2-Amino-4,5-diphenylfuran-3-carbonitrile (2) reacted with N-[bis(methylthio)methylene]glycine ethyl ester (1) to afford a double cyclized product 5-methylthio-8,9-diphenylfuro[3,2-e]imidazo [1,2-c]pyrimidin-2(3H)-one (3). Compound 2 also reacts with benzonitrile to give 4-amino- 2,5,6-triphenylfuro[2,3-d]pyrimidine (4). Treatment of 2 with HCONH2, under reflux, afforded 4-amino-5,6-diphenylfuro[2,3-d]pyrimidine (5) which was then allowed to react with chloroacetaldehyde to give 8,9-diphenylfuro[3,2-e]imidazo[1,2-c]pyrimidine (6). Reaction of 2 with HCOOH gave 5,6-diphenylfuro[2,3-d]pyrimidin-4(3H)-one (7) which was then converted to its tosyl derivative (8). The antimicrobial activity of the synthesized compounds 2–8 was tested.2-Amino-4,5-difenilfuran-3-karbonitril (2) u reakciji s etilnim esterom N-[bis(metiltio)metilen]glicina (1) daje produkt dvostruke ciklizacije – 5-metiltio-8,9-difenilfuro[3,2-e]imidazol[1,2-c]pirimidin-2(3H)-on (3). Također, u reakciji s benzonitrilom spoj 2 daje 4-amino-2,5,6-trifenilfuro[2,3-d]pirimidin (4). Grijanjem spoja 2 s HCONH2 dobiven je 4-amino-5,6-difenilfuro[2,3-d]pirimidin (5), koji reakcijom s kloracetaldehidom daje 8,9- difenilfuro[2,3-d]imidazo[1,2-c]pirimidin (6). Reakcijom 2 s HCOOH dobiven je 5,6-difenilfuro[2,3-d]pirimidin- 4(3H)-on (7), koji je preveden u tozilat (8). Spojevima 2-8 ispitana je antimikrobna aktivnost

