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Synthesis, Reactions, Structure-Activity Relationship of 2-Benzimidazole Analogs As Anticancer Agents and Study Their Molecular Docking

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Synthesis, Reactions, Structure-Activity Relationship of 2-Benzimidazole Analogs As Anticancer Agents and Study Their Molecular Docking Available online a t www.derpharmachemica.com Scholars Research Library Der Pharma Chemica, 2013, 5(5):243-257 (http://derpharmachemica.com/archive.html) ISSN 0975-413X CODEN (USA): PCHHAX Synthesis, reactions, structure-activity relationship of 2-benzimidazole analogs as anticancer agents and study their molecular docking Nahed F. Abdel-Ghaffar Department of Chemistry , Faculty of Science(Girls), Al-Azhar University, Nasr City, Cairo, Egypt _____________________________________________________________________________________________ ABSTRACT A new series of benzimidazolederivatives , 1,2,3 are reported herein. Their reactions with some nucleophiles gave 4 and 6. The reaction of 3 with sodium azide gave 5and with primary amines gave 7a-c. Treatment of 7c with acrylonitrile, cinnamaldehyde, phenylisothiocyanate, gave 8,9 and 10. Treatment of 10 with chloroacetic acid and/or malonic acid gave 11 and 12 . The benzimidazol-2-thione derivative 2 reacted with acetylacetone to give the dicarbonyl derivative 13 which on hydrazinolysis gave the pyrazole derivative 14. Reaction of 2 with benzalacetophenone derivative, anthranilic acid, sodium nitrite and/or thiourea gave 15,16,17 and 18 respectively. The formation of the 2-benzimidazolyl pyrimidine thione derivative 19 was also investigated. Some of the new synthesized derivatives were screened for their antitumor activities and theirmolecular docking and the results were encouraging. Keywords: Benzimidazolederivatives , Biological activity , Synthesis, Antitumor activity _____________________________________________________________________________________________ INTRODUCTION Benzimidazole derivatives represent one of the most biologically active classof compounds, possessing a wide spectrum of activities and these are well-documented in literature asthey show selective neuropeptides YY, receptor antagonists [1], potent inhibitors of TiE-2 and VEGFER_2 tyrosine kinase receptor [2], gamma-amino butyric acid (GABA) agonists and 5-HT3 antagonists [3]. They have been showing promising activities in the treatment of several diseases like epilepsy, diabetes, and antifertility [4]. For these reasons, they gained much attention as important pharmacophore and privileged structure in medicinal chemistry [5] encompassing a diverse range of biological activities [6]. The benzimidazole derivatives have found commercial application in veterinarian medicine as anthelmintic agents and diverse human therapeutic areas [7]. Structures containing benzimidazole moiety, well-known to have a wide range of biological properties, have commercial applications in various realms of therapy, including antiulcerative, anti-hypertensive, antiviral, antifungal, anti-tumorand antihistaminic agents, and antihelminthic agents in veterinary medicine [8]. Furthermore, these heterocycles are considered to be privileged structures by medicinal chemists. The preparation of benzimidazoles has gained considerable attention in recent years. Thebenzimidazole is found in a variety of naturally occurring compounds and is of significantimportance in medicinal chemistry [9]. 