and neuropeptide Y antagonistic activities [9]. In addition, these heterocycles include several inhibitors of p38 MAP kinases [10-13] which are thought to be involved in a variety of inflammatory and immunological disorders, and some derivatives such as mitronidazole, etomidate and ketoconazole which have found application in drug therapy [14]. Recently certain imidazole based compounds were reported to possess antimicrobial activities [15]. Further recent literature revealed that N1-substitution of imidazoles improves the antibacterial activity [16]. Among the five membered nitrogen heterocycles, the 1,3,4-oxadiazoles are associated with broad spectrum of biological activities [17-19]. Their derivatives have been known to possess antibacterial [20], antimicrobial [21], insecticidal [22], herbicidal, fungicidal [23], anti-inflammatory [24], hypoglycemic [25] characteristics, antiviral [26], and anti-tumour activities [27]. On the other hand, the acyclic C-nucleoside analogues possess a wide range of biological properties, including antibiotic, antiviral, and anti-tumour activities [28-37]. Consequently, newly synthesized compounds containing imidazole and 1,3,4-oxadiazole moieties as well as their substituted sugar derivatives will be expected of enhanced biological activities. Owing to the above facts and our interest in the attachment of carbohydrate residues to newly synthesized heterocycles [38-40] searching for potent leads as antimicrobial agents, our aim is the synthesis and antimicrobial evaluation of new substituted 5-nitroimidazol and their acyclic nucleoside analogues.

Experimental

Melting points were determined with a Kofler block apparatus and are uncorrected. The IR spectra were recorded on a Perkin-Elmer model 1720 FTIR spectrometer for KBr discs. NMR spectra were recorded on a Varian Gemini 200 NMR Spectrometer at 300 MHz for 1H NMR with TMS as a standard. The progress of the reactions was monitored by TLC using aluminum silica gel plates 60 F 245. Elemental analyses were performed at the Microanalytical data centre at Faculty of science, Cairo University, Egypt.

1-Ethoxycarbonylmethyl-2-methylbenzimidazole (172)

Ethylcholoroacetate (1.4 g, 0.01 mol) was added to a solution of 2-methylbenzimidazol (171) (1.32 g, 0.01 mol) in dry acetone (30 ml) and anh. Potassium carbonate (1.38 g, 0.01 mol). The reaction mixture was heated under reflux for 5 h, poured on crushed-ice, filtered off, and recrystallized from ethanol to give 172 as a white needles (1.82 g, 83%); m.p.=115-117°C. IR spectrum (KBr), ν, cm-1: 1730 (C=O), 1455 (CH2), 1375 (CH3). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 1.32 (t, 3H, J=5.6 Hz, CH3CH2), 1.87(s,3H, CH3), 4.20 (q, 2H, J=5.6 Hz, CH3CH2), 5.08 (s, 2H, NCH2), 7.12- 8.14(m, 4H, Ar-H). Mass spectrum, m/z (I, %): 218[M+] (20).

1-(2-Methylbenzimidazol-1-yl) acetic acid hydrazide (173)

A solution of the respective ester 172 (2.18 g, 0.01 mol) in absolute ethanol (30 ml) and hydrazine hydrate (1.5 g, 0.03 mol) was refluxed for 3 h. The solvent was removed under reduced pressure and the remaining precipitate was collected, dried, and recrystallized from ethanol to afford 173 as a pale yellow powder (1.7 g, 83%); m.p.=88- 90°C. IR spectrum (KBr), ν, cm-1: 1637 (C=O), 3351 (NH), 3567 (NH2). Mass spectrum, m/z (I, %): 204 [M+] (100).

General procedure for the synthesis of Sugar (2-methylbenzimidazol-1-yl)acetylhydrazones 178-181

Hydrazide 173 (0.65 g, 0.032 mol) in ethanol (10 ml) was added to a stirred solution of the respective monosaccharide (0. 032 mol) in water (1 ml) and glacial acetic acid (1 ml). The mixture was heated under reflux, the excess of ethanol was removed under reduced pressure and the residue was triturated with (10 ml) diethyl ether to produce compounds as brown viscous material to afford the corresponding sugar hydrazones 178-181.

L-(-)-Arabinose(2-methylbenzimidazol-1-yl acetylhydrazone (178)

Pale brown gum (0.75 g, 70%); IR spectrum (KBr), ν, cm-1: 3350 (OH), 3469 (NH). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):1.00 (s,1H, CH3), 3.25-3.74 (m, 5H, H-2′, H-3′, H-4′, H-5′, H-5′′), 4.45(brs, 2H, 2xOH), 4.60 (s, 2H, CH2), 4.96 (brs, 2H, 2xOH), 7.09(d, 1H, J=2.5 Hz, H-1′), 7.12-7.45 (m, 4H, Ar-H), 9.63 (brs, 1H, NH).

D-(+)-Xylose(2-methylbenzimidazol-1-yl)acetylhydrazone (179)

Pale brown gum (0.82 g, 76%); IR spectrum (KBr), ν, cm-1: 3373 (OH), 3426 (NH). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.96 (s,1H, CH3), 3.21-3.70 (m, 5H, H-2′, H-3′, H-4′, H-5′, H-5′′), 4.43(bs, 2H, 2xOH), 4.65 (s, 2H, CH2), 5.22 (bs, 2H, 2xOH), 7.09(d, 1H, J=2.5 Hz, H-1′), 7.12-7.45 (m, 4H, Ar-H), 9.63 (brs, 1H, NH).

D-(+)-Galactose(2-methylbenzimidazol-1-yl acetylhydrazone (180)

Pale brown gum (0.95 g, 81%); IR spectrum (KBr), ν, cm-1: 3295(OH), 3402 (NH). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):1.00 (s,3H, CH3), 3.24-3.85 (m, 5H, H-3′, H-4′, H-5′, H-6′, H-6′′), 4.19 (m, 1H, H-2′), 4.42 (bs, 1H, OH), 4.55 (bs, 2H, 2xOH), 4.62 (s, 2H, CH2), 5.00 (bs, 2H, 2xOH), 7.11(d, 1H, J=2.5 Hz, H-1′), 7.38-7.94 (m,4H, Ar-H), 8.88(brs,1H,NH). Mass spectrum, m/z (I, %): 366[M+] (100).