Khandker M. M. Rahman

M. A. Rahim

M. I. Hossain

M. K. Hossain

M. M. H. Bhuiyan

English

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Fused Pyrimidines. Part II: Synthesis and Antimicrobial activity ofSome Furo[3,2-e]imidazo[1,2-c]pyrimidines and Furo[2,3-d]pyrimidinesM. M. H. Bhuiyan*, Khandker M. M. Rahman, M. K. Hossain, M. A. Rahim, and M. I. HossainDepartment of Chemistry, University of Chittagong, Chittagong-4331, BangladeshRECEIVED MARCH 1, 2004; REVISED APRIL 1, 2005; ACCEPTED JUNE 28, 20052-Amino-4,5-diphenylfuran-3-carbonitrile (2) reacted with N-bis(methylthio)methyleneglycineethyl ester (1) to afford a double cyclized product 5-methylthio-8,9-diphenylfuro3,2-eimida-zo1,2-cpyrimidin-2(3H)-one (3). Compound 2 also reacts with benzonitrile to give 4-amino-2,5,6-triphenylfuro2,3-dpyrimidine (4). Treatment of 2 with HCONH2, under reflux, afforded4-amino-5,6-diphenylfuro2,3-dpyrimidine (5) which was then allowed to react with chloro-acetaldehyde to give 8,9-diphenylfuro3,2-eimidazo1,2-cpyrimidine (6). Reaction of 2 withHCOOH gave 5,6-diphenylfuro2,3-dpyrimidin-4(3H)-one (7) which was then converted to itstosyl derivative (8). The antimicrobial activity of the synthesized compounds 2–8 was tested.Key wordsPyrimidinesfuropyrimidinesfuro-imidazo-pyrimidinesantimicrobial activity* Author to whom correspondence should be addressed. (E-mail: mosharef65@yahoo.com)CROATICA CHEMICA ACTACCACAA 78 (4) 633¿636 (2005)ISSN-0011-1643CCA-3057Original Scientific PaperINTRODUCTIONPyrimidines, being an integral part of DNA and RNA,exhibit diverse pharmacological properties as effectivebactericide, fungicide, viricide, insecticide, medicide.1–3Certain pyrimidines and annulated pyrimidine deriva-tives are also known to display anticancer, antimalarial,antileishmanial and antifilarial activities.4–7 Some furansare shown to be useful for the inhibition of thrombin for-mation.8 Furans have also been extensively investigatedfor their pharmacological uses. Some heterocyclic sys-tems constructed on furans, possess antihypertensive,antialergic and antidepressent activities.9–11 In continua-tion of our earlier work12 and the biodynamic propertiesof these ring systems prompted us to design a system,which combines these two biolabile components in aring together to give compact structures for screeningtheir antimicrobial activities.EXPERIMENTALGeneralMelting points were determined on an electrothermal appa-ratus in an open capillary tube and are uncorrected. The 1H-and 13C-NMR were measured on Bruker AC 200 spectro-meter using DMSO-d6 or CDCl3 as the solvent and chemicalshifts were expressed as  values in ppm against TMS as aninternal standard. TLC using silica G routinely checked thepurity of the compounds and the spots were exposed in io-dine vapour for visualization.N-Bis(methylthio)methylenglycine ethyl ester (1)To a solution of glycine ethyl ester hydrochloride (50mmol) and carbon disulfide (50 mmol) in chloroform (50ml) triethylamine (105 mmol) was added dropwise. After 1h stirring methyl iodide (55 mmol) was added and refluxedthe mixture for another 1 h. The resultant mixture waswashed with water (2  20 ml), dried (Na2SO4) and evapo-rated the solvent. The crude oil was dissolved in acetone(30 ml), anhydrous K2CO3 (10 g) and methyl iodide (60.2mmol) were added. The reaction mixture refluxed for 3 hand stirring was continued for overnight at r.t. After evapo-ration of the solvent, the residue was diluted with ether (20ml), washed with water (2  20 ml), dried (Na2SO4) and thesolvent was removed by