IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 Synthesis o f 3-C-Spiro Ring Nucleoside Analogues, of Possible Biological Activity E. M.Hussain Departme nt of Chemistry, College of Education, I bn Al-Haitham Unive rsity of Baghdad Abstract In this study , new derivatives of 3-C-sp iro ring nucleoside analo gues wer e sy nthesized. The structures of these derivatives were characterized by infrared sp ectroscopy , 1 HNM R (some of them) and elemental analy sis. The nucleoside derivatives were test ed for inhibition of E-coli and were all found to be active. Introduction Nucleosides and nucleotides p lay a key role in many biosy nthesis and regulatory p rocess, an extremely imp ortant function takes p lace at the lev el of st ructure of ribo – and deoxy ribonucleic acids [1] . Several novel 5-substitut ed 2 / -deoxy uridine analogu es were evaluated as substrates for high ly p urified herpes simplex virus ty p e 1 (HSV-1) encod ed thy midine kinase d erived from HSV-1 (T K) gene- transfected murin e mammary car cinoma cells ,and hu man p latelet t hy midine p hosp hory lase [2,3] . The potential use of nucleoside analogues in antip arasite chemotherap y is also of great imp ortance and about three billion p eople in the world are affected by p arasitic diseases [4].Prot ozoan and helmintic p arasites have both a deficiency in denovo sy nthesis of p urine nucleotides , and the p urine salvage pathways are essential for their survival and growt h [5,6]. Thus,formy cin B [7],allopurinol riboside [8] and thiop urinol riboside [9] figure (1) are converted by a nucleoside p hosp hotransferase to their corresp onding nucleotides , which can either act as inhibitors of other essential enzy mes in p urine metabolism [6,9] or be incorp orated into t he nucleic acids of t hese organisms [8,10] . Eman [11] has sy nthesized different derivatives of 3 \ -alky l nucleoside analo gues [figur e 2]. These derivatives were tested for the inhibition of E-coli and were all found to be active. Sp irobicyclic cores disp lay an imp ortant role in the field of the d evelopment of new bioactive substances [12]. Firas [13] has p repared some derivatives of sp iro fused ring and imine p osition -3 of D-glucofur anose Fi gure (3) and were all found to have biolo gical activity . In this work I decided to sy nthesize new derivatives of nucleoside analo gues with sp iro ring at p osition-3 on D- glucofuranose ring. Experime ntal Materials All chemicals which were used were supp lied from M erk chemical Fluka AG, BDH chemicals, R iedel .De Haen AG,Acros Organics, Janssen Chemical and Hop kin and Wiliams. / HNM R sp ectra were recorded in Hitachi Perkin Emelr ,R-24 B at 60 M Hz , elemental analyzer was carried out by using Carlo Erba /M od 1106 and Infrared sp ectra were recorded by using Shimadzu -408 .All sy nthesized comp ounds were p urified by column chromatogr aphy by using silica gel (60-120) mesh .The biomaterials were obtained from Biomerieu x Ltd. IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 S ynthesis of 1,2:5,6 –Di-O-isopropylidene -3-C-p-tolouenoyl methyl - α –D-allo-he xo- Furanose .