D-(+)-Mannose(2-methylbenzimidazol-1-yl)acetylhydrazone (181)

Pale brown gum (0.85 g, 72%); IR spectrum (KBr), ν, cm-1: 3295(OH), 3402 (NH). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):1.00 (s,3H, CH3), 3.20-3.65 (m, 5H, H-3′, H-4′, H-5′, H-6′, H-6′′), 4.19 (m, 1H, H-2′), 4.44 (bs, 1H, OH), 4.55 (bs, 2H, 2xOH), 4.65 (s, 2H, CH2), 5.00 (bs, 2H, 2xOH), 7.11(d, 1H, J=2.5 Hz, H-1′), 7.38- 7.94 (m,4H, Ar-H), 9.00(brs,1H,NH).

General procedure for the synthesis of sugar of tetra-O-acetyl- and penta-O-acetyl(2-methylbenzimidazol-1-yl)acetylhydrazones 183-187

Acetic anhydride (3.06 g, 0.03 mol) was added to a solution of sugar hydrazones 178-181 (0.001 mol) in pyridine (7 ml) with stirring at room temperature for overnight. The mixture was cooled and poured on crushed ice. Hydrochloric acid was added with stirring until the odor of pyridine was removed and extracted by chloroform. The product was separated in pure form as brown viscous material to afford 182-185.

2,3,4,5-Tetra-O-acetyl-L-(-)-arabinose(2-methylbenzimidazol- 1-yl)acetylhydrazone (182)

Pale yellow gum (0.54 g, 60%); 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.87 (s,3H, CH3), 1.99, 2.01, 2.10, 2.49 (4s, 12H, 4xCH3CO), 3.40,3.41 (2m, 2H, H-5′, H-5′′), 4.23 (m, 1H, H-4′), 4.60 (s, 2H, CH2), 4.97 (m, 1H, H-3′), 5.73 (m, 1H, H-2′), 7.26 (d, 1H, J=2.5 Hz, H-1′), 7.38-7.94 (m,4H, Ar-H), 9.43(brs,1H,NH).

2,3,4,5-Tetra-O-acetyl-D-(+)-xylose(2-methylbenzimidazol-1-yl)acetylhydrazone (183)

Pale yellow gum (0.50 g, 66%), m.p.=>300°C. NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.87 (s,3H, CH3), 1.99, 2.01, 2.10, 2.49 (4s, 12H, 4xCH3CO), 3.40,3.41 (2m, 2H, H-5′, H-5′′), 4.23 (m, 1H, H-4′), 4.60 (s, 2H, CH2), 4.97 (m, 1H, H-3′), 5.73 (m, 1H, H-2′), 7.26 (d, 1H, J=2.5 Hz, H-1′), 7.38-7.94 (m,4H, Ar-H), 9.43(brs,1H,NH).

2,3,4,5,6-Penta-O-acetyl-D-(+)-galactose(2-methylbenzimidazol- 1-yl)acetylhydrazone (184)

Pale brown gum (0.53 g, 67%); 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.89(s,3H, CH3), 1.98, 2.02, 2.04, 2.07, 2.48 (5s, 15H, 5xCH3CO), 3.40,3.42 (2m, 2H, H-6′,H-6′′), 4.12 (m, 1H, H-5′), 4.14(s, 2H, CH2), 5.00 (m, 1H, H-4′), 5.30 (m, 1H, H-3′), 5.49 (m, 1H, H-2′), 7.27 (d, 1H, J=2.5 Hz, H-1′),7.68-7.69 (m, 4H, Ar-H), 9.43 (brs, 1H, NH).

2,3,4,5,6-Penta-O-acetyl-D-(+)-mannose(2-methylbenzimidazol- 1-yl)acetylhydrazone (185)

Pale brown gum (0.60 g, 77%); 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.91(s,3H, CH3), 1.99, 2.00, 2.04, 2.10, 2.48 (5s, 15H, 5xCH3CO), 3.40,3.42 (2m, 2H, H-6′,H-6′′), 4.10 (m, 1H, H-5′), 4.52(s, 2H, CH2), 5.07 (m, 1H, H-4′), 5.30 (m, 1H, H-3′), 5.49 (m, 1H, H-2′), 7.32 (d, 1H, J=2.5 Hz, H-1′),7.55-7.66 (m, 4H, Ar-H), 9.33 (brs, 1H, NH).

General procedure for the synthesis of 4-acetyl-5-(tetra-and penta-O-acetylalditolyl)-2-(2-methylbenzimidazol-1-yl)-1, 3, 4-oxadiazolines 186- 189

A solution of sugar hydrazones 178-181 (0. 01 mol) in acetic anhydride (5 ml) was heated at 100°C for 5 h. The resulting solution was poured onto crushed-ice and the product that separated out was filtered off, washed with a saturated solution of sodium bicarbonate followed by water, and then dried. The products were recrystallized from ethanol to give 186-189.

4-Acetyl-5-(1,2,3,4-tetra-O-acetyl-L-arabinotetritolyl)-2-(2- methylbenzimidazol-1-yl)-1,3,4-oxadiazoline (186)

Pale yellow gum (0.53 g, 65%); IR spectrum (KBr), ν, cm-1: 1741 (COCH3),1650(C=N). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.89(s,3H, CH3), 1.83, 1.90, 2.01, 2.10, 2.48 (5s, 15H, 5xCH3CO), 3.85 (s, 2H, CH2), 4.01, 4.09 (2m, 2H, H-4′,H-4′′), 4.97 (m, 1H, H-3′), 5.18 (m, 1H, H-2′), 5.40 (dd, 1H, J=3.2, 6.2 Hz, H-1′),5.89 (d, 1H, J=8.8 Hz, oxadiazoline H-5), 7.68-7.69 (m, 4H, Ar-H).

