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  CE: Pratima ED: Maitreyee Op: Anuj EPJ: LWW_EPJ_112-9 Original article 1 Synthesis and antioxidant and antibacterial activities of new 2-(1,5,6-trimethyl-1H-benzo[d]imidazole-2-carbonyl)-2, 3-dihydro-1H-pyrazole-4-carbonitriles, (1,3,4-oxadiazol-2-yl)-1H- benzo[d]imidazol-5-yl)(phenyl)methanones, and (1,3,4-oxadiazol- 2-yl)-1,5-dihydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitriles: QSAR and molecular modeling Fatma A. Bassyouni a,b , Hanaa A. Tawfik a , Ahmed R. Hamed b,c , Maha M. Soltan b,c , Mahmoud ElHefnawi d , Ahmed A. ElRashedy d , AQ1 Maysa E. Moharan e  and Mohamed a Department of Chemistry of Natural and Microbial Objectives  A. Rehim f Products,  b Pharmaceutical Research Group, Center of Excellence for Advanced Sciences,  c Department of Chemistry of Medicinal Plants,  d Biomedical Informatics and Chemo Informatics Group, Department of Informatics and Systems, Centre of Excellence for Advanced Sciences,  e Department of Microbial Chemistry, National Research Centre, Dokki, Cairo, Egypt and  f  Department of Analytical Chemistry, Stockholm University, Stockholm, Sweden Correspondence to Fatma A. Bassyouni, PhD, Department Chemistry of Natural and Microbial Products and Pharmaceutical Research Group, Center of Excellence for Advanced Sciences, National Research Centre, 12311 Cairo, Egypt AQ2 Tel: + 20 21 118 596 967; fax: + 20 233 370 931; e-mail: fatma.nrc@hotmail.com Received 19 February 2012  Accepted 6 June 2012 Egyptian Pharmaceutical Journal 2012, 00:000-000 Introduction  A new series of 2-(1,5,6-trimethyl-1H-benzo[d]imidazole-2-carbonyl)-2,3-dihydro-1H- AQ3 pyrazole-4-carbonitrile (6a,b), (1,3,4-oxadiazol-2-yl)-1H-benzo[d]imidazol-5-yl)(phenyl) methanone (9-11), and (1,3,4-oxadiazol-2-yl)-1,5-dihydro-[1,2,4]triazolo[1,5-a] pyridine-8-carbonitrile (14-16) derivatives were synthesized and were evaluated for their antioxidant and antimicrobial activities; in addition, their quantitative structure-activity relationships and molecular docking were investigated. Methods The target compounds 6a,b were synthesized by the following method: reaction of 5,6-dimethyl-1H-benzoimidazole-2-carbohydrazide (2) with 4-(dimethyl amino)benzaldehyde or anthracene-9-carbaldehyde yielded Schiff  ’s bases 3a,b, which were reacted with ethyl cyanoacetate to yield 1H-pyrazole-4-carbonitriles 4a,b; N-methylation of 4a,b afforded 5a,b, which reacted with 4-aminoantipyrine to give 6a,b. In addition, 5-benzoyl-1H-benzo[d]imidazole-2-carbohydrazide (8) or 8-cyano-6- isocyano-5-oxo-7-phenyl-1,5-dihydro-[1,2,4]triazolo[1,5-a]pyridine-2-carbohydrazide (13) reacted with different carboxylic acids such as crotonic acid, 3,4-diaminobenzoic acid, and 6-hydroxy-4-methoxybenzofuran-5-carboxylic acid to form compounds 9-11 and 14-16, respectively. The