Quim. ov, Vol. 39, o. 1, 19-25, 2016 http://x.oi.org/10.5935/0100-4042.20150171 SYTHESIS AD BILGIAL ATIVITY F EW SEIES F GATI(IV) ESTES WITH, DIAETYLGLYIE Muhmm Ashfq,#, Muhmm Mhoo Ahme, Slm Shheen, ukhsn Tussm n Gilro iver, * Deprtment of hemistry, The Islmi University of Bhwlpur, Bhwlpur, Pkistn Institute of hemil Sienes, Bhuin Zkriy University, Multn, Pkistn entro e Biotenologí Genómi, Instituto Politénio ionl, eynos, 88710, Méxio Artigo eeio em 27/05/2015; eito em 14/09/2015; pulio n we em 11/11/2015 A iotive,-ietylglyine (DAG) n new orgnotin(iv) omplexes (Ts) (1-7) were synthesize. Spetrosopi tehniques were employe to hrterize DAG n Ts. FTI ws employe to verify, protetion of glyine y etyl groups. The ispperne of υ(h) t 3000-2600 m -1 showe e-protontion of free lign. The Δυ 150<200 m -1 of Ts 4-7 verifie ientte oorintion with tetrherl geometry. The Δυ of Ts 1 n 3 ws <200 m -1 exhiiting trns-otherl geometry while T 2 imer ws ssigne unique sinusoil view. The 1 H M spetr of Ts verifie their synthesis y e-protontion of DAG n no hemil shift ws foun ownfiel for roxyli i proton. The 13, 119 M n Mss spetrometri t lso supporte FTI n 1 H M esriptions. The Ts 4, 5, 6 n 7 (500 ppm) prove twie s tive ginst Esherihi oli s the stnr ntiioti enoxin (1000 ppm). The promising property of the Ts (4, 5, 6 n 7) is lerly ue to their tetrherl. The Ts 4 n 5 exhiite exellent tivity ginst M. minimum n goo tivity ginst T. stneum. LD 50 of ll the ompouns were etermine n Ts 4, 5 n 7 were foun to e tive. Keywors:,-iethylglyine; orgnotin(iv); omplexes; ntiteril; insetiie. ITDUTI rgnotin(iv) omplexes (Ts) hve een investigte on ount of ro spetrum of their uses in ily fiel of life. Prtiulrly, orgnotin(iv) esters hve een given importne on ount of their pplitions in the fiels of pestiie, ntiteril, n ntitumor gents, woo preservtives, mong others. 1-4 n the other hn, mino is n their erivtives show ntioxint tivity n enhne hormonl immunity whih inhiits lti i level. Interestingly, glyine ts s ntioxint s well s improves hormonl immune system. Therefore, lign,-ietylglyine hs een synthesize on the sis of potentil of glyine esrie in the literture. 3-5 The orgnotin(iv) esters hve een given speil ttention in the reent yers ue to their exellent phrmologil importne. 5,6 Moreover, orgnotin esters of mino is n -protete mino is hve een reporte s ioies for exmple, triylohexyltin(iv) lninte is use s fungiie n teriie n trilkyltin(iv) erivtives of oth mino is n -etylmino is ply s intermeite role for the synthesis of pepties. 