evaporation. The residue was dis-tilled under reduced pressure to furnish 1 (80 %) as colour-less syrup, b.p. 96–98 °C, 0.08 mm Hg. 1H-NMR (CDCl3)/ppm: 4.29 (q, 2H, J = 7.09 Hz, OCH2), 4.24 (s, 2H, CH2),2.56 (s, 3H, SCH3), 2.45 (s, 3H, SCH3), 1.28 (t, 3H, J =7.09 Hz, CH3).13C-NMR (CDCl3) /ppm: 169.3, 162.2,60.1, 53.7, 14.4, 14.0, 13.7.5-Methylthio-8,9-diphenylfuro3,2-eimidazo1,2-c-pyrimidin-2(3H)-one (3)Equimolar amounts of 1 and 2 in acetic acid were refluxedfor 8 h. The reaction mixture was cooled and poured intowater. The solid so formed was collected by filtration andcrystallized from EtOH to furnish 3 as yellowish crystals(82 %), m.p. > 270 °C. Analysis Calcd. for C21H15N3O2S(373.44): C 67.54, H 4.05, N 11.25; Found: C 67.49, H 4.11,N 11.21. 1H-NMR (CDCl3) /ppm: 7.69 (m, 5H, Ar-H),7.47 (m, 5H, Ar-H), 4.20 (s, 2H, CH2), 2.70 (s, 3H, SCH3).13C-NMR (CDCl3) /ppm: 170.14, 166.32, 162.07, 139.63,137.52, 132.76, 131.14, 130.18, 129.53, 129.11, 128.45,127.51, 125.41, 121.78, 113.31, 50.43, 13.25.4-Amino-2,5,6-triphenylfuro2,3-dpyrimidine (4)A mixture of 2 (1.92 mmol), NaOMe (3.84 mmol) and ben-zonitrile (1.92 mmol) in 2-propanol (10 ml) was refluxedfor 20 h. On cooling the precipitate was filtered off and re-crystallized from EtOH to afford 4 (68 %) as brown crystals,m.p. 250–252 °C. Analysis Calcd. for C24H17N3O (363.42):C 79.32, H 4.72, N 11.56; Found: C 79.28, H 4.74, N 11.52.1H-NMR (DMSO-d6) /ppm: 7.89 (m, 5H, Ar-H), 7.62 (m,5H, Ar-H), 7.40 (m, 5H, Ar-H), 4.95(s, 2H, NH2).13C-NMR(DMSO-d6) /ppm: 170.14, 140.26, 131.19, 129.00, 128.60,128.18, 127.45, 127.26, 127.05, 126.66.4-Amino-5,6-diphenylfuro2,3-dpyrimidine (5)A solution of 2 (3.85 mmol) in formamide (5 ml) was re-fluxed for 2 h. The precipitate that formed on cooling wasfiltered off and recrystallized from EtOH to give 5 (63 %) asbrown crystals, m.p. 252–254 °C. 1H-NMR (CDCl3) /ppm:7.16 (s, 1H, CH), 7.02 (m, 10H, 2  Ph), 6.12 (s, 2H, NH2).13C-NMR (CDCl3) /ppm: 163.27, 156.25, 151.57, 144.57,129.93, 127.86, 127.41, 126.83, 124.36, 113.65.8,9-Diphenylfuro3,2-eimidazo1,2-cpyrimidine (6)A mixture of 5 (0.52 mmol), NaOAc (0.1 g) and 40 %chloroacetaldehyde (0.45 ml) in water (1.5 ml) was heatedon steam bath for 2 h with stirring. Extraction by chloro-form and evaporation of solvent to give 6 (66 %), m.p. >270 °C. Analysis Calcd. for C20H13N3O (311.35): C 77.16,H 4.21, N 13.50; Found: C 77.13, H 4.24, N 13.48. 1H-NMR(CDCl3) /ppm: 8.31 (s, 1H, H-5), 7.60 (d, 1H, J = 2.4 Hz,H-2), 7.50 (d, 1H, J = 2.4 Hz, H-3), 7.41 (m, 10H, 2  Ph).13C-NMR (CDCl3) /ppm: 165.34, 157.41, 153.15, 147.67,134.51, 131.21, 130.21, 129.72, 128.80, 127.13, 126.50,114.41.5,6-Diphenylfuro2,3-dpyrimidin-4(3H)-one (7)A suspension of 2 (1.92 mmol) in formic acid (10 ml, 85 %)was refluxed for 4 h. The solid that precipitated was col-lected and recrystallized from EtOH to give 7 (75.2 %), m.p.210–212 °C. 1H-NMR (CDCl3) /ppm: 8.00 (s, 1H, NH),7.84 (s, 1H, H-2), 7.57 (m, 5H, Ar-H), 7.52 (m, 5H, Ar-H).13C-NMR (CDCl3) /ppm: 187.96, 164.02, 144.82, 139.89,130.56, 130.18, 129.27, 128.74, 128.30, 126.77.4-Oxo-5,6-diphenylfuro2,3-dpyrimidin-3-p-toluenesulfonate ester (8)A solution of 7 (0.86 mmol), p-TsCl (0.86 mmol) in ether(5 ml) was heated at 30 °C for 5 h. After evaporation ofether, the resulting solid was recrystallized from EtOH togive 8 (66 %) as yellowish crystals, m.p. > 270 °C. AnalysisCalcd. for C25H18N2O4S (442.50): C 67.86, H 4.10, N 6.33;Found: C 67.81, H 4.15, N 6.36. 