synthesized compounds were evaluated for their antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl radical, the scavenging assay, and the diffusion plate method for antimicrobial activity. Results and conclusion  Among other tested compounds, compounds 15, 11, and 10 possessed the highest antioxidant activity, whereas compounds 4a, 5b, 6b, 10, and 11 displayed high activity against Staphylococcus aureus, Salmonella typhimurium, and Candida albicans. The quantitative structure-activity relationships of the studied compounds 4a, 4b, 5b, AQ4 6b, 10, 11, 14, 15, and 16 indicated a high correlation (r  2  = 0.82) between the predicted and actual activities as obtained from molecular descriptors and the inhibitory activity of this set of tested molecules measured as antioxidant activity. Moreover    The 3D pharmacophore was generated using the Flexigen algorithm : one hydrogen bond acceptor , one hydrophobic centroid and two aromatic planer ring center . Finally ,   docking of the most active antibacterial compound 4a against the dihydropteroate synthase enzyme gave comparable scores and hydrogen bond interaction (- 13.5 kcal/mol) and binding mode to the reference antibiotic sulfamethoxazole (- 13.00 kcal/mol).   Keywords: antibacterial, antioxidant, benzimidazoles, molecular docking, quantitative structure-activity relationships, triazoles Egypt Pharm J 00:000-000 &  2012 Division of Pharmaceutical and Drug Industries Research, National Research Centre 1687-4315 depressants [1-6]. A large number of benzotriazole derivatives are currently used in clinical applications Benzimidazoles have a wide range of biological activities such as anticancerous and fungicidal activities; they also serve as antioxidants and central nervous system 1687-4315  &  2012 Division of Pharmaceutical and Drug Industries Research, National Research Centre [7-9]. In addition, they are of great value as intermedi- ates and final products in organic synthesis [10]. Fused heterocyclic compounds containing 1,2,4-triazoles have DOI: 10.7123/01.EPJ.0000422113.69898.e0    2 Egyptian Pharmaceutical Journal  biological potency such as central nervous system depressant [11], antifungal [12], antiviral, and antibac- terial activities [13]. Therefore, triazole derivatives have consistently attracted scientific and practical interest  because of their widely varying chemical properties, syn- thetic versatility, and pharmacological activities [14,15]. Herein, we aim to prepare a new series of 2- (1,5,6-trimethyl-1H-benzo[d]imidazole-2-carbonyl)-2,3- dihydro-1H-pyrazole-4-carbonitrile, (1,3,4-oxadiazol-2- yl-1H-benzo[d]imidazol-5-yl)(phenyl) methanone, and (1,3,4-oxadiazol-2-yl)-1,5-dihydro-[1,2,4]triazolo [1,5-a]  pyridine-8-carbonitrile derivatives and evaluate them for their antioxidant and antibacterial activities. In addition, the quantitative structure-activity relationships (QSAR) of this series will be investigated. Subjects and methods Chemistry AQ6 All melting points were determined using the Electro thermal capillary melting point apparatus and were uncor- rected.  