4-Acetyl-5-(1,2,3,4-tetra-O-acetyl-D-xylotetritolyl)-2-(2-methylbenzimidazol- 1-yl)-1,3,4-oxadiazoline (187)

Pale yellow gum (0.45 g, 55%); IR spectrum (KBr), ν, cm-1: 1738 (COCH3), 1650 (C=N). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.89(s,3H, CH3), 1.91, 1.95, 1.97, 1.98, 2.11 (5s, 15H, 5xCH3CO), 3.89 (s, 2H, CH2), 4.00, 4.12 (2m, 2H, H-4′,H-4′′), 5.07 (m, 1H, H-3′), 5.22 (m, 1H, H-2′), 5.47 (dd, 1H, J=3.2, 6.2 Hz, H-1′),5.89 (d, 1H, J=8.8 Hz, oxadiazoline H-5), 7.68-7.69 (m, 4H, Ar-H).

4-Acetyl-5-(1,2,3,4,5-penta-O-acetyl-D-galactopentitolyl)-2- (2-methylbenzimidazol-1-yl)-1,3,4-oxadiazoline (188)

Pale yellow gum (0.62 g, 73%); IR spectrum (KBr), ν, cm-1: 1738 (COCH3), 1674 (C=N). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.89(s,3H, CH3), 1.90, 1.91, 1.95, 1.97, 1.98, 2.11 (6s,18H,6xCH3CO), 3.89 (s, 2H, CH2), 4.05, 4.12 (2m,2H,H-5′,H-5′′), 4.98 (m,1H,H-4′), 5.23 (m, 1H, H-3′), 5.33 (m,1H,H-2′), 5.43 (dd,1H, J=3.2, 6.2 Hz,H-1′),5.89 (d, 1H, J=8.8 Hz,oxadiazoline H-6), 7.68-7.69 (m, 4H, Ar-H).

4-Acetyl-5-(1,2,3,4,5-penta-O-acetyl-D-mannopentitolyl)-2- (2-methylbenzimidazol-1-yl)-1,3,4-oxadiazoline (189)

Pale yellow gum (0.58 g, 69%); IR spectrum (KBr), ν, cm-1: 1742(COCH3), 1679 (C=N). 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz): 0.89(s,3H, CH3), 1.90, 1.91, 1.95, 2.03, 2.10, 2.13 (6s, 18H, 6xCH3CO), 3.95 (s, 2H, CH2), 4. 0.89(s,3H, CH3), 11, 4.17 (2m, 2H, H-5′,H-5′′), 4.92 (m, 1H, H-4′), 5.19 (m, 1H, H-3′), 5.31 (m, 1H, H-2′), 5.43 (dd, 1H, J=3.2, 6.2 Hz, H-1′),5.89 (d, 1H, J=8.8 Hz, oxadiazoline H-6), 7.68-7.69 (m, 4H, Ar-H).

2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazole-2- thiol (194)

To a solution of (173) (4.8 g, 0.02 mole) in ethanol (50 mL) was added a solution of potassium hydroxide (1.12 g, 0.02 mole) in water (2 mL) and carbon disulphide (5 mL). The solution was heated under reflux for 15 h. The solvent was evaporated and the residue was dissolved in water, filtered, and acidified with dilute hydrochloric acid. The precipitate was filtered off, washed with water and recrystallized from ethanol. Yield 80%; mp=200-202°C; IR (KBr): ν 3415 (NH), 1622 cm-1 (C=N). 1H NMR (DMSO-d6, 300 MHz): δ1.00 (s,1H, CH3), 4.58 (s, 2H, CH2), 7.97-8.22 (m, 4H, Ar-H), 12.80 (s, 1H, SH). m/z=246 [M+].

2-(Methylthio)-2-[(2-methylbenzimidazol-1-yl)methyl]- 1,3,4-oxadiazole (195)

To a solution of (194) (2.46 g, 0.01 mole) and potassium hydroxide (0.56 g, 0.01 mole) in a mixture of water (25 mL) and ethanole (10 mL), was added the methyl iodide (0.01 mole). The solution was stirred at room temperature for 4 h. The resulting precipitate was filtered off and crystallized from ethanol to give 195. Yield 71%; mp=87-89°C; IR (KBr): ν 1622 cm-1 (C=N). 1H NMR (DMSO-d6, 300 MHz): δ 0.9(s, 3H, CH3), 2.65 (s, 1H, SCH3), 5.55 (s, 2H, CH2), 7.98-8.22(m, 4H, Ar-H).

2-Hydrazinyl-2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4- oxadiazole (196)

A mixture of (195) (0.01 mole) EtOH (8 mL), and N2H4.H2O (1 g, 0.02 mole) was refluxed for 4 h and the solvent was removed under reduced pressure. The remaining precipitate was collected, dried, and recrystallized from EtOH to afford compound 196. Yield 74%; m.p.=174-176°C; IR (KBr): ν 1620 cm-1 (C=N). 1H NMR (DMSO-d6, 300 MHz): δ1.00(s,3H, CH3), 5.58 (s, 2H, CH2), 5.80 (s, 2H, NH2), 7.95- 8.22(m, 4H, Ar-H),9.45(brs, 1H, NH).

General procedures for the reaction of (196) with aromatic aldehydes to afford Schiff′s bases 200-202

A solution of 196 (2.44 g, 0.01 mol), an aromatic aldehyde (0.01 mol) in abs. ethanol (30 ml) and glacial acetic acid (1 ml) was refluxed for 4-6 h (TLC). The solvent was evaporated under reduced pressure and the residue was filtered off and recrystallized from ethanol to afford 200-202.

N′-(Benzylidene)-2-[(2-methylimbenzimidazol-1-yl)methyl] -1,3,4-oxadiazole (200).

yellow powder (2.78 g, 83%); m.p.=270-272°C. 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):0.94(s,3H, CH3), 4.51 (s, 2H, CH2), 7.80 (s, 1H, CH), 7.86-8.01 (m, 8H, Ar-H), 9.93 (brs, 1H, NH).