243 www.scholarsresearchlibrary.com Nahed F. Abdel-Ghaffar Der Pharma Chemica, 2013, 5 (5):243-257 ___________________ __________________________________________________________ The present investigation deals with synthesis of some benzimidazol derivatives, study some of their behavior towards some nucleophilic as well as electrophilic reagents in the hope of obtaining new derivatives of biological interest and potential target compounds. The substituted benzimidazoles were tested for their cytotoxic activity and their structure activity relationship were examined. MATERIALS AND METHODS 2.1.Chemistry All melting points are uncorrected. IR spectra (KBr) were recorded with a Perkin Elmer Spectrum RXIFT-IR system. 1HNMR were measured with a Varian Gemini 200 MHz instrument using TMS as internal standard and mass spectra were measured with a Shimadzu GC–MS–QP 100 EX mass spectrometer. 2.2.General procedure preparation of compounds 2.2.1.Synthesis of 1H-benzo[d]imidazol-2(3H)-one 1 and 1H-benzo[d]imidazole-2(3H)-thione 2 Both of 1H-benzo[d]imidazol-2(3H)-one 1 and 1H-benzo[d]imidazole-2(3H)-thione 2 were prepared according to L.Srikanthet.al [10]. Analysis of 1 C7H6N2O(134)(%)calcd: C 62.68 , H 4.47 , N 20.89. Found: C 62.70 , H 4.50 , N 20.90. Analysis of 2 C7H6N2S(150)(%)calcd: C 56.00 , H 4.00 , N 18.66. Found: C 56.02 , H 4.02 , N 18.70. 2.2.1.1.Synthesis of 2-chloro-1H-benzo[d]imidazole 3 A mixture of 1 (0.01 mol), phosphorus oxychloride (3 ml) and phosphorus pentachloride (0.5 gm) was heated on a steam bath for 2 hours. It was poured into crushed ice and the solid that separated was filtered off, washed well and crystallized from ethanol as yellowish white crystals 3of60% yield and m.p. 147˚C. Analysis of 3 C7H5N2Cl (152.5)(%) calcd: C 55.08 , H 3.28 , N 18.36 , Cl 23.28 . Found: C 55.16 , H 3.32 , N 18.43 , Cl 23.32 2.2.1.1.1.Synthesis of 2-hydrazinyl-1H-benzo[d]imidazole 4 A mixture of 3 (0.01 mol) and hydrazine hydrate (0.01 mol) in 30 ml of ethanol was refluxed for 6 hours. After concentration and cooling the solid obtained was crystallized from ethanol white crystals 4of 75%yield andm.p 190 ˚C. Analysis of 4 C7H8N4 (148)(%) calcd: C 56.76 , H 5.41 , N 37.84 . Found: C 56.82 , H 5.47 , N 37.91. Found: C 56.82 , H 5.38 , N 37.90 2.2.1.1.2.Synthesis of[1,2-d]tetrazol-4H-benzimidazole 5 A mixture of 3 (0.01mol) , sodium azide (0.02 mol,1.3gm)dissolved in 5 ml of water and dimethylformamide (20 ml) was refluxed for 2 hours and cooled. The solid obtained upon dilution with water was filtered off and recrystallized from ethanol to give 5 as greenish crystals of 60% yield and m.p178 ˚C. Analysis of 5C7H5N5 (159)(%) calcd: C 52.83 , H 3.14 , N 44.02. Found: C 52.90 , H 3.00 , N 44.00 2.2.1.1.3.Synthesisof4-(1H-benzo[d]imidazol-2-ylamino) – N-(4-aminophenyl)benzenesulfonamide 6 A mixture of 3 (0.01 mol) and sulphaniline (0.01 mol) in ethanol (50 ml) was refluxed for 10 hours , the solid product obtained after evaporating the solvent was crystallized from ethanol to give 6 as orange crystals of 85% yield and m.p 276 ˚C. Analysis of 6C19 H17N5SO 2 (379)(%) calcd: C 60.14 , H 4.52 , N 18.46 , S 8.45. Found: C 60.00 , H 4.48 , N 18.52 , S 8.53 2.2.1.1.4.Reaction of 2-chloro-1H-benzo[d]imidazole3 with amines: Formation of 7 a-c A mixture of 3 (0.01 mol) anddifferent amines namely 2-amino pyridine , benzyl amine and/or p-phenylenediamine (0.01 mol) in (30 ml) ethanol was refluxed for 6 hours. After concentration and cooling the solid obtained was crystallized from ethanol to give N-(pyridin-2-yl)-1H-benzo[d]imidazol-2-amine 7a as white crystals of 60% yield 244 www.scholarsresearchlibrary.com Nahed F. Abdel-Ghaffar Der Pharma Chemica, 2013, 5 (5):243-257 ___________________ __________________________________________________________ and m.p 324 ˚C, N-benzyl-1H-benzo[d]imidazol-2-amine 7b as yellowish crystals of 65% yield and m.p 300 ˚C and N1-(1H-benzo[d]imidazol-2-yl)benzene-1,4-diamine 7c as brownish crystals of 75% yield and m.p 297 ˚C. Analysis of 7a C12 H10 N4 (210)(%) calcd: C 68.57 , H 4.76 , N 26.66. Found: C 68.60 , H 4.80 , N 26.70. Analysis of 7b C14 H13 N3 (223)(%) calcd: C 75.33 , H 5.82 , N 18.83. Found: C 75.00 , H 5.78 , N 18.80. Analysis of 7c C13 H12 N4 (224)(%) calcd: C 69.64 , H 5.35 , N 25.00. Found: C 69.60 , H 5.80 , N 25.30 2.2.1.1.4.1. Reaction of 7c with acrylonitrile: Formation ofN-(4-(1H-pyrazol-1-yl)phenyl)-1H-benzo[d]imidazol-2- amine 8 To (0.01 mol) of 7c wasadded (0.02 mol) of acrylonitrile in 20 ml pyridine , the mixture was heated under reflux for 6 hours. After cooling , it was poured into ice and HCl mixture and the product that separated was filtered off , washed well with water , dried and recrystallized from ethanol to give 8 as brown crystals of 60% yield and m.p 218 ˚C. Analysis of 8 C16 H13 N5 (275)(%) calcd: C 69.81 , H 4.72 , N 25.45. Found: C 69.84 , H 4.69 , N 25.42 2.2.1.1.4.2.Reaction of 7c with cinnamaldehyde: Formation of (N 4E)-N1-(1H-benzo[d]imidazol-2-yl)-N4-(3- phenylallylidene)benzene-1,4-diamine asShiff ,s base 9 A mixture (0.01 mol) of 7c in (30 ml) absolute ethyl alcohol and (0.05 mol) of sodium ethoxide (prepared by dissolving sodium metal (0.02 mol) in 20 ml of absolute ethanol) and cinnamaldehyde (0.01 mol) wasstirrered for 2 hours. Filter the precipitate and recrystallize it from ethanol as yellowish powder 9 in 48% yield and m.p 205˚C. Analysis of 9 C22 H18 N4 (338)(%) calcd: C 78.10 , H 5.32 , N 16.56. Found: C 78.09 , H 5.29 N 16.52 2.2.1.1.4.3.Reaction of 7c with phenylisothiocyanate: Formation of 1-(4-(1H-benzo[d]imidazol-2-ylamino)phenyl)- 3-phenylthiourea 10 A mixture of 7c (0.01 mol) and phenylisothiocyanate (0.013 mol) in 20 ml of pyridine was refluxed for 6 hours cooled , then poured into ice – HCl mixture. The solid that separated was filtered off , washed well with water and recrystallized from ethanol to give 10 as yellow crystals in 80% yield and m.p 203˚C. Analysis of 10 C20 H17 N5S (359)(%) calcd: C66.85 , H 4.73 , N 19.49 , S 8.91. Found: C 66.90 , H 4.70 , N 19.52 , S 9.00 2.2.1.1.4.3.1.Reaction of 10 with chloroacetic acid: Formation of N-(3-(4-(1H-benzo[d]imidazol-2-ylamino)phenyl)- 4-oxothiazolidin-2-yl)benzamide 11 A mixture of 10 (0.01 mol) ,chloroacetic acid (0.03 mol) and dry acetone (50 ml) in the presence of anhydrous potassium carbonate (0.03 mol) was heatedon a water bath for 24 hours.
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