1 H nuclear magnetic resonance (NMR) and  13 C  NMR spectra were measured in DMSO-d 6  using a JEOL- 500 spectrometer with Me 4 Si as an internal standard. Mass spectra were obtained using a Finigan gas chromatography-mass spectrometry spectrometer at 70 eV. The IR spectra (4000-400 cm  - 1 ) were recorded using KBr pellets in a Jasco FT/IR 300 E Fourier transform infrared spectrophotometer and in the 500- 100 cm  - 1 region using polyethylene-sandwiched nujol mulls on a Perkin Elmer FT-IR 1650 spectrophotometer. Elemental analyses were carried out at the Micro analytical Laboratory of the National Research Centre, Cairo, Egypt. Silica gel thin-layer chromatography cards AQ7 were purchased from Merck (silica gel precoated aluminum cards with fluorescent indicator at 254 nm). Visualization was performed by illumination with a UV light source. Compounds 1, 7, and 12 were prepared according to the reported literature [16]. 5,6-Dimethyl-ethyl-2-benzimidazole carboxylate (1) Yield 9.1 g (84%), melting point (MP) 180-1821C. 1 H NMR d:1.30 (3H, t, CH 3 ), 2.15 (6H, s, 2CH 3 ), 4.10-4.30 ( 2 H, q, CH 2 ), 10.70 (1H, s, NH benzimida- zole), 7.22- 7.46 (2H, m, Ar’H). IR (KBr; cm -1 ): 3350 (NH), 1730 (C = O), 1640 (C = N). MS: m/z = 218 [M  +  ]. Anal. calcd for C 12 H 14  N 2 O 2 : C, 66.04; H, 6.47;  N, 12.84. Found: C, 66.09; H, 6.40; N, 12.80. Synthesis of 5,6-dimethyl-1,3-benzimidazole-2-carboxyhydrazide (2) 5,6-Dimethyl-ethyl-2-benzimidazole carboxylate (1; 0.025 mol, 5.40 g) was dissolved in absolute ethanol (30 ml). The hydrazine hydrate (0.050 mol, 1 ml) was added dropwise under stirring and refluxed for 6 h. The reaction mixture was cooled to room temperature and poured into ice-cold water. The solid formed was filtered, washed with water, dried, and then recrystallized from absolute ethanol to yield 4.15 g (80%), MP 230-2321C.  1 H NMR d: 2.15 (6H, s, 2CH 3 ), 5.56 (2H, br,  NH 2 , D 2 O- exchangeable), 9.56 (1H, s, NH), 10.70 (1H, s,  NH benzimidazole), 7.22- 7.46 (2H, m, Ar’H). IR (KBr; cm -1 ): 3340-3350 (NH), 3290 (NH 2 ), 1725 (C = O), 1640 (C = N). MS: m/z = 208 [M  +  ]. Anal. calcd for C 10 H 12  N 4 O: C, 58.81; H, 5.92; N, 27.43. Found: C, 58.86; H, 5.87; N; 27.48. General procedure for the synthesis of N 0 -(4-(dimethylamino) benzylidene)-5,6-dimethyl-1H-benzo[d]imidazole-2- carbohydrazide (3a) and N 0 -(anthracen-9-ylmethylene)-5, 6-dimethyl-1H-benzo[d]imidazole-2-carbohydrazide (3b). To a solution of 5,6-dimethyl-1,3-benzimidazole-2-car-  boxyhydrazide (2; 1 mmol, 0.208 g) in absolute ethanol (30 ml), the appropriate aromatic aldehydes, namely 