N′-(4-Chlorobenzylidene)-2-[(2-methylimbenzimidazol- 1-yl)methyl]-1,3,4-oxadiazole (201)

White powder (3.24 g, 88%); m.p.=145-147°C. 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):0.94(s, 3H, CH3), 4.55 (s, 2H, CH2), 8.00 (s, 1H, CH), 8.42-8.64 (m, 8H, Ar-H), 9.93 (brs, 1H, NH). Mass spectrum, m/z (I, %): 366 [M+] (60).

N′-[5-(Methylfuran-2-yl)methylene]-2-[(2-methylimbenzimidazol- 1-yl)methyl]-1,3,4-oxadiazole (201).

White powder (3.10 g, 92%); m.p.=299-300°C. 1H NMR spectrum (300 MHz, DMSO-d6), δ, ppm (J, Hz):0.95(s,3H, CH3), 2.32 (s, 3H, CH3), 4.65 (s, 2H, CH2), 6.24 (s, 1H, H-4-furan), 6.79 (s, 1H, H-3- furan), 7.22-7.55 (m, 4H, Ar-H), 8.22 (s, 2H, CH=N,),9.96 (brs, 1H, NH). Mass spectrum, m/z (I, %): 336 [M+] (23).

General procedure for the synthesis of sugar hydrazinyl derivatives 205,206

To a well stirred solution of the respective monosaccharides (xylose and galactose) (0.01 mole) in water (2 mL), and glacial acetic acid (0.2 mL) was added to 196 (2.44 g, 0.01 mole) in ethanol (10 mL). The mixture was heated under reflux for 3 h, the resulting solution was concentrated and left to cool. The precipitate formed was filtered off, washed with water and ethanol, then dried and recrystallized from ethanol.

2-D-Xylotetritolylidenehydrazinyl)-2-((2-methylbenzimidazol- 1-yl)methyl)-1,3,4-oxadiazole (205)

Yield 80%; mp=194-196°C; IR (KBr): ν 3445 (OH), 3346 (NH) 1612 cm-1 (C=N). 1H NMR (DMSO-d6, 300 MHz): δ1.05(s,3H, CH3), 3.69 (m, 2H, H-5′, H-5′′), 4.18 (m, 1H, H-4′), 4.37 (dd, 1H, J=2.8 Hz, J=5.8 Hz, H-3′), 4.44 (t, 1H, J=5.8 Hz, H-2′),4.61 (m, 1H, OH), 4.75 (d, 1H, J=6.3 Hz, OH), 4.90 (m, 1H, OH), 4.98 (t, 1H, J=4.5 Hz, OH), 4.97 (s, 2H, CH2), 7.45-7.86(m,4H,Ar-H) 8.10 (d, 1H, H-1′), 11.18 (s, 1H, NH).

2-[2-D-Galactopentitolylidenehydrazinyl)-2-((2-methylbenzimidazol- 1-yl)methyl)-1,3,4-oxadiazole (206)

Yield 82%; mp=182-184°C; IR (KBr): ν 3448 (OH), 3382 (NH), 1612 cm-1 (C=N). 1H NMR (DMSO-d6, 300 MHz): δ 1.05(s,3H, CH3), 3.48 (m, 2H, H-6′, H-6′′), 3.52 (m, 1H, H-5′), 4.18 (m, 1H, H-4′), 4.36 (dd, 1H, J=2.8 Hz, J=5.8 Hz, H-3′), 4.42 (t, 1H, J=5.8 Hz, H-2′), 4.58 (s, 2H, CH2), 4.61 (m, 1H, OH), 4.74 (d, 1H, J=6.3 Hz, OH), 4.91 (m, 1H, OH), 4.97 (t, 1H, J=4.5 Hz, OH), 5.37 (t, 1H, J=4.5 Hz, OH), 7.45-7.86(m,4H,Ar-H), 8.44 (d, 1H, H-1′), 11.14 (s, 1H, NH).

General procedure for the synthesis of per-O-acetyl-sugar hydrazinyl derivatives 209,210

To a solution of compounds 205,206 (0.001 mole) in pyridine (7 mL) was added to acetic anhydride (1.02 g, 0.01 mol). The mixture was stirred at room temperature for 5 h. The resulting solution was poured onto crushed ice, and the product that separated out was filtered off, washed with a solution of sodium hydrogen carbonate followed by water and then dried. The products were recrystallized from ethanol.

2-[2-(2,3,4,5-Tetra-O-acetyl-D-xylotetritolylidene)hydrazinyl]- 2-[(2- methylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazole (209)

Yield 72%; mp=174-176°C; IR (KBr): ν 1740 (C=O), 3282 (NH), 1614 cm-1 (C=N).

2-[2-(2,3,4,5,6-Penta-O-acetyl-D-galactopentitolylidene) hydrazinyl]-2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4- oxadiazole (210)

Yield 78%; mp=188-190°C; IR (KBr): ν 1740 (C=O), 3282 (NH), 1614 cm-1 (C=N). 1H NMR (DMSO-d6, 300 MHz): δ1.02(s,1H, CH3), 1.93, 1.95, 2.03, 2.07, 2.10 (5s, 15H, 5xCH3CO), 3.98 (dd, 1H, J=11.2 Hz, J=2.8 Hz, H-6′), 4.07 (dd, 1H, J=11.2 Hz, J=3.2 Hz, H-6′′), 4.18 (m, 1H, H-5′), 4.22 (t, 1H, J=7.5 Hz, H-4′), 4.82 (s, 2H, CH2), 5.18 (dd, 1H, J=2.8 Hz, J=6.5 Hz, H-3′), 5.24 (dd, 1H, J=7.5.2 Hz, J=9.5 Hz, H-2′), 7.20 (d,1H, J=7.8 Hz, H-1′), 7.45-7.86(m,4H,Ar-H), 11.20 (s, 1H, NH).