( 1 ) Compund 1 was used as astarting material, this derivative was p repared from the reaction of 3-ulose [14, 15] with p -methy lacetop henon according to the reference [11]. S ynthesis of 3-p-Tolouenoylelhene -1/2:5, 6-di-O-isopropylidne -α-D-glucofuranose.( 2) The mixture of dimethy l sulp hoxide (40ml), acetic anhydride (20ml), comp ound 1 (5.0g, 37.26 mmol) is made in a stopp ered conical f lask, and was stirred at room temp erature for (72h) and tlc (benzene: ether 9:1) showed that t he reaction was comp lete .The mixture was diluted with ice water (50ml) and the brown sy rup was separated by the decantation and the sy rup was washed with ice water (3x20ml), followed by the extraction with chloroform .The organic layer was dried and the solvent was remov ed under r educed pressure to afford a sy rup residue of deriv ative 2. S ynthesis of 1-[( / 1, / 2 –O-Isopropylidene ) ethyl ]-3,4-O-isopropylidene -8-( / 4-tolyl)-2- oxa-6-aza phe nyl spiro[4,4] nona -7-i mine . ( 3 ) A mixture of 2 (5.0 g, 13.36 mmo l), p henyl hy drazine (1.4 mL) and (5-10 drop s) of diethy lamine dissolved in (100mL) absolute ethanol, was r eflu xed for (48h). The solvent was evap orated and the residue was diluted with water and extracted with chlorofor m (3 x30ml). The organic layer was dried ov er ma gnesium sulp hate and the solvent was remov ed to give 3 as asy rup . S ynthesis of 1-[ / 1, / 2 –Dihydroxy ethyl ] -3,4,-O-isopropylidene -8- ( / 4-tolyl ) -2-oxa-6-aza phe nyl spiro [4,4] nona -7-imine .( 4) A solution of 3 (5.0g, 10.77 mmol) in (66%) acetic acid (20mL) was stirred for (24h) at room temp erature. The solution was evap orated under reduced p ressure and the resulting residue was re-evaporated with toluene twice (20ml) to give 4 as sy rup . S ynthesis of 1-[ / 1-Hyroxy methyl ] -3, 4-O-isopropylidene -8-( / 4-tolyl) – 2-oxa -6-aza phe nyl spiro [4, 4] nona-7-imine.( 5) Was added to a well st irred solution of 4 (5.0g, 11.79 mmol) in ethanol (40ml). A saturated solution of sodium hy drogen carbonate (12ml) followed by a solution of sodium p eriodate (2.5g, 10.75 mmol) in (50 ml) water. The mixture was st irred for (1h) at roo m temp erature. Ethy lene glycol (2ml) was added, and the solution was further stirred for (5) minutes .Sodium borohydride (0.44 g, 11.62 mmo l) was added to t he resulting aldehy do sugar with continuous stirring for (1h). The r eaction mixture was filtrated and extracted with chloroform .The or ganic lay er was dried and evap orated to give 5 as sy rup . S ynthesis of 1-[ / 1 – Benz oyl methyl ] -3, 4-O- isopropylidine -8-( / 4-tolyl) -2-oxa -6-aza phe nyl spiro [4, 4] nona -7-imine. (6) Compound 5 (4.0g,10.15 mmo l) in anhydrous benzene (60 ml) containin g p y ridine (6mL) was benzoy lated with benzoy l chloride (1.42 ml,10.10 mmo l).After stirring for (24h) at room temp erature ,the mixture was p oured into ice water (100ml) .The or ganic lay er was sep arated and washed with water (3x30ml) ,dr ied and evap orated to give 6 as sy rup . S ynthesis of 1-[ / 1-Benzoyl methyl]-8- ( / 4-tolyl)-2-oxa-6-aza phe nyl spiro [4, 4] nona -7- imino -3, 4-di-O-triflouro acetate. (7) water (2ml) and trifluoroacetic acid (20ml) was added to a solution of 6(5.0g,10.04mmol) in acetic acid (20ml) ,.The resulting mixture was st irred for (5h) at room temp erature .The reaction mixture was then neutralized with solid sodium hy drogen carbonate and extracted with dich loromethane (2 x100ml).The combined extracts were dr ied and the solvent was removed to give a sy rup .This sy rup was immediately treated with t rifluoroacetic anhydride (4ml) in a mixture of anhy drous benzene (40ml) and anhydrous py ridine (8ml) with st irring for (24h) at room temp erature .Ice water was added to the mixture and the or ganic lay er was sep arated ,dried and concentrated under reduced p ressure .Traces of py ridine were removed by co -evaporation with dry toluene (2x30 ml) to give 7 as sy rup . S ynthesis of 7 [ / 1-Benz oyl methyl] - / 4-O-trifloouro acetyl - / 8-(4-tolyl) - / 2-oxa- / 6-aza phe nyl spiro [4, 4] nona- / 7- imino] the ophylline .( 8 ) IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 The theop hy lline mer cury salt 9 was sy nthesized according to the reference [16]. This salt(0.56 g,1.54 mmol) was p owdered ,susp ended in (50ml) sodium dried xy lene and the solvent was distilled of to remove the traces of water azeotrop ically .When the temperature of mixture was raised to 137c o ,the suspension was allowed to cool (below 50c o ) .Compound 7 (1g,1.53 mmol) in xy lent (20mL) was added to the suspension and reflu xed with st irring for (30 h ) .The traces of theop hy lline salt was filtrated from the hot xy lene and washed with dichloromethane (20ml) .The or ganic layer was dried and remov ed to give acety lated nucleoside 8 as a sy rup . 1 HNM R (CDCL3) δ:2.5(3H,S,CH3Ar) ; 2.82(2H,s,CH2- / 9); 3.2,3.4(6H,s,s,2NCH3); 3.8-4.9 (4H,m,H- / 4,H- / 1 and H a ,H b CH2OBZ); 5.9 (1H,d,H- / 3), 6.8-8.8 (15H,m,ArH and base ) . S ynthesis of 7[( / 1-Hydroxy methyl) - / 4-hydroxy - / 8-(4-tolyl)- / 2-oxa- / 6-aza phenyl spiro [4,4] nona- / 7-imino] theophyllene.( 10 ) Compound 8(0.5 g, 0.69 mmol) and sodium metho xid (0.3 g, 5.55 mmol) wer e dissolved in ethanol (30mL) .The solution was stirred under reflu x for (24h) .The solvent was removed to give 10 as a sy rup . S ynthesis of 1[( / 1-Benzoyl methyl)- / 4-O-triflouro acetyl - / 8-(4-tolyl) - / 2-oxa- / 6- aza phenyl spiro [4, 4] nona - / 7-imino] uracil. ( 12 ) Anhy drous stannic chloride (0.6 ml) and few p ellets of molecular sive 4A was added to a mixture of 7 (2.0g,3.07 mmol) and silylated uracil 13 (0.8g,3.12 mmol)[comp ound 13 was sy nthesized by using the reference [17] ] in (40 ml) of anhydrous dichloromethane.The mixture was st irred at 20c o for (24h)The reaction mixture was p oured in to an excess of sodium bicarbonate solution and extracted with di chloromethane (3x40ml) .The or ganic layer was dried and r emoved to give 12 as semi solid . 1 HNM R (CDCL3).δ:2.4(3H,s,CH3Ar) ;2.7 (2H,s,CH2- / 9) ;3.7-4.9 [6H,m,H- / 1,H- / 4,H-4,H-5,and (H a ,H b ) CH2-OBZ];5.8(1H,d,H- / 3) ; 6.5(1H,b,NH) ;6.9-8.9(14H,m,ArH). S ynthesis of 1[( / 1-Hydroxy methyl ) - / 4-hydroxy - / 8- (4-tolyl) - / 2-oxa- / 6-aza phenyl spiro [4, 4] nona - / 7-imino] uracil. (14) Flowing the same p rocedure of the p reparation of comp ound 10, the comp ound 12 (0.5g, 0.74 mmo l) and sodium metho xide (0.3 g, 5.55mmol) were dissolved in ethanol (30mL). The reaction mi xture was st irred under reflux for (18h) to give 14 as a sy rup . Results and Discussions Compound (1) was chosen as a starting material for the sy nthesis of a new derivative of 3-C-sp iro ring nucleoside analo gues .The st rategy used for the sy nthesis of 2, 3, 4, 5,6,7,8,10,11,12 and 14 was st arted with derivative 1 in a ser ies of reactions [scheme 1]. Compound 2 was sy nthesized by the dehy dration of 1 with DM SO / Ac2O [18, 19] and gave 2. The IR sp ectra of 2 showed the disapp earance of st retching band at 3360cm -1 for hy droxy l group with appearance of st retching b and at 1640cm -1 for (C=C).Tables (1) and (2) showed the characterist ic IR absorp tion bands and p hy sical p rop erties for all of the new d erivations .The α , β-unsaturated branched chain 2 undergoes 1/3-and addin g the diamine (p henyl hy drazine ) to give the sp iro derivative 3 [20,21].Co mpound 3 was characterized by IR and elemental analysis .The IR sp ectra of 3 showed the disapp earance of st retching band at 1640 cm -1 for ( C=C ) and disapp earance of (CO) group at 1690cm -1 .To obtain the derivative 5 ,t he isop ropy lidene acetal at C- / 1 and C- / 2 was removed with acetic acid followed by p eriodate oxidation and borohy dride r eduction .The / 1-hy droxy l group was p rotected with benzoy l group by using benzoy l chloride to give the derivative 6.The IR sp ectra of 6 showed a st retching band at 1700cm -1 for (CO) group with the disapp earance of (OH) group at 3385cm - 1 .Compound 6 was t reated with a mixture of trifluoroacetic acid and acetic acid followed by the reaction with trifluoroacetic anhydride gave 7. Compound 8 was p repared by using the Koenigs-Knorr condensation method [22,23].The 1 HNM R sp ectrum of 8 showed a singlet at 2.5 for p -methy l group ,singlet at 2.82 for methy lene group (CH2-9 / ),two singlet at 3.2 ,3.4 for (2NCH3) , multiplet at 3.8-4.9 for (H-4 / ,H-1 / and H a , H b CH2OBz) ,doublet at 5.9 for H-3 / and IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 multiplet signals at 6.8-8.8 for aromatic rings p rotons and base. The treatment of comp ound 8 with sodium methoxide in ethanol under r eflu x [24] gave 10.Compound 7 was treated with silylated uracil [17] gave12.The suggest ed mechanism of the nucleoside formation 12 is given below [scheme 2].The 1 HNM R sp ectrum of 12 showed a singlet at 2.4 for p -methy l group , singlet at 2.7 for methy lene group , multip let at 3.7-4.9 for H- / 1 , H- / 4 , H-4 , H-5 and H a , H b for CH2-OBz , doublet at 5.8 for H- / 3 ,broad signal at 6.5 for NH uracil and multiplet at 6.9-8.9 for aromatic p rotons. The treatment of comp ound 12 with sodium methoxide in ethanol gave 14 as a sy rup .Compound 10 and 14 exhibited a biolo gical activity against E-coli b acteria. Compound 10 exhibited ahigher d egree of activity than the other (table 3). Re ferences 1.Perigaud, C.and Gosselin, G. (1992) J.L:Imb ach, Nucleosides and Nucleotides; 11(2-4): 903-945. 2.Clercq ,De. (1993) E, Adv. Virus, 42: 1-55. 3.Christina Bohman,Jan Balzarin i,Pict Wigerinck,Art hur Van Aershot, Piet Herdewijn, and Erik De Cler cq(1994)American Society Biochemistry and M olecular Biolo gy ,Ine,269,11,8036-8043. 4.Wan g, C.C. (1982) Treds Biochem. Sci; 7:354-356. 5.Wan g, C.C. (1984) J.M ed.Chem. 27:1-9. 6.Jaffe, J.J. and Ann.N.Y. (1975), Acad.Sci, 255:306-316. 7.Carsan, D.A.and Chang, K.P. (1981) Bioch em.Biophy s, Res., 100:1377-1383. 8.Nelson,D.J.; LaFon,S.W.; Tuttle,J.V.; M iller,W.H.; M iller,R.L.; Krenitsky ,T. A.; Elion,G.B.; Beodns,R.L and M arr,J.J,(1979), Biol.Chem., 245:11544-11549. 9.M arr,J.J.;Berens,R.L.;Nelson,D.J.;Krenitsky ,T.A.;sp ector,T.;Lafon,S.W.and Elion,G.B. (1982), Biohem.Pharmacol., 31 :143-148. 10. Rainey, P.; Santi, D.V.I., (1983), Natal Acad . Sci.USA, 80:288-292. 11.Eman, M .H. (2001); ''Sy nthesis of 3/ -C-alkyl nucleoside analogues of p ossible biological activity ''; .Ph.D.thesis, Baghdad University . 12.Boivin, T.L.B.(1987), Tetrahedron, 43:3309. 13.Al-Joboury ,F.S. (2006) Sy nthesis of new sp iro, Fused ring and imine derivatives of D- glucose at C-3 and study their effect on serum (ALP and GGT)''. Ph.D.thesis, Baghdad University . 14.Glen,W.L.;M y ers,G.S. and Grant,G.A. (1951) J.chem.Soc.,2569. 15.Butterworth, R.F. (1971), Hanessian, S.Sy nthesis, 76: 16.Freestone,A.J.; Hough, L. and Rich ardson, A.C. (1973), Carbohy drate Research, 28:382. 17.EL-Barbary ,A.A.;EL-Brollosy ,N.A.and Pedersen,E.B. (1996),Nielsen C. Sul- ur letters,20:36. 18.AL-Ghrary , N.F. (1997),'' Sy thesis of 3/, 3-gem-di-C-nitromethy l nucleoside analogu es of p ossible biolo gical activity ''.Ph.D.Thesis, Baghdad University . 19.AL-Shara , ey,A.A.(2000), ''Sythesis of 3/,3/-gem-di-C-alkyl and 3/-C-alkyl nucleoside analogues''.Ph.D.T hesis, Baghd ad university . 20.Kennedy J.F. and Willams.N.R. (1979), Carbohy d .Chem. 13:96. 21.Rosenthal .A. and Dooley.K. (1976), Carbohy d. Res., 52:79. 22.M otgmery ,J.A. and Thomas,H.J.,(1962),Advan.Carbohy dr. Chem., 301: 17. . 638:3,.Ed.Inter.Chem.Angew,)1964( .W,Pfl idererand . E,Buhler . 23 IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 (S cheme 1) H3C H3C O O O O O CH3 CH3 CH2C O H3C HO H3C H3C O O O O CH3 CH3H3C C CH O O H3C H3C O O O Ph N N C CH2 R O O CH3 CH3 O HO HO Ph N N C R CH2 O O C H3 CH3 HO Ph N N C R CH2 O O O CH3 CH3 BZ O Ph N N C R C H2 O O O CH3 CH3 BZO Ph N N C R CH2 O O C O Cf3 O C O Cf3 BZ O Ph N N C R CH2 O N N N N O O CH3 CH3 O C Cf3 O N N O H OO BZ O Ph N N C R CH2 O C O Cf 3 N N O H O OHO Ph N N C R C H2 OH N NN N CH3 O CH3 O O OH CH2 C R N N Ph HO R= CH3 a: DMSO , Ac2O. b: Phenyl hydrazine, Die thyl amine, Absol ute ethanol. c:66%AcOH, d: NaIO4 the n NaBH4. e: BzCl,Pyridine, Benzene. f:CF3COOH, CH3COOH, H2O than (CF3CO)2O,Benzene,Pyridine. g: The ophylline Mercuric salt, Xylene, Δ . h: CH3ONa, C2 H5OH, reflux. i: Si lylated Uracil, CH2Cl 2. a b c d i h f g e (4) (3) (2) (1) (10) (8) (6) (5) (12) (14) (7) h IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 (S cheme 2) Fig.1 Fig.( 2) N N N N O X HOHO H O N N N O HO HO HO OH Allopurinol riboside (X=OH) Thiopurinol riboside (X=SH) Formy cin B N N N N OHO HO OH CH3 O O CH 3 R N N O HO OH R H O HO ) CH 3CH OH C H H , N N H3 C H3C O R = ( IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 Fig.( 3) Table (1): Characteristic IR a bsorption bands of the ne w derivatives Infrared data (υ max cm -1 ) (film) Compound No. (C=C) stretching alip hatic 1640;(CO)1690; (C=C) aromatic ring 1480 – 1610; (C=C) bendin g 815 2 (C=C) aromatic ring 1460-1630;(C=N) 1660 ;( C=C) bendin g 780. 3 (OH) 3400 ; (C=C) aromatic rin g 1480-1640,(C=N) 1660; (C=C) bending 800. 4 (OH) broad 3385;(C=C) aromatic ring1500-1620;(C=N) 1640 (C=C) bending 815. 5 (CO)1700;(C=C) aromatic ring 1480-1610; (C=N)1630;(C=C)bending for p -substitutions ring 830 ;(C=C)bendin g for benzoy l ring 670. 6 (CO) for OBz 1710;(CO) for CO2Cf3 1690;(C=C) aromatic rin g 1460-1610 ;(C=N) 1630;(C=C) bendin g 810-720. 7 (CO) for OBz and CO2Cf3 1700,1685;(CO) for CONH 1675;(C=C) aromatic rin g 1445-1620 ;(C=N) 1640 (C=C) bending 700,800. 8 (OH)3340,(CO) 1680;(C=C)1520-1600;(C=N)1610; (C=C) bending 820. 10 (NH)3410;(CO) for OBz andCO2Cf3 1700,1680;CONH 1670;(C=C),aromatic rin g 1460-1610 ;(C=N)1620 (C=C) bending 710,825. 12 (NH,OH)3200,3400;(CO)1670; (C=C) aromatic ring 1500-1610;( C=N)1620 ;( C=C) bendin g 810. 14 H3 C H3C O O O O O CH 3 CH 3NH O O O H3 C H3C O O O O O O N OCH3 O O C H3 C H3 IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 Table (2): Physical propertie s and elemental analysis for new derivatives. Elemental analysis calcul ated(found) Yiel d % N% H% C% Rat of flow in thi n lyer chromatograp hy (tl c),Rf (sol vent) Physi c al state Formul a & Comp . No. 65 6.95 (7.15) 67.37 (67.1) 0.62 (benzene: ether 9:1) Sy rup C21 H26 O6 (2) 50.2 7 6.03 (5.89 ) 6.89 (6.77) 69.82 (70) 0.57 (benzene:n- hexane9:1) Sy rup C27H32N2O5 (3) Elemental analysis calcul ated(found) Yiel d % N% H% C% Rat of flow in thi n lyer chromatograp hy (tl c),Rf (sol vent) Physi c al state Formul a & Comp . No. 60.5 5 6.6 (6.35 ) 6.6 (6.15) 67.92 (68.12 ) 03.5 (benzene; methanol 9.5 :0.5) Sy rup C24H28N2O5 (4) 30.2 7.10 (6.88 ) 6.59 (6.25) 70.05 (70.3) 0.42 (benzene; methanol 9:0.5) Sy rup C23H26N2O4 (5) 67.8 5.62 5.33) ( 6.02 (6.04) 72.28 (71.91 ) 0.72 (benzene;ethy la cetate 9.5;0.5) Sy rup C30H30N2O5 (6) 48 4.3 3.98) ( 3.69 (3.49) 57.23 (56.89 ) 0.65 (benzene: methanol 9:0.5) sy rup C31H24N2 O7F6 (7) 71.5 4.3 (3.98 ) 3.69 (3.44) 57.23 (56.89 ) 0.48 (benzene: methanol 9:0.5) sy rup C36 H31 N6 O7F3 (8) 55 11.7 3 (11.5 3) 4.32 (4.59) 62.79 (63.11 ) 0.33 (benzene: methanol 9:0.5) sy rup C27H28N6O5 (10) 79.2 8.64 (8.28 ) 4.16 (3.86) 61.11 (61.46 ) 0.52 (benzene: methanol 9:0.5) Semi solid C33H27N4O7F3 (12) 42.3 12.5 (12.2 1) 5.35 4.97)( 64.28 (64.81 ) 0.4 (benzene: methanol 9:0.5) sy rup C24H24N4O5 (14) IBN AL- HAITHAM J. FO R PURE & APPL. SC I VO L.22 (4) 2009 Table (3):Effect of antimicrobial agents on Esche richia Coil Effect of nucleosid e derivatives on the growt h of E-coli b acteria Con. gm/m l 0.0 9 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0. 9 1 Com . No. + _ _ _ _ _ _ _ _ _ _ 10 + _ _ _ _ _ _ _ 14 + U. base + T. base + Blan k (-) No growt h, U=Uracil (+) Growth , T=Theop hy lline 2009) 4 (22مجلة ابن الهیثم للعلوم الصرفة والتطبیقیة المجلد فعالیة بایولوجیة و ذویرسباحلقة C-3–وسید من نوع تحضیر ممثالت نیوكلی محتملة محمد حسینأیمان جامعة بغداد، ابن الھیثم – كلیة التربیة ،الكیمیاءقسم الخالصة اختیـر اذ3 فـي موقـع وسـبا یـر النیوكلیوسـید تحتـوي علـى حلقـة لمماثالتتم في هذا البحث تحضیر مشتقات جدیدة مـع 1 المـشتق مفاعلـهتـم اذ ، التفـاعالتسله من النیوكلیوسید بعد مروره بسل مماثالت لغرض تحضیر ابتدائیةة ماد1المشتق لغــرض . 2المــشتق مــن الموقــع ثالثــة للحــصول علــى مــاءجریئــةهیدریــد الخلیــك لغــرض ســحب نالسلفوكــسید وا ثنـائي مثیــل تحــیزا. 3طــى المــشتق أع،اذالفنیــل هیــدرازین مـع 2 المــشتق ةمفاعلــ تمــت ثالثــةالحـصول علــى حلقــة ســبایرو فــي موقـع حــامض الخلیـك تبعتهـا عملیـة أكـسدة واختـزال للحـصول علــى المع باسـت2و1فـي الموقـع )دیناالیزوبروبیلـ(مجموعـة الحمایـة إلزاحـــةالمناســـبة باســتخدام كاوریـــد البنزویـــل یــوفر الفرصـــة 1-أن حمایـــة مجموعـــة الهیدروكــسیل فـــي الموقـــع . 5 المــشتق بمـزیج مـن حـامض الخلیـك وثالثـي فلوریـد 6 عومـل المـشتق. 6عطـى المـشتق ،اذ أ 4 - و3-ي الموقـع فـمجموعـة االسـیتال مـع ملـح الزئبـق للثیـوفلین 7 المـشتق ةمفاعلـتمـت . 7 المـشتق إلعطـاءالخلیـك الخلیك تبعه التفاعل مع ثالثي فلورید انهیدریـد أن. 12النیوكلیوســید مماثـلأعطـى مـع مـشتق الـسیالیل للیوراسـیل 7 المـشتق تفاعـلأن. 8مماثـل النیوكایوسـید الـذي أعطـى 14 و 10یوسـید الحـرة المیثـانول أعطـى مـشتقات النیوكل كل علـى انفـراد مـع میثوكـسید الـصودیوم فـي12و8تسخین المشتقین ن لهــا فعالیـة بایولوجیــةأقــد وجـد ضـد بكتریــا القولـون و14 و 10البایولوجیـة للمــشتقات تمــت دراسـة الفعالیــة. علـى التـوالي .10وأكثرها فاعلیة كان المشتق