7-9 In the lst two ees very little literture is foun on the orgnotin(iv) esters of -protete mino is. 10-14 n ount of ro spetrum of pplitions of orgnotin(iv) roxyltes s well -protete mino is n interesting fining of our erlier reserh work here we report the spetrosopi hrteriztion, n preliminry iologil investigtion of Ts of,-ietylglyine. 15-17 The toxiity iossys were lso stuie in ition to ntiteril n insetiil iossys of ll 1-7 Ts ginst Esherihi oli, Pseuomons eruginos, Klesiell pneumoni n Slmonell typhi strins with linil interest n Monomorium minimum, melyug n triolium stneum pests insets, respetively. 18 *e-mil: gilrors@hotmil.om # lterntive e-mil: hshfqiu@yhoo.om EXPEIMETAL Mterils n instruments Glyine, i-n-utyltin(iv) oxie, triphenyltin(iv) hlorie, triylohexyltin(iv) hlorie n triethylmine of Merk hemils were use s suh. The i- n tri-enzyltin(iv) hlorie were prepre oring to reporte proeure. 19 All orgni solvents were rie s per reporte proeures. 20 The FTI spetr were rrie out on JAS 302-ghgA spetrometer y KBr smpling tehnique from 4000-400 m -1. Finnign MAT 12 spetrometer ws use to reor EI-MS spetr for the etermintion of % m/z. Bruker AM 400 M ws use to reor 1 H, 13 n 119 spetr t HEJ Institute of hemil Sienes, University of Krhi. The hemil shifts were reporte reltive to (H 3 ) 4 Si n (H 3 ) 4 signl use s internl stnrs. Enoxin s referene rug ws use to etermine ntiteril tivity using is iffusion metho. Hlf mximl lethl ose (LD 50 ) of ompouns ws etermine y Brine Shrimp hthing metho s reporte. 21 Synthesis of,-ietylglyine (DAG) Glyine 5 g (66.7 mmol) n etyl hlorie 10.0 ml (133.4 mmol) were e in 100.0 ml ioxne n refluxe for 6 hours of retion time. The solvent ws remove uner vuum n the prout ws otine in n-hexne (Sheme 1). 22 4 3 2 1 H Sheme 1. Struture of, -ietylglyine (DAG)
20 Ashfq et l. Quim. ov Yiel: 60%, m.p.: 220 o, Soluility: H 2, H 3 H, H 3 H 2 H, n Hl 3. H nlysis (%) ntipyrene:, 45.2 (45.2); H, 5.7 (5.7) n, 8.7 (8.8), theoretil vlues re given in the prenthesis. FTI (KBr) m -1 : H: 3000-2600 ; (etyl): 1770 mw; (ronyl): 1730 sym, sp, 1610 sym msp; (ether linkge): 1080 sp. 1 H M (Dl 3 ) δ: H: 9.7 s; H-2: 3.90 s; H-3: 2.35 s. 13 M (Dl 3 ) δ: -1: 169.22; -2: 42.45; -3: 171.90; -4: 21.68. MS m/z: [H 2 H 2 (H 3 ) 2 ] + M + 159 (10%); [H 2 (H 3 ) 2 ] + 142 (15%); [H 2 (H 3 ) 2 ].