Antimicrobial testing

Antimicrobial screening: The agar diffusion method reported by Cruickshank et al. [41] was used for the screening process. The bacteria and fungi were maintained on nutrient agar and Czapek’s-Dox agar media, respectively. The assay medium flasks containing 50 ml of nutrient agar for bacteria and Czapek’s-Dox agar medium for fungi respectively were allowed to reach 40-50°C to be inoculated with 0.5 ml of the test organism cell suspension. The flasks were mixed well and poured each into a Petri dish (15 × 2 cm) and allowed to solidify. After solidification, holes (0.6 cm diameter) were made in the agar plate by the aid of a sterile cork poorer (diameter 6 mm). The synthesized target compounds were dissolved each in 2 ml DMSO. In these holes, 100 μl of each compound was placed using an automatic micropipette. The Petri dishes were left at 5°C for 1 h to allow diffusion of the samples through the agar medium and retard the growth of the test organism. Plates were incubated at 30°C for 24 h for bacteria and 72 h of incubation at 28°C for fungi. DMSO showed no inhibition zones. The diameters of zone of inhibition were measured and compared with that of the standard and the solvent alone was used as negative control, the values were tabulated. Ciprofloxacin [42,43] (50 μg/ml) and Nystatin [44] (50 μg/ml) were used as standard for antibacterial and antifungal activity respectively. The observed zones of inhibition are presented in Tables 1 and 2.

Compound Gram-positive Gram-positive Gram-negative Gram-negative Gram-negative
Staphylococcus aureus Micrococcus Salmonella typhi Salmonella para typhi Escherichia coli
171 0 0 0 0 0
172 0 0 0 0 220
178 0 250 130 125 0
179 150 225 0 0 0
180 0 0 0 0 0
181 150 0 125 125 0
182 80 0 100 0 0
183 0 130 weak 100 80
184 125 500 0 225 75
185 0 0 0 0 0
186 0 100 130 125 75
187 0 125 0 0 0
188 0 240 140 0 100
189 75 350 125 225 100
190 75 0 100 110 100
191 0 110 100 125 75
192 0 0 0 0 0
205 110 200 0 0 75
206 0 0 0 0 0
207 0 0 0 0 0
208 0 0 0 0 0
209 0 0 0 0 0
210 0 0 0 0 0
211 0 0 0 0 0
212 75 350 0 0 125
213 0 0 0 0 0
214 75 250 0 0 125
215 0 0 0 0 0
216 0 0 0 0 0
217 0 0 0 0 0
218 125 225 0 225 130
219 0 0 0 o 0
220 0 100 0 140 0
221 0 100 0 0 75
222 0 0 0 0 0
223 0 125 0 0 75
Ciprofloxacin 125 110 220 225 225
DMSO 0 0 0 o 0

Table 1: Minimum inhibitory concentrations (MIC in μg/ml) of the title Compounds against bacteria species. The negative control DMSO showed no activity.

Compound Fungi Fungi Fungi Fungi
Aspergillus flavus Aspergillus fumigates Aspergillus ochraceus Candida albicans
171 0 0 0 0
172 0 0 0 0
179 0 0 0 0
181 0 0 0 0
184 0 0 0 0
187 0 0 0 0
189 0 0 0 0
190 0 0 0 0
191 0 0 0 0
205 0 0 0 0
209 0 0 0 0
210 0 0 0 0
211 0 0 0 0
212 120 500 0 500
214 0 0 0 0
216 0 0 0 0
218 0 0 0 0
221 0 0 0 110
222 0 0 0 0
223 0 0 0 0
Nystatin DMSO 250 150 45 225
  0 0 0 0

Table 2: Minimum inhibitory concentrations (MIC in μg/ml) of the title Compounds against fungi species. The negative control DMSO showed no activity.

The synthesized compounds were screened in vitro for their antimicrobial activities against Staphylococcus aureus (G+ve bacteria), Micrococcus (G+ve bacteria), Salmonella typhi (G-ve bacteria), Salmonella para typhi (G-ve bacteria) and Escherichia coli (G-ve bacteria) in addition to strains of fungi species Aspergillus flavus, Aspergillus fumigates, Aspergillus ochraceus and Candida albicans which were isolated from milk and milk products. The diameters of zone of inhibition were measured and compared with that of the standard and the solvent alone was used as negative control. The values of minimal inhibitory concentrations (MICs) of the tested compounds are presented in Tables 1 and 2. The MIC values of the results obtained revealed that compounds showed varying degrees of inhibition against the tested microorganisms. The results indicated generally that tested compounds did not show high activity against fungi under test except 194 that exhibited high antifungal activities against (Aspergillus fumigates and Candida albicans) and some antifungal activity against Aspergillus flavus, in addition to 196 that exhibited some antifungal activities against Candida albicans. Also the results indicated that among the compounds tested in antibacterial screening Compound 209 revealed high activities against Micrococcus while Compounds 182, 183, 184, 185, 186 and 187 exhibited good antibacterial activities in addition to Compounds 188, 189, 201, 191 that exhibited appreciable activity against Micrococcus. Compounds 172, 181, 182, 183, 184, 185, 186, 187 and 188 exhibited mild to moderate antibacterial activity against Salmonella para typhi. Compounds 189, 194, 196, 200, 201, 202,205 and 206 exhibited notable antibacterial activity against Salmonella typhi. Compounds 172, 184, 188, 189, 194, 209 and 210 exhibited notable antibacterial activity against Escherichia coli followed by compounds 183, 186, 195 and 206. Compounds 179, 181, 184 and 205 exhibited notable antibacterial activity against Staphylococcus aureus followed by compounds 182, 189, 201, 202 and 205.