1H-NMR (CDCl3) /ppm:7.62 (s, 1H, H-2), 7.51 (d, 2H, J = 8.0 Hz, Ar-H), 7.45 (m,5H, Ph), 7.32(m, 5H, Ph), 7.15 (d, 2H, J = 8.0 Hz, Ar-H),2.24 (s, CH3).13C-NMR (CDCl3) /ppm: 188.14, 183.43,182.74, 179.50, 160.10, 153.91, 148.48, 144.83, 131.50,130.55, 129.08, 128.55, 127.60, 118.39, 28.92.RESULTS AND DISCUSSIONThe annelating reagent, N-bis(methylthio)methylenegly-cine ethyl ester (1) was prepared by reacting glycineethyl ester hydrochloride with CS2/Et3N/MeI and subse-quently accomplishing the alkylation of the intermediatethus obtained with MeI/K2CO3 as described in the litera-ture.13The starting material, 2-amino-4,5-diphenylfuran-3--carbonitrile (2) was prepared according to a modifiedGewald method.14Refluxing an equimolar mixture of 1 and 2 in dryacetic acid allows one-pot annelation yielded in a re-markably easy way and efficient double cyclized product5-methylthio-8,9-diphenylfuro3,2-eimidazo1,2-cpyri-midin-2(3H)-one (3) in 82 % yield (Scheme 1). The1H-NMR spectrum of 3 exhibited a two-proton singletfor CH2 at  4.20 ppm, a three-proton singlet for oneSCH3 at  2.70 ppm, two multiplets at  7.69 and 7.47ppm for ten protons of two phenyl groups. No peakswere found for NH2 ( 5.10 ppm) and a carboethoxygroup ( 4.29 and 1.28 ppm). The 13C-NMR spectrumdisplayed signals at  170.14 ppm for C=O carbon andat  50.43 ppm for methylene carbon at position C-3 ofthe molecule. The rest of the spectrum was in goodagreement with the structure 3.634 M. M. H. BHUIYAN et al.Croat. Chem. Acta 78 (4) 633¿636 (2005)Compound 2 was readily cyclized to the correspond-ing 4-amino-2,5,6-triphenylfuro2,3-dpyrimidine (4) upontreatment with benzonitrile and NaOMe in refluxing 2-propanol (Scheme 2). Reaction of compound 2 with for-mamide gave the corresponding 4-amino-5,6-diphenyl-furo2,3-dpyrimidine (5) which was then allowed to reactwith chloroacetaldehyde to yield 8,9-diphenylfuro3,2-e-imidazo1,2-cpyrimidine (6). The 1H-NMR and 13C-NMRspectra supported the assigned products 4, 5 and 6 re-spectively (see Experimental).Compound 2 also underwent cyclization with formicacid to afford 5,6-diphenylfuro2,3-dpyrimidin-4(3H)-one(7) which was then converted to its tosyl derivative (8)with p-TsCl. The proposed structures for the products 7and 8 were supported by their spectral data (see Experi-mental).ANTIMICROBIAL SCREENINGAntibacterial activityNewly synthesized compounds 3–8 were screened in vi-tro for their antimicrobial activities against bacteria B.cereus, S. dysenteriae and S. typhi using disc diffusionmethod.15 N,N-Dimethyl formamide (DMF) was used, asa solvent to prepare desired solution (1 %) of the com-pounds initially. Proper control was maintained with DMF.The inhibition zones of microbial growth (100 g/disc)produced by different compounds were measured in mil-limeters at the end of an incubation period of 48 h at(352) °C (Table I). DMF alone showed no inhibiton zone.Ampicillin (25 g/disc) was used as a standard antibioticfor the evaluation of the antimicrobial activity. The screen-ing results indicate that not all compounds exhibited an-tibacterial activity. Some compounds showed weak to mo-derate activity against all the organisms tested. Compound3 showed better activity compared with other synthesiz-ed products.Antifungal activityNewly synthesized compounds 3–8 were screened for theirantifungal against M. phaseolina, F. equiseti, A. alternataand C. corchori using poisoned-food technique.16 DMF(1 %) was used as solvent and the inhibition zones weremeasured in millimeters at the end of an incubation pe-riod of 48 h at (352) °C (Table II). Nystatin was used asa reference to evaluate the potency of the tested