+ 114 (100%); [H 2 - (H 3 )] + 71 (27%); [H 2 H 3 )] + 56 (38%); [H 2 ] + 28 (45%). Synthesis of orgnotin(iv) omplexes Diorgnotin(IV) omplexes (1 n 2) hve een synthesize y tking iutyltin(1v) oxie n,-ietylglyine in 2:1 (monomer) n 1:l (imer) molr rtios in ethnol n toluene (3:1, v/v) with the zeotropil removl of wter. The pproprite molr rtio (2:1/1:1) of silver slt of DAG n the orresponing orgnotin(iv) hlorie were refluxe for 6 h in hloroform to synthesize ompouns 3-7. The solvent were remove uner vuum. The synthesize ompouns were rerystllize in ifferent solvents. Ts hve een synthesize y opting the proeures s ite in literture n given in Sheme 2. 2,15-17,23 The ompouns re solule in orgni solvents n stle on room temperture. The nlytil t is orne to the propose stoihiometri rtio of omplexes. Diutyltin(IV)-i-,-ietylglyine(monomer) (1): [( 4 H 9 ) 2 { 2 H 2 (H 3 ) 2 }:,-ietylglyine 1 g (6.29 mmol) ws rete with iutyltin(iv) oxie 0.47 g (3.14 mmol) in 2:1 rtio in 66.0 ml ethnol n 33.0 ml toluene. erystllize in hloroform n ethnol in 1:2 rtio. Yiel: 78%. m.p.: 202-204 o. Soluility: H 3 H, H 3 H 2 H, Hl 3 n l 4. H nlysis (%) ntipyrene:, 43.7 (43.7); H, 6.2 (6.2) n, 5.8 (5.10), theoretil vlues re given in the prenthesis. FTI (KBr) υ(m -1 ): (etyl): 1765 mw; (ronyl): 1620 sym, sp, 1470 sym msp; Δυ:150; (ether linkge): 1025 sp; : 517 w; : 498 sp. 1 H M (Dl 3 ) δ: H-2: 3.82 s; H-4: 2.35 s; H-: 1.04 t (7); H-: 1.59 m; H-: 1.26 m; H-: 0.90 t (7). 13 M (Dl 3 ) δ: -1: 172.73; -2: 40.10; -3: 168.50; -4: 21.78; -: 23.50; -: 27.13; -: 26.48; -: 13.55. 119 M (H 3 ) 4 :-190.35. MS m/z: [( 4 H 9 ) 2 { 2 H 2 (H 3 ) 2 } 2 ].+ M + 548 (4%); [( 4 H 9 ){ 2 H 2 (H 3 ) 2 } 2 ] + 491 (53%); [( 4 H 9 ) 2 { 2 H 2 (H 3 ) 2 }] + 390 (100%); [( 4 H 9 ) 2 {H 2 (H 3 ) 2 }].+ 346 (37%); [{ 2 - H 2 (H 3 ) 2 } 2 ].+ 400 (21%); [{H 2 (H 3 ) 2 } 2 ] + 312 (27%); [( 4 H 9 ) 2 ] + 232 (15%); [( 4 H 9 )] + 175 (30%); [/H] + 119/120 (5%); [H 3 H 2 - H 2 ] + 43 (55%); [H 3 H 2 ] + 29 (33%); [H 3 ] + 15 (14%). Diutyltin(IV)-i-stnnoxne-i--etylglyine (imer) (2): [{( 4 H 9 ) 2 2- H 2 (H 3 ) 2 } 2 ] 2 :,-ietylglyine1 g (6.29 mmol) ws rete with iutyltin(iv) oxie 0.94 g (6.29 mmol) in 2:1 rtio in 66.0 ml ethnol n 33.0 ml toluene. erystllize in hloroform n n-hexne in 1:2 rtio. Yiel: 72%. m.p.: 220 o. Soluility: H 3 H, H 3 H 2 H, Hl 3 n l 4. H nlysis (%) ntipyrene:, 41.3 (41.3); H, 6.4 (6.4) n, 3.4 (3.4). FTI (KBr) υ(m -1 ): (etyl): 1755 w; (ronyl): 1608 sym, sp, 1455 sym msp; υδ: 143; (ether linkge): 1018 sp; : 522 m; : 490 sp. 1 H M (Dl 3 ) δ: H-2: 4.00 s; H-4: 2.36 s; H-: 1.91 t (7); H-: 1.61 m; H-: 1.27 m; H-: 0.94 t (7). 