Results and Discussion

2-Metylbenzimidazole (171) was allowed to react with ethylcholoroacetate in dry acetone and in the presence of anhydrous potassium carbonate to afford 1-ethoxycarbonylmethyl-2- methylbenzimidazole (172) in 83% yield. Treatment of 172 with hydrazine hydrate in absolute ethanol at reflux temperature gave the corresponding hydrazide 173 in 83% yield following the reported procedure 146. The structure of 172 was confirmed by IR spectra which showed the presence of characteristic absorption bands corresponding to (CH2) groups at ν 1455 cm-1 and (CO) group at ν 1730 cm-1. 1H NMR showed a signal corresponding to CH3CH2 group as a triplet at δ 1.32 ppm, signal corresponding to CH3CH2 group as a quartet at δ 4.20 ppm, signal corresponding to NCH2 group as a singlet at δ 5.08 ppm, and signal for aromatic at δ 7.12 - 8.14 ppm. Mass spectrum, m/z (I, %): 218[M+] (20). The structure of 173 was confirmed by IR spectra which showed the presence of characteristic absorption bands corresponding to (CO) group at ν 1637 cm-1, (NH) group at ν 3351 cm-1 and (NH2) group at ν 3567 cm-1 in addition confirmed by mass spectra revealed the presence characteristic signals corresponding to the molecular ion peaks corresponding to their molecular formulas. 1-(2-Methylbenzimidazol-1-yl) acetic acid hydrazide (Scheme 1). 173 was allowed to react with L-(-)-arabinose, D-(+)-xylose, D-(+)- galactose and D-(+)-mannose in an aq. ethanolic solution with a catalytic amount of acetic acid, to afford the corresponding sugar N-acylhydrazones 178-181 in 70-81% yields. The structures of these compounds were confirmed by analytical and spectral data. The IR spectra of 178-181 showed the presence of characteristic absorption bands corresponding to (OH) group in the region ν 3295–3350 cm-1. The 1H NMR spectra showed signals of the sugar chain protons at δ 3.24-3.85 ppm, the C-1 methine proton as a doublet in the range δ 7.09- 7.11 ppm, in addition to the aromatic protons in the region δ 7.12-7.94 ppm. Treatment of the sugar hydrazones 178-181 with acetic anhydride in pyridine at room temperature gave the corresponding per-O-acetyl derivatives 182 -185 in 60-77% yields. The 1H NMR spectra of 182-185 showed the signals of the O-acetyl-methyl protons at δ 1.98-2.48 ppm. The rest of the sugar protons appeared in the range δ 3.40-5.73 ppm. The reaction of sugar arylhydrazones with boiling acetic anhydride is well known to give either the corresponding per-O,N-acetyl derivatives or the respective per-O,N-acetyl-1,3,4-oxadiazolin derivatives 147- 149. However, reaction of the sugar hydrazones 178-181 with acetic anhydride at 100°C gave the sugar-substituted 1,3,4-oxadiazoline derivatives 186-189 in 74-81% yields. The IR spectra of 188-192 showed the presence of characteristic absorption bands corresponding to (CO) group in the region ν 1738-1742 cm-1 and bands corresponding to (C=N) group in the region ν 1650-1679 cm-1. The 1H NMR spectra of 186-189 showed signals of the O- and N-acetyl-methyl protons as singlets in the range δ 1.83-2.48 ppm. The rest of the sugar chain protons appeared in the range δ 4.05-5.34 ppm and the aromatic protons as multiplets in the region δ 7.68-7.69 ppm (Scheme 2). When the hydrazide 173 was reacted with carbon disulphide in ethanol in the presence of potassium hydroxide at reflux temperature, it afforded 2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazole-2-thiol (194) in 80% yield. The 1H NMR spectrum of the 1,3,4-oxadiazole-2- thione showed a signal corresponding to the CH2 group as a singlet at δ 4.58 ppm, Ar-H signals as multiplet at δ 7.97 - 8.48 ppm in addition to the SH signal at δ 12.80 ppm. Alkylation of the 1,3,4-oxadiazolethione 194 with methyl iodide in alkaline medium afforded the corresponding S-methyl derivative 195 in 71% yield. Hydrazinolysis of 195 gave 2-hydrazinyl-2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4- oxadiazole (196) in 74% yield. The 1H NMR spectra of 195 showed the signals of the methyl group as a singlet which disappeared in the 1H NMR spectrum of 196 in which the NH2 signal appeared at δ 5.80 ppm (Scheme 3). 2-Hydrazinyl-2-[(2-methylbenzimidazol-1-yl)methyl]- 1,3,4-oxadiazole (196) was refluxed with various aromatic aldehydes in ethanol and in the presence of a catalytic amount of acetic acid to afford the corresponding Schiff′s bases 200-202 in 89-95 yields. The structures of 201 and 202 were confirmed by mass spectra which revealed the presence of the characteristic signals corresponding to the molecular ion peaks corresponding to their molecular formulas. The structures of 200, 201, and 202 were confirmed by 1H NMR spectra which showed a signal corresponding to the CH2 group as a singlet at δ 4.51-4.65 ppm, signals of the aromatic protons at δ 7.22-8.64 ppm, a signal corresponding to the CH group (H-4-furan and H-3-furan) as a singlet at δ 6.24 and 6.79 ppm respectively, NH signal at δ 9.93-9.96 ppm, in addition to the CH=N signals as tow singlet at δ 7.80,8.8.00 and 8.22 ppm (Scheme 4). 196 was allowed to react with D-(+)-xylose and D-(+)- galactose in an aq. ethanolic solution with a catalytic amount of acetic acid. The structures of these compounds were confirmed by spectral data. The IR spectra of 205, 206 showed the presence of characteristic absorption bands corresponding to (OH) group in the region ν 3445–3448 cm-1.

organic-chemistry-current-research-acetic-acid

Scheme 1: 1-(2-Methylbenzimidazol-1-yl) acetic acid hydrazide.

organic-chemistry-current-research-methylbenzimidazol

Scheme 2: 2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazole-2-thiol (194).

organic-chemistry-current-research-methylbenzimidazol

Scheme 3: 2-hydrazinyl-2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazole (196).

organic-chemistry-current-research-afford-Schiff

Scheme 4: General procedures for the reaction of (196) with aromatic aldehydes to afford Schiff's bases 200-202.

The 1H NMR spectra showed signals of the sugar chain protons at δ 3.48-4.44 ppm, the C-1 methine proton as a doublet in the range δ 8.10-8.44 ppm, in addition to the aromatic protons in the region δ 7.45-7.86 ppm. Treatment of the sugar hydrazones 205, 206 with acetic anhydride in pyridine at room temperature gave the corresponding per-O-acetyl derivatives 209, 210 in 72, 78% yields. The 1H NMR spectra of 209, 210 showed the signals of the O-acetyl-methyl protons at δ 1.93-2.10 ppm. The rest of the sugar protons appeared in the range δ 3.98-5.24 ppm (Scheme 5).

organic-chemistry-current-research-methylbenzimidazol

Scheme 5: 2-[2-(2,3,4,5,6-Penta-O-acetyl-D-galactopentitolylidene) hydrazinyl]-2-[(2-methylbenzimidazol-1-yl)methyl]-1,3,4-oxadiazole (210).

References

  1. Ohta S, Osaki T, Nishio S, Furusawa A, Yamashiunta M, et al. (2000) Serial double nucleophilic addition of amines to the imidazole nucleus. Tetrahedron Lett 41: 7503-7506.
  2. Kubicki M (2004) Two tautomers in one crystal: 4(5)-nitro-5(4)-methoxyimidazole. Acta Crystallogr B 60: 191-196.
  3. MaekiJ, Taehtinen P, Kronberg L, Klika KD (2005) J Phys Org Chem 18: 240.
  4. Zhong YL, Lee J, Reamer RA, Askin D (2004) New method for the synthesis of diversely functionalized imidazoles from N-acylated alpha-aminonitriles. Org Lett 6: 929-931.
  5. Bossio R, Marcaccini S, Pepino R, Torroba T(1996)Studies on Isocyanides and Related Compounds. Synthesis of 1-Aryl-2-(tosylamino)-1H-imidazoles, a Novel Class of Imidazole Derivatives. J Org Chem 61: 2202-2203.
  6. Markwalder JA, Pottorf RS, Seitz SP (1997)One-pot conversion of alpha -ureido and alpha -thioureido esters to imidazol-2-ones and imidazole-2-thiones. Synlett 521-522.
  7. Reader VA (1998) An efficient synthesis of 2-(methylaminomethyl)-4,5-dialkyl-1h imidazoles. Synlett 1077-1078.
  8. Munk SA, Harcourt DA, Arasasingham PN, Burke JA, Kharlamb AB, et al. (1997) Synthesis and evaluation of 2-(arylamino)imidazoles as alpha 2-adrenergic agonists. J Med Chem 40: 18-23.
  9. Khanna I, Yu Y, Huff R, Weier R, Xu X, et al. (2000) Selective cyclooxygenase-2 inhibitors: heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents. J Med Chem 43: 3168-3185.
  10. Habersaat N, Froehlich R, Wuerthwein E (2004)4H-Imidazoles and Imidazoles from anionic and dipolar electrocyclization reactions of 2,4-diazapenta-1,3-dienes. Eur J Org Chem 2567-2581.
  11. Yamada M, Yura T, Morimoto M, Harada T, Yamada K, et al. (1996) 2-[(2-Aminobenzyl)sulfinyl]-1-(2-pyridyl)-1,4,5,6-tetrahydrocyclopent[d]imidazoles as a novel class of gastric H+/K+-ATPase inhibitors. J Med Chem 39: 596-604.
  12. Marwaha A, Singh P, Mahajan MP, Velumurugan D (2004) An efficient unprecedented synthesis of novel functionalized imidazoles from secondary amino-N-carbothioic acid (phenyl-p-tolylimino-methyl)amides and dimethyl acetylenedicarboxylate. Tetrahedron Lett 45: 8945-8947.
  13. Derstine CW, Smith DN, Katzenellenbogen JA (1996)Trifluoromethyl-Substituted Imidazolines:  Novel Precursors of Trifluoromethyl Ketones Amenable to Peptide Synthesis. J Am Chem Soc 118: 8485-8486.
  14. Derstine CW, Smith DN, Katzenellenbogen JA (1997)Trifluoromethyl-Substituted Δ3-Imidazolines: Synthesis and Reactivity. Tetrahedron Lett 38: 4359-4362.
  15. Sparks RB, Combs AP (2004) Microwave-assisted synthesis of 2,4,5-triaryl-imidazole; a novel thermally induced N-hydroxyimidazole N-O bond cleavage. Org Lett 6: 2473-2475.
  16. Siamaki AR, Arndtsen BA (2006) A direct, one step synthesis of imidazoles from imines and acid chlorides: a palladium catalyzed multicomponent coupling approach. J Am Chem Soc 128: 6050-6051.
  17. Bon RS, Hong C, Bouma MJ, Schmitz RF, de Kanter FJ, et al. (2003) Novel multicomponent reaction for the combinatorial synthesis of 2-imidazolines. Org Lett 5: 3759-3762.
  18. Bon RS, van Vliet B, Sprenkels NE, Schmitz RF, de Kanter FJ, et al. (2005) Multicomponent synthesis of 2-imidazolines. J Org Chem 70: 3542-3553.
  19. Pridgen LN, Mokhallalati MK, McGuire MA(1997) A Stereospecific Synthesis of Both Enantiomers of 2-(1'-Amino-2'-Methylpropyl) Imidazole, a Key Synthon in the Synthesis of SB 203386; a Potent Protease Inhibitor. Tetrahedron Lett 38: 1275-1278.
  20. Le Bihan G, Rondu F, Pelé-Tounian A, Wang X, Lidy S, et al. (1999) Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 2. Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines and isosteric analogues of imidazoline. J Med Chem 42: 1587-1603.
  21. McKenna JM, Halley F, Souness JE, McLay IM, Pickett SD, et al. (2002) An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J Med Chem 45: 2173-2184.
  22. Bilodeau MT, Cunningham AM (1998) PEG-Supported Synthesis of 3,5-Disubstituted-1,2,4-Triazoles. J Org Chem 63: 2800.