4-dimethyl amino benzaldehyde (1 mmol, 0.133 g) and anthracene-9-carbaldehyde (1 mmol, 0.206 g), were added with a few drops of piperidine and refluxed under stirring for 7 h. After cooling, the product was poured into crushed ice; the formed solid was filtered, washed with water, and recrystallized from absolute ethanol to give 3a and 3b. N 0 -(4-(Dimethylamino)benzylidene)-5,6-dimethyl-1H-benzo [d]imidazole-2-carbohydrazide (3a) Yield 0.22 g (86%), MP 166-1681C.  1 H NMR d: 2.15 (6H, s, 2CH 3 ), 3.17 (6H, s, N-CH 3 ), 6.88-7.10 (4H, m, AQ8 Ar- ’H), 7.22 -7.46 (2H, m, Ar- ’H), 8.10 (1H, s, N = CH),  9.60 (1H, s, NH), 10.70 (1H, s, NH benzimidazole). C 13  NMR: 19.80 (CH 3 ), 40.50 (N-CH 3 ), 110.30, 115.50, 123.50, 125.30, 130.50, 135.90 (Ar-CH), 145.80 (C = N). IR (KBr; cm -1 ): 3350-3 3 60 (NH), 1720 (C = O), 1640 (C = N). Anal. calcd for C 19 H 21  N 5 O: C, 68.04; H, 6.31;  N, 20.88. Found: C, 68.09; H, 6.38; N, 20.84. N 0 -(Anthracen-9-ylmethylene)-5,6-dimethyl-1H-benzo[d] imidazole-2-carbohydrazide (3b) Yield 0.32 g (84%), MP 190-1921C.  1 H NMR d: 2.15 (6H, s, 2CH 3 ), 7.20-7.46 (2H, m, Ar- ’H), 7.50 -7.95 (9H, m, Ar- ’H), 8.10 (1H, s, N = CH), 9.60 (1H, s, NH), 10.70 (1H, s, NH benzimidazole), C 13  NMR: 19.80 (CH 3 ), 115.50, 110.30, 123.50, 125.30, 128.20, 130.50, 131.80, 135.90 (Ar-CH), 145.80 (N = CH), 142.30 (C = N), 155.50 (C = O). IR (KBr; cm -1 ): 3350-3365 (NH), 1720 (C = O), 1640 (C = N). Anal. calcd for C 25 H 20  N 4 O: C, 76.51; H, 5.14; N, 14.28. Found: C, 76.56; H, 5.18;  N, 14.33. General procedure for the synthesis of 2-(5,6-dimethyl- 1H-benzo[d]imidazole-2-carbonyl)-5-(4-(dimethylamino) phenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carbonitrile (4a) and 5-(anthracen-9-yl)-2-(5,6-dimethyl-1H-benzo[d]imidazole-2- carbonyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carbonitrile (4b) Compound 3a (1 mmol, 0.335 g) or 3b (1 mmol, 0.392 g) was dissolved in dry benzene (25 ml) and ethyl cyanoa- cetate (1 mmol, 0.15 ml), and a few drops of TEA were added. The reaction mixture was heated under reflux with stirring for 5 h. It was cooled to room temperature and poured into ice-cold water. The precipitate was filtered off and purified by crystallization from chloroform to form compounds 4a or 4b.    2-(5,6-Dimethyl-1H-benzo[d]imidazole-2-carbonyl)-5-(4- (dimethylamino)phenyl)-3-oxo-2,3-dihydro-1H-pyrazole- 4-carbonitrile (4a) Yield 0.3 g (84%), MP 242-2441C.  1 H NMR d:2.15 (6H, s, 2CH 3 ), 6.85-7.10 (4H, m, Ar- ’H), 7.20 -7.46 (2H, m, Ar- ’H), 10.70 (1H, s, NH benzimidazole), 11.20 (1H, s,  NH pyrazole). C 13  NMR: 19.80 (CH 3 ), 40.50 N(CH 3 ) 2 , 115.90 (CN), 110.50, 123.50, 125.30, 130.50, 131.80, 135.90 (Ar-CH), 142.30 (C = N), 150.50 (C = O), 165.20 (C = O). IR (KBr; cm -1 ): 3370-3380 (NH), 1710- 1720 (C = O), 1640 (C = N), 2150 (CN). MS: m / z = 401[M  +  + 1]. Anal. calcd for C 22 H 20  N 6 O 2 : C, 65.99; H, 5.03; N, 20.99. Found: C, 65.95; H, 5.07; N, 20.96. MS: m/z = 401[M  +  + 1]. 5-(Anthracen-9-yl)-2-(5,6-dimethyl-1H-benzo[d]imidazole-2- carbonyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carbonitrile (4b) Yield 0.35 g (80%), MP 210-2121C.  1 H NMR d: 2.15 (6H, s, 2CH 3 ), 3.17-3.30 [6H, s, N-(CH 3 ) 2 ], 7.20-7.46 (2H, m, Ar- ’H), 7.50 -7.95 (9H, m, Ar- ’H), 10.70 (1H, s, NH),  11.20 (1H, s, NH pyrazole). C 13  NMR: 19.80 (CH 3 ), 32.40 (CH 3 ), 115.90 (CN), 110.50, 123.50, 125.30, 130.50, 131.80, 135.90 (Ar-CH), 142.30 (C = N), 150.50 (C = O), 165.20 (C = O). IR (KBr; cm -1 ): 3354-3360 (NH), 1 710-1720 (C = O), 1640 (C = N), 2165 (CN). MS: m/z = 458 [M  +  + 1]. Anal. calcd for C 28 H 19  N 5 O 2 : C, 73.51; H, 4.19; N, 15.31. Found: C, 73.56; H, 4.24; N, 15.36. General procedure for the synthesis of 5-(4-(dimethylamino) phenyl)-3-oxo-2-(1,5,6-trimethyl-1H-benzo[d]imidazole-2- carbonyl)-2,3-dihydro-1H-pyrazole-4-carbonitrile (5a) and 5-(anthracen-9-yl)-3-oxo-2-(1,5,6-trimethyl-1H-benzo[d] imidazole-2-carbonyl)-2,3-dihydro-1H-pyrazole-4-carbonitrile (5b) Method A: A solution of methyl iodide (2 ml) in n-hexane (2 ml; 1/1, v/v) was added to the reaction mixture of compound 4a (1 mmol, 0.40 g) or 4b (1 mmol, 0.45 g) and sodium hydride/DMF (0.1 g sodium hydride/1.0 ml DMF) and stirred at room temperature. The reaction was stopped by the careful addition of a few drops of water followed by 20 ml of water under stirring at room temperature for 8 h. The product was extracted with 30 ml of n-hexane, dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under vacuum to afford 5a or 5b in yields up to 78-80%, respectively. Method B: A mixture of compound 4a (1 mmol, 0.40 g) or 4b (1 mmol, 0.45 g), anhydrous K  2 CO 3  (0.01 mol, 1.0 g), and dimethyl carbonate (DMC; 0.03 mol, 2.5 ml) in DMF (10 ml) was refluxed for 3 h. The reaction mixture was cooled to room temperature, following which ice water was added; the precipitated solid was filtered, dried, and crystallized from ethanol to afford 5a or 5b in yields up to 85-88%, respectively. 5-(4-(Dimethylamino)phenyl)-3-oxo-2-(1,5,6-trimethyl-1H- benzo[d]imidazole-2-carbonyl)-2,3-dihydro-1H-pyrazole-4- carbonitrile (5a) Yield 0.36 g (88%) by method B, MP 234-2361C. 1 H NMR d: 2.15 (6H, s, 2CH 3 ), 4.00 (3H, s, CH 3 ), Synthesis, antioxidant, antibacterial effects Bassyouni et al. 3 6.88-7.10 (4H, m, Ar- ’H), 7.20 -7.46 (2H, m, Ar- ’H),   10.70 (1H, s, NH), 11.20 (1H, s, NH pyrazole). IR (KBr; cm -1 ): 3320 (NH), 1710-1720 (C = O), 1640 (C = N). MS: m/z = 413 [M  +  - 1]. Anal. calcd for C 23 H 22  N 6 O 2 : C, 66.65; H, 5.35; N, 20.28. Found: C, 66.70; H, 5.40; N; 20.25. MS: m/z  =  414 [M  +  ]. 5-(Anthracen-9-yl)-3-oxo-2-(1,5,6-trimethyl-1H-benzo[d] imidazole-2-carbonyl)-2,3-dihydro-1H-pyrazole-4-carbonitrile (5b) Yield 0.40 g (85%) by method B, MP 205-2071C.  1 H  NMR d: 2.15 (6H, s, 2CH 3 ), 4.00 (3H, s, CH 3 ), 7.20-7.46 (2H, m, Ar-H), 7.50- 7.95 (9H, m, Ar‘ -H), 10.70 (1H, s,  NH), 11.20 (1H, s, NH pyrazole). IR (KBr; cm -1 ): 3345 (NH), 1710-1720 (C = O), 1640 (C = N). MS: m/z = 471 [M  +  ]. Anal. calcd for C 29 H 21  N 5 O 2 : C, 73.87; H, 4.49; N, 14.85. Found: C, 73.84; H, 4.55; N, 14.90. General procedure for the synthesis of 3-(1,5-dimethyl-3- oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)-5-(4- (dimethylamino)phenyl)-2-(1,5,6-trimethyl-1H-benzo[d] imidazole-2-carbonyl)-2,3-dihydro-1H-pyrazole-4-carbonitrile (6a) and 5-(anthracen-9-yl)-3-(1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazol-4-ylimino)-2-(1,5,6-trimethyl-1H- benzo[d]imidazole-2-carbonyl)-2,3-dihydro-1H-pyrazole-4- carbonitrile (6b) Compound 5a (1 mmol, 0.41 g) or 5b (1 mmol, 0.47 g) was dissolved in absolute ethanol (25 ml), followed by the addition of 4-aminoantipyrine (1 mmol, 0.20 g) in the  presence of acetic acid (2 ml). The reaction mixture was heated under reflux for 8 h. After cooling, the solvent was evaporated under vacuum and the precipitated product was crystallized from ethanol to afford 6a or 6b. 3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol- 4-ylimino)-5-(4-(dimethylamino)phenyl)-2-(1,5,6-trimethyl- 1H-benzo[d]imidazole-2-carbonyl)-2,3-dihydro-1H-pyrazole- 4-carbonitrile (6a) Yield 0.5 g (85%), MP 168-1701C.  1 H NMR d: 2.10 (6H, s, 2CH 3 ), 4.00 (3H, s, CH 3 ), 6.85-7.10 (4H, m, Ar- ’H),  7.20-7.46 (2H, m, Ar- ’H), 10.70 (1H, s, NH). IR   (KBr; cm -1 ): 3358 (NH), 1640-1645 (C = N), 1690, 1685 (C = O), 2100 (CN). MS: m/z = 598 [M  +  - 1]. Anal. calcd for C 34 H 33  N 9 O 2 : C, 68.10; H, 5.55; N, 21.02. Found: C, 68.02; H, 5.50; N, 20.96. 5-(Anthracen-9-yl)-3-(1,5-dimethyl-3-oxo-2-phenyl-2,3- dihydro-1H-pyrazol-4-ylimino)-2-(1,5,6-trimethyl-1H-benzo[d] imidazole-2-carbonyl)-2,3-dihydro-1H-pyrazole-4-carbonitrile (6b) Yield 0.54 g (83%) MP 177-1791C.  1 H NMR d: 2.10 (6H, s, 2CH 3 ), 4.00 (3H, s, CH 3 ), 7.20-7.46 (2H, m, Ar-H), 7.50-7.95 (9H, m, Ar‘ -H), 10.90 (1H, s, NH). IR (KBr; cm -1 ): 3369 (NH), 1640-1665 (C = N), 1690, 1680 (C = O), 2120 (CN). Anal. calcd for. C 40 H 32  N 8 O 2 : C, 73.15; H, 4.91; N, 17.06. Found: C, 73.11; H, 4.87;  N, 16.96. Synthesis of compounds 7 and 12 Compounds 7 and 12 were synthesized using the same  procedure as that described for the synthesis of    4 Egyptian Pharmaceutical Journal compound 1 and were obtained in 77 and 74% yields, respectively. Ethyl 5-benzoyl-1H-benzo[d]imidazole-2-carboxylate (7): Yield (77%), MP 158-160 1C.  1 H NMR d: 2.25 (3H, s, CH 3 ), 3.80 (2H, q, CH 2 ), 7.4 0-7.60 (2H, m, Ar-H), 7.80-7.90 (4H, m, Ar‘ -H), 11.80 (1H, s, NH). IR (KBr; cm -1 ): 3320 (NH), 1700 (C = O), 1660 (C = N). Anal. calcd for C 16 H 14  N 2 O 3 : C, 68.00, H, 6.90, N, 9.90. Found: C, 68.15; H, 6.82; N, 9.81. Synthesis of compounds 8 and 13 Compounds 8 and 13 were synthesized by adopting the general procedure used for the preparation of compound 2 and were obtained in 75 and 78% yields, respectively. 5-Benzoyl-1H-benzo[d]imidazole-2-carbohydrazide (8): Yield (75%), MP 182-1841C.  1 H NMR d: 5.60 (2H, s, NH 2 ), 7.4 0-7.60 (2H, m, Ar-H), 7.80- 7.90 (4H, m, Ar‘ -H), 11.80 (1H, s, NH). IR (KBr; cm -1 ): 3320 (NH), 3250 (NH 2 ), 1700 (C = O), 1660 (C = N). Anal. calcd for C 15 H 12  N 4 O: C, 68.18; H, 5.30; N, 10.60. Found: C, 68.1; H, 5.23; N, 10.61. General procedure for the synthesis of compounds 9-11 To a solution of compound 8 (3 mmol, 0.792 g) in dry DMF (5 ml), POCl 3  was added dropwise (6 mmol, 1 ml), followed by 3 mmol of each acid, namely crotonic acid (3 mmol, 0.30 g), 3,4-diaminobenzoic acid (3 mmol, 0.75 g), and 6-hydroxy-4-methoxybenzofuran-5-carboxylic acid (3 mmol, 0.63 g). The reaction mixture was stirred at room temperature for 15 min, thereafter at 80-901C for 5 h. After cooling, the reaction mixture was poured into crushed ice and neutralized by NaHCO 3  (20%). The  precipitated product 9, 10, or 11 was filtered, washed with ice water, dried, and crystallized from ethanol. Phenyl(2-(5-(prop-1-enyl)-1,3,4-oxadiazol-2-yl)-1H-benzo[d]i- midazol-5-yl)methanone (9): Yield 0.25 g (75%), MP 223-2251C.  1 H NMR d: 2.20 (3H, d, CH 3 ), 5.80 (1H, d, CH), 5.95 (1H, m, CH), 7.4 0-7.60 (2H, m, Ar-H), 7.80- 7.90 (4H, m, Ar‘ -H), 11.80 (1H, s, NH). IR (KBr) cm -1 : 3320 (NH), 1700 (C = O), 1640-1645 (C = N). MS: m/z = 330 [M  +  ]. Anal. calcd for C 19 H 14  N 4 O 2 : C, 69.08; H, 4.27; N, 16.96. Found: C, 69.12; H, 4.20;  N, 16.90. (2-(5-(3,4-Diaminophenyl)-1,3,4-oxadiazol-2-yl)-1H-benzo[d]i- midazol-5-yl)(Phenyl) methanone (10): Yield 0.308 g (78%), MP 188-190 1C.  1 H NMR d: 5.60 (2H, m, NH 2 ), 6.80-7.10 (3H, m, Ar-H), 7.40-7.60 (2H, m, Ar‘ -H), 7.80-7.90 (4H, m, Ar- ’H), 11.80 (1H, s, NH). IR (KBr; cm -1 ): 3320 (NH), 1700 (C = O), 1640-1650 (C = N). MS: m/z = 396 [M  +  ]. Anal. calcd. for C 22 H 16  N 6 O 2 : C, 66.66; H, 4.07; N, 21.20. Found: C, 66.71; H, 21.25;  N, 8.12. (2-(5-(6-Hydroxy-4-methoxybenzofuran-5-yl)-1,3,4-oxadiazol- 2-yl)-1H-benzo[d]imidazol-5-yl)(phenyl)methanone (11): Yield 0.346 g (77%), MP 198-2001C.  1 H NMR d: 2.35 (3H, s, CH 3 ), 3.60 (3H, s, OCH 3 ), 6.40-6.60 (2H, m, CH furan), 6.70 (1H, m, CH furan), 6.90 (1H, m, CH aromatic), 7.40-7.60 (4H, m, Ar-H), 7.80- 7.90 (2H, m, Ar‘ -H), 11.80 (1H, s, NH). IR (KBr; cm -1 ): 3320 (NH), 1700 (C = O), 1640-1655 (C = N). Anal. calcd for C 25 H 16  N 4 O 5 : C, 66.30; H, 3.54; N, 12.39. Found: C, 66.39; H, 3.59; N, 12.45. Ethyl 8-cyano-6-isocyano-5-oxo-7-phenyl-1,5-dihydro-[1,2,4] triazolo[1,5-a]pyridine-2-carboxylate (12): Yield 0.215 g (74%), MP 236-2381C.  1 H NMR d: 2.20 (3H, s, CH 3 ), 3.80 (2H, q, CH 2 ), 7.30-7.75 (4H, m, Ar-H), 10.90 (1H, s, NH). IR (KBr; cm -1 ): 3350 (NH), 1720 (C = O), 2120-2127 (CN). Anal. calcd f or C 16 H 11  N 5 O 3 : C, 63.90; H, 3.78; N, 24.05. Found: C, 63.82; H, 3.70; N, 24.10. 8-Cyano-6-isocyano-5-oxo-7-phenyl-1,5-dihydro-[1,2,4]triazo- lo[1,5-a]pyridine-2-carbohydrazide (13): Yield 0.25 g(78%), MP193-1951C.  1 H NMR d: 5.80 (1H, m, CH), 5.90 (1H, d, CH), 6.50 (2H, s, NH 2 ), 7.30-7.75 (4H, m, Ar-H), 9.80 (1H, s, NH), 10.90 (1H, s, NH). IR (KBr; cm -1 ): 3320 (NH), 3210 (NH 2 ), 1710 (C = O), 2150-2155 (CN). Anal. calcd for C 14 H 9  N 7 O2: C, 52.33; H, 2.80; N, 34.89. Found: C, 52.28; H, 2.72; N, 34.82. General procedure for the synthesis of compounds 14-16 To a solution of compound 13 (1 mmol, 0.321 g) in dry DMF, POCl 3 (5 ml) was added dropwise (3 mmol, 0.50 ml), followed by the addition of 1 mmol of each of the following carboxylic acids: crotonic acid, 3,4-diami- nobenzoic acid, or 6-hydroxy-4-methoxybenzofuran-5- carboxylic acid. The reaction mixture was stirred at room temperature for 15 min and then at 80-901C for 6 h. After cooling, the reaction mixture was poured into crushed ice and neutralized by NaHCO 3  (20%); the precipitated  products 14, 15, or 16 were filtered, washed with ice water, dried and, crystallized from methanol. 6-Isocyano-5-oxo-7-phenyl-2-(5-(prop-1-enyl)-1,3,4-oxadiazol- 2-yl)-1,5-dihydro-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile (14): Yield 0.30 g (82%), MP 239-2411C.  1 H NMR d: 2.28 (3H, d, CH 3 ), 5.80 (1H, m, CH), 5.90 (1H, d, CH), 7.30-7.75 (4H, m, Ar-H), 10.90 (1H, s, NH). IR (KBr; cm -1 ): 3320 (NH), 1710 (C = O), 2150-2156 (CN). MS: m/z = 369 [M  +  ]. Anal. calcd for C 19 H 11  N 7 O 2 : C, 61.79; H, 3.00; N, 26.55. Found: C, 61.84; H, 3.06; N, 26.59. 2-(5-(3,4-Diaminophenyl)-1,3,4-oxadiazol-2-yl)-6-isocyano-5- oxo-7-phenyl-1,5-dihydro-[1,2,4]triazolo[1,5-a]pyridine-8-car-  bonitril (15): Yield 0.34 g (80%), MP 220-2221C.  1 H NMR d: 5.60 (2H, m, NH 2 ), 6.90-7.10 (3H, m, Ar-H), 7.30- 7.75 (5H, m, Ar‘ -H), 10.90 (1H, s, NH). IR (KBr; cm -1 ): 3320 (NH), 1710 (C = O), 2140-2150 (CN). Anal. calcd for C 22 H 13  N 9 O 2 : C, 60.69; H, 3.01; N, 28.95. Found: C, 60.75; H, 3.06; N, 29.05. 1,5-Dihydro-2-(5-(6-hydroxy-4-methoxybenzofuran-5-yl)-1,3,4- oxadiazol-2-yl)-6-isocyano-5-oxo-7-phenyl-[1,2,4]triazolo[1,5-a]  pyridine-8-carbonitrile (16): Yield 0.40 g (81%), MP 230-2321C.  1 H NMR d: 2.35 (3H, s, CH 3 ), 3.60 (3H, s, OCH 3 ), 6.40-6.60 (2H, m, CH furan), 6.70 (1H, m, CH furan), 6.90 (1H, m, CH aromatic), 7.30-7.75 (5H, m, Ar‘ -H), 10.90 (1H, s, NH). IR (KBr; cm  - 1 ): 3320 (NH), 1710 (C = O), 2150-2156 (CN). Anal. calcd for- C 25 H 13  N 7 O 5 : C, 61.09; H, 2.64; N, 19.96. Found: C, 61.15; H, 2.70; N, 20.09.
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