chemi-cals.Amongst the synthesized compounds screened for theantifungal activity, compounds 3, 4 and 6 showed excel-lent results against F. equiseti, which were also greaterthan that of the standard antibiotic, Nystatin. Compound3 also showed better inhibition for other fungi. The othercompounds also exhibited moderate to good activityagainst the tested organisms.SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME FUSED PYRIMIDINES 635Croat. Chem. Acta 78 (4) 633¿636 (2005)TABLE I. Antibacterial activity of compounds 3–8.Comp. B. cereus S. dysenteriae S. typhi3 14 9 174 7 – –5 – – –6 6 – 87 8 6 –8 6 – 7Ampicillin 21 30 24TABLE II. Antifungal activity of compounds 3–8.Comp. M. phaseolina F. equiseti A. alternata C. corchori3 65.52 68.75 42.31 22.724 29.4 55.0 27.1 35.55 42.0 28.35 61.30 33.06 25.7 55.0 48.2 20.457 31.9 29.0 22.9 22.108 50.0 19.2 52.4 26.68Nystatin 71.78 44.7 51.55 40.51O NH2PhPhCNNNNOOSCH3PhPhNCH3S SCH3CO2EtO NPhPhNHSCH3COOEtNOPhPh NNNHSCH3OOEtEtOHCH3SH+132Scheme 1.O NNHOPhPhO NH2PhPhCNO NNNH2PhPhO NNNH2PhPh PhNNNOPhPhO NN-TsOPhPhClCH2CHOHCONH2HCO2HPhCN2 45678p-TsClScheme 2.REFERENCES1. C. C. Cheng, Prog. Med. Chem. 6 (1969) 67–75.2. D. B. Scott McNair, T. L. V. Ulbrient, M. L. Rogers, E. Chu,and C. Rose, Cancer Res. 19 (1959) 15–19.3. Sankyo Co Ltd; Ube Industries Ltd. Japan Kokai Tokyo Ko-ho JP 59 36,667; Chem. Abstr. 101 (1984) 110939z.4. J. P. Jonak, S. F. Zakrzewski, and L. H. Mead, J. Med. Chem.15 (1972) 662–64.5. E. A. Falco, Br. J. Pharmacol. 6 (1961) 185–190.6. V. J. Ram, Arch. Pharm. (Weinheim, Ger.), 323 (1990)895–899.7. R. E. Howells, J. Tinsley, E. Devaney, and G. Smith, ActaTrop. 38 (1981) 289–305.8. De Angelis, G. Gerald, and H. J. E. Hess, US Pat (1973)3755583; Chem. Abstr. 79 (1973) 115624e.9. F. Sauter, J. Frohlich, and A. Z. M. S. Chowdhury, Sci. Pharm.64 (1996) 647–653.10. V. M. Patil, S. S. Sangapure, and Y. S. Agasimudin, IndianJ. Chem., Sect. B 23 (1984) 132–135.11. H. Takashi, S. Kenji, and T. Y. Nakayama, J. Heterocycl.Chem. 28 (1991) 263–267.12. M. M. H. Bhuiyan, K. M. M. Rahman, M. K. Hossain, andM. Fakruddin, Pakistan J. Sci. Ind. Res. 47 (2004) 256–258.13. F. Sauter, J. Frohlich, K. Blasl, and K. Gewald, Heterocycles40 (1995) 851–866.14. K. Gewald, E. Schinke, and H. Bottcher, Chem. Ber. 99(1966) 94–100.15. A. W. Bauer, W. M. M. Kirby, J. C. Sherris, and M. Turck,Am. J. Clin. Pathol. 45 (1966) 493–496.16. R. K. Grover and J. D. Moore, Phytopathology 52 (1962)876–880.SA@ETAKKondenzirani pirimidini. II dio: Sinteza i antimikrobna aktivnost nekihfuro[3,2-e]imidazo[1,2-c]pirimidina i furo[2,3-d]pirimidinaM. M. H. Bhuiyan, Khandker M. M. Rahman, M. K. Hossain, M. A. Rahim i M. I. Hossain2-Amino-4,5-difenilfuran-3-karbonitril (2) u reakciji s etilnim esterom N-bis(metiltio)metilenglicina (1)daje produkt dvostruke ciklizacije – 5-metiltio-8,9-difenilfuro3,2-eimidazol1,2-cpirimidin-2(3H)-on (3). Ta-ko|er, u reakciji s benzonitrilom spoj 2 daje 4-amino-2,5,6-trifenilfuro2,3-dpirimidin (4). Grijanjem spoja 2 sHCONH2 dobiven je 4-amino-5,6-difenilfuro2,3-dpirimidin (5), koji reakcijom s kloracetaldehidom daje 8,9-difenilfuro2,3-dimidazo1,2-cpirimidin (6). Reakcijom 2 s HCOOH dobiven je 5,6-difenilfuro2,3-dpirimi-din-4(3H)-on (7), koji je preveden u tozilat (8). Spojevima 2-8 ispitana je antimikrobna aktivnost.636 M. M. H. BHUIYAN et al.Croat. Chem. Acta 78 (4) 633¿636 (2005)

Kondenzirani pirimidini. II dio: Sinteza i antimikrobna aktivnost nekih furo[3,2-e]imidazo[1,2-c]pirimidina i furo[2,3-d]pirimidina

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