  23. Peddibhotla S, Jayakumar S, Tepe JJ (2002) Highly diastereoselective multicomponent synthesis of unsymmetrical imidazolines. Org Lett 4: 3533-3535.
  24. Kitbunnadaj R, Hashimoto T, Poli E, Zuiderveld OP, Menozzi A, et al. (2005) N-substituted piperidinyl alkyl imidazoles: discovery of methimepip as a potent and selective histamine H3 receptor agonist. J Med Chem 48: 2100-2107.
  25. Kitbunnadaj R, Zuiderveld OP, De Esch IJ, Vollinga RC, Bakker R, et al. (2003) Synthesis and structure-activity relationships of conformationally constrained histamine H(3) receptor agonists. J Med Chem 46: 5445-5457.
  26. De Esch IJ, Vollinga RC, Goubitz K, Schenk H, Appelberg U, et al. (1999) Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine. J Med Chem 42: 1115-1122.
  27. Neipp CE, Ranslow PB, Wan Z, Snyder JK (1997) Dienophilicity of Imidazole in Inverse Electron Demand Diels-Alder Reactions; Intramolecular Reactions with 1,2,4-Triazines. Tetrahedron Lett 38: 7499-7502.
  28. Li HY, Drummond S, DeLucca I, Boswell GA(1996)Singlet oxygen oxidation of pyrroles - synthesis and chemical-transformations of novel 4,4-bis(trifluoromethyl)imidazoline analogs. Tetrahedron 52: 11153-11162.
  29. Hrabie JA, Citro ML, Chmurny GN, Keefer LK (2005) Carbon-bound diazeniumdiolates from the reaction of nitric oxide with amidines. J Org Chem 70: 7647-7653.
  30. Larter ML, Phillips M, Ortega F, Aguirre G, Somanathan R, et al. (1998) Synthesis of racemic cis and trans 2,4,5-tripyridylimidazolines. Tetrahedron Lett 39: 4785-4788.
  31. Mohammadpoor-Baltork I, Zolfigol MA, Abdollahi-Alibeik M(2004) Novel, mild and chemoselective dehydrogenation of 2-imidazolines with trichloroisocyanuric acid. Synlett 2803-2805.
  32. Mohammadpoor-Baltork I, Zolfigol MA, Abdollahi-Alibeik M (2004) Novel and chemoselective dehydrogenation of 2-substituted imidazolines with potassium permanganate supported on silica gel. Tetrahedron Lett 45: 8687-8690.
  33. Abdollahi-Alibeik M, Mohammadpoor-Baltork I, Zolfigol MA (2004) Alumina supported potassium permanganate: an efficient reagent for chemoselective dehydrogenation of 2-imidazolines under mild conditions. Bioorg Med Chem Lett 14: 6079-6082.
  34. Mohammadpoor-Baltork I, Abdollahi-Alibeik M (2005) Mild, efficient, and chemoselective dehydrogenation of 2-imidazolines, bis-imidazolines, and N-substituted-2-imidazolines with potassium permanganate supported on montmorillonite K-10. Can J Chem 83: 110-114.
  35. Anastassiadou M, Baziard-Mouysset G, Payard M(2000) New one-step synthesis of 2-aryl-1H-imidazoles: Dehydrogenation of 2-aryl-Delta 2-imidazolines with dimethylsulfoxide. Synthesis 1814-1816.
  36. Giorgio E, Minichino C, Viglione RG, Zanasi R, Rosini C, et al. (2003) Assignment of the molecular absolute configuration through the ab initio Hartree-Fock calculation of the optical rotation: can the circular dichroism data help in reducing basis set requirements? J Org Chem 68: 5186-5192.
  37. Lovely CJ, Du H, Dias HVR(2003) The Regioselective Preparation of 1-Benzyl- and 1-Methyl-4-vinylimidazole and their reactions with N-Phenylmaleimide. Heterocycles 60: 1-7.
  38. Muri E, Mishra H, Avery M, Williamson J(2003) Design and Synthesis of Heterocyclic Hydroxamic Acid Derivatives as Inhibitors of Helicobacter pylori Urease. Synth Commun 33: 1977-1995.
  39. Hayakawa Y, Kimoto H, Cohen L, Kirk K (1998)Syntheses of (Trifluoromethyl)imidazoles with Additional Electronegative Substituents. An Approach to Receptor-Activated Affinity Labels. J Org Chem 63: 9448-9454.
  40. Shafiee A, Rastkary N, Foroumadi A (1998)Syntheses of 2-(2-arylethyl) imidazoles. J Heterocycl Chem 35: 607-610.
  41. Cruickshank R, Duguid JP, Marion BP, Swain RHA (1975) Medicinal Microbiology.12thedn. Churchill Livingstone, London.p: 196.
  42. Dahiya R (2008)Synthesis, characterization and antimicrobial studies on some newer imidazole analogs. Sci Pharm 76: 217-239.
  43. Su HC, Ramkissoon K, Doolittle J, Clark M, Khatun J, et al. (2010) The development of ciprofloxacin resistance in Pseudomonas aeruginosa involves multiple response stages and multiple proteins. Antimicrob Agents Chemother 54: 4626-4635.
  44. Poyner TF, Dass BK (1996) Comparative efficacy and tolerability of fusidic acid/hydrocortisone cream (Fucidin H cream) and miconazole/hydrocortisone cream (Daktacort cream) in infected eczema. J Eur Acad Dermatol Venereol 7: S23-S30.
Citation: Amer HH, El-Kousy SM, Salama WM, H-H Sheleby A (2016) Synthesis and Antimicrobial Activity of New Synthesized Benzimidazole Derivatives and their Acyclic Nucleoside Analogues. Organic Chem Curr Res 5: 157.

Copyright: © 2016 Amer HH, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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