13 M (Dl 3 ) δ: -1: 173.73; -2: 41.19; -3: 170.44; -4: 22.51; -: 29.50; -: 27.59; -: 26.63; -: 14.10. 119 M (H 3 ) 4 : -210.4, -216.2. MS m/z: [{( 4 H 9 ) 2 2 H 2 (H 3 ) 2 } 2 ] 2 + M + ; [( 4 H 9 ) 2 2 H 2 (H 3 ) 2 ] + 390 (58%); [( 4 H 9 ) 2 H 2 (H 3 ) 2 ].+ 346 (38%); [( 4 H 9 ) 2 H 2 (H 3 ) 2 ] + 333(16%); [ 2 H 2 (H 3 ) 2 ].+ 276 (34%); [H 2 (H 3 ) 2 ] + 232 (45%); [( 4 H 9 ) 2 ] + 229 (100%); [/H] + 119/120 (13%); [H 3 H 2 H 2 ] + 43 (70%); [H 3 H 2 ] + 29(27%); [H 3 ] + 15 (42%). Dienzyltin(IV)-i-,-ietylglyine (3): [( 6 H 5 H 2 ) 2 { 2 H 2 (H 3 ) 2 } 2 ]:,-ietylglyine 1 g (6.29 mmol) n Ag 3 1.06 g (6.29 mmol) were rete with ienzyltin(iv) hlorie 1.16 g (3.14 mmol) in 2:1 rtio in 100.0 ml hloroform. erystllize in hloroform n enzene in 1:2 rtio. Yiel: 79%. m.p.: 166 o. Soluility: DMS, H 3 H, H 3 H 2 H, Hl 3 n l 4. H nlysis (%) ntipyrene:, 50.5 (50.5); H, 4.9 (4.9) n, 4.5 (4.5). FTI (KBr) υ(m -1 ): (etyl): 1760 m sp; (ronyl): 1635 sym, sp, 1462 sym msp; Δυ: 173; (ether linkge): 1032 m; : 515 m; : 505 w. 1 H M (Dl 3 ) δ: H-2: 3.80 s; H-4: 2.10 s; H-: 2.87 s; H-: 7.05 t (7); H-: 7.37 m; H-e: 7.80 t (7). 13 M (Dl 3 ) δ: -1: 171.34; -2: 39.23; -3: 169.89; -4: 21.62; -: 20.14; -: 136.19; -: 127.60; -: 130.34; -e: 125.53. 119 M (H 3 ) 4 : -127.5. MS m/z (%): [( 6 H 5 H 2 ) 2 {( 2 H 2 (H 3 ) 2 } 2 ] + M + 616 (7%); [( 6 H 5 H 2 ){ 2 H 2 (H 3 ) 2 } 2 ] + 525 (77%); [( 6 H 5 H 2 ) 2 { 2 H 2 (H 3- ) 2 }].+ 458 (100%); 2 +2 / H 2 ( / ) 2 (p.1) 4 2 +4 / H [{ 2 ( / )} 2 ] 2 (p.2) 2 2 l 2 +2 / H+2Ag 3 ( / ) 2 2 +2Agl (p. 3) 3 l + / H +Ag 3 ( / ) 3 +Agl (p.4-7) / =(H 3 ) 2 H 2 -, =H 3 H 2 H 2 H 2 - = e,,, Sheme 2. Synthesis of orgnotin(iv) omplexes
Vol. 39, o. 1 Synthesis n iologil tivity of new series of orgnotin(iv) esters with,-ietylglyine 21 [{ 2 H 2 (H 3 ) 2 } 2 ] + 434 (10%); [( 6 H 5 H 2 ) 2 - {H 2 (H 3 ) 2 }] + 414 (57%); [{H 2 (H 3 ) 2 } 2 ] + 346 (41%); [( 6 H 5 H 2 ) 2 ].+ 300 (15%); [( 6 H 5 H 2 )] + 209 (55%); [/H] + 119/120 (10%); [ 6 H 5 H 2 ] + 91 (48%); [ 6 H 5 ] + 77 (18%). (21%); [( 6 H 5 ) 3 ] + 349 (25%); [ 2 H 2 (H 3 ) 2 ] + 276 (32%); [( 6 H 5 ) 2 ] + 272 (30%); [H 2 (H 3 ) 2 ].+ 232 (38%); [H 2 (H 3 ) 2 ] + 114 (43%); [( 6 H 5 )] + 195 (36%); [/H] + 119/120 (17%); [( 6 H 5 )] + 77 (24%).[H 2 -(H 3 )] + 71 (17%). Trienzyltin(IV)-,-ietylglyine (4): [( 6 H 5 H 2 ) 3-2 H 2 (H 3 ) 2 ]:,-ietylglyine 1 g (6.29 mmol) n Ag 3 1.06 g (6.29 mmol) were rete with trienzyltin(iv) hlorie 2.64 g (6.29 mmol) in 1:1 rtio in 100.0 ml hloroform. erystllize in hloroform n ethnol in 1:2 rtio. Yiel: 82%. m.p.: 191 o. Soluility: ( 2 H 5 ) 2, H 3 H 2 H n Hl 3. H nlysis (%) ntipyrene:, 58.9 (58.9); H, 5.3 (5.3) n, 2.5 (2.5) the lulte vlues re in the prenthesis. FTI (KBr) υ(m -1 ): (etyl): 1753 m w; (ronyl): 1660 sym, sp, 1488 sym msp; Δυ: 188; (ether linkge): 1050 m; : 510 m; : 498 w. 1 H M (Dl 3 ) δ: H-2: 3.92 s; H-4: 2.25 s; H-: 2.64 s; H-: 7.73 t (7); H-: 7.29 m; H-e: 7.91 t. 13 M (Dl 3 ) δ: -1: 168.66; -2: 40.25; -3: 170.35; -4: 21.57; -: 19.87; -: 138.10; -: 129.18; -: 128.43; -e: 124.93. 119 M (H 3 ) 4 : -142.71. MS m/z: [( 6 H 5- H 2 ) 3 2 H 2 (H 3 ) 2 ] + M + 549 (7%); [( 6 H 5 H 2 ) 2 2- H 2 (H 3 ) 2 ] + 458 (100%); [( 6 H 5 H 2 ) 3 ] + 391 (72%); [( 6 H 5- H 2 ) 2- H 2 (H 3 ) 2 ].+ 367 (50%); [ 2 H 2 (H 3 ) 2 ].+ 276 (40%); [( 6 H 5 H 2 ) 2- ] + 300 (57 %); [H 2 - (H 3 ) 2 ] + 232 (45%); [( 6 H 5 H 2 )- ] + 209 (52%); [/ H] + 119/120 (8%), [H 2 (H 3 ) 2 ] + 114 (38%); [ 6 H 5 H 2 ] + 91 (34%); [ 6 H 5 ] + 77 (12%); [H 2 - (H 3 )] + 71 (30%). Triutyltin(IV)-,-ietylglyine (5): [( 4 H 9 ) 3 2 H 2 - (H 3 ) 2 ]:,-ietylglyine 1 g (6.29 mmol) n Ag 3 1.06 g (6.29 mmol) were rete with triutyltin(iv) hlorie 2.04 g (6.29 mmol) in 1:1 rtio in 100.0 ml hloroform. erystllize in hloroform. Yiel: 85%. m.p.: 105 o. Soluility: H 3 H, H 3 H 2 H, Hl 3 n THF. H nlysis (%) ntipyrene:, 48.2 (48.2); H, 7.8 (7.8) n, 3.1 (3.1). FTI (KBr) υ(m -1 ): (etyl): 1765 m w; (ronyl): 1674 sym, sp, 1515 sym msp; Δυ: 159; (ether linkge): 1043 m; : 517 m; : 505 w. 1 H M (Dl 3 ) δ: H-2: 3.77 s; H-4: 2.55 s; H-: 0.76 t; H-: 1.39 m; H-: 1.25 m; H-: 0.88 t (7). 13 M (Dl 3 ) δ: -1: 172.95; -2: 40.11; -3: 170.61; -4: 21.71; -: 16.50; -: 27.12; -: 26.30; -: 13.56. 119 M (H 3 ) 4 : 123.7. MS m/z: [( 4 H 9 ) 3 2 H 2 (H 3 ) 2 ] + M + 447 (4%); [ 4 H 9 ) 2 2 H 2 (H 3 ) 2 ] + 390 (100%); [ 4 H 9 ) 2 H 2 (H 3 ) 2 ] + 333 (35%); [ 4 H 9 ) 3 ] + 289 (85%); [ 2- H 2 (H 3 ) 2 ].+ 276 (39%); [( 4 H 9 ) 2 ] + 233 (22%); [H 2 (H 3 ) 2 ].+ 232 (49%); [( 4 H 9 )] + 175 (45%); [H 2 (H 3 ) 2 ] + 114 (37%); [/H] + 119/120 (5%); [H 2 (H 3 )] + 71 (17%); [H 3 H 2 ] + 29 (25%); [H 3 ] + 15 (8%). Triphenyltin(IV)-,-ietylglyine (6 ) : [( 6 H 5 ) 3 2 H 2 (H 3 ) 2 ]:,-ietylglyine 1 g (6.29 mmol) n Ag 3 1.06 g (6.29 mmol) were rete with triphenyltin(iv) hlorie 2.42 g (6.29 mmol) in 1:1 rtio in 100.0 ml hloroform. erystllize in hloroform n ether in 1:2 rtio. Yiel: 78%. m.p.: 126 o. Soluility: ( 2 H 5 ) 2, H 3 H 2 H, Hl 3 n THF. H nlysis (%) ntipyrene:, 56.7 (56.7); H, 4.5 (4.5) n, 2.7 (2.7), the lulte vlues re in the prenthesis. FTI (KBr) υ(m -1 ): (etyl): 1745 m w; (ronyl): 1656 sym, sp, 1471 sym msp; Δυ: 185; (ether linkge): 1027 m; : 547 m; : 512 w. 1 H M (Dl 3 ) δ: H-2: 3.80 s;h-4: 2.78 s; H-: 7.64. t (7); H-: 7.28 m; H-: 7.15 t (7). 13 M (Dl 3 ) δ: -1: 172.26; -2: 40.73; -3: 170.45; -4: 21.37; -: 135.61; -: 133.54; -: 131.18; -: 130.39. 119 M (H 3 ) 4 : -99.29. MS m/z: [( 6 H 5 ) 3 2 H 2 (H 3 ) 2 ] + M + 507 (5%); [( 6 H 5 ) 2 2 H 2- (H 3 ) 2 ] + 430 (100%); [( 6 H 5 ) 2 H 2 (H 3 ) 2 ] + 353 Triylohexyltin(IV)-,-ietylglyine (7): [( 6 H 11 ) 3-2 H 2 (H 3 ) 2 ]:,-ietylglyine 1 g (6.29 mmol) n Ag 3 1.06 g (6.29 mmol) were rete with triylohexyltin(iv) hlorie 2.64 g (6.29 mmol) in 1:1 rtio in 100.0 ml hloroform. erystllize in hloroform. Yiel: 76%. m.p.: 112 o. Soluility: ( 2 H 5 ) 2, H 3 H, H 3 H 2 H n Hl 3. H nlysis (%) ntipyrene:, 54.7 (54.7); H, 7.8 (7.8) n, 2.6 (2.6). FTI (KBr) υ(m -1 ): (etyl): 1747 mw; (ronyl): 1645 sym sp, 1490 sym msp; Δυ: 155; (ether linkge): 1035 m; : 540 m; : 518 w. 1 H M (Dl 3 ) δ: H-2: 3.76 s; H-4: 2.81 s; H-: 1.14. t (7); H-: 1.35 m; H-: 1.55 m; H-: 1.81m. 13 M (Dl 3 ) δ: -1: 172.17; -2: 39.35; -3: 168.71.; -4: 21.57; -: 22.69; -: 28.89; -: 26.44; -: 25.50. 119 M (H 3 ) 4 : 9.1. MS m/z: [( 6 H 11 ) 3 2 H 2 (H 3 ) 2 ] + M + 525 (3%); [( 6 H 11 ) 2 2 H 2 - (H 3 ) 2 ] + 442 (100%); [( 6 H 11 ) 3 ] + 367 (75%); [( 6 H 11 ) 2 H 2 (H 3 ) 2 ] + 340 (44%); [( 6 H 11 ) 2 ] + 284 (52%); [ 2 H 2 (H 3 ) 2 ] + 276 (30%); [H 2 - (H 3 ) 2 ].+ 232 (22%); [H 2 (H 3 ) 2 ] + 114 (27%); [ 6 H 11 ] + 201 (42%); [/H] + 119/120 (15%); [ 6 H 11 ] + 83 (30%); [H 2 (H 3 )] + 71 (11%). Biotivity stuies Antiteril iossy For the purpose ntiteril tivity, glsswre ws sterilize t 150 for 20 minutes efore use. The miroil speimens were umulte s sws of pus, loo, urine, sputum, siemen et. from the Bhwl Vitori Hospitl (BVH) of Bhwlpur. E. oli, P. eruginos, K. pneumoni n S. typhi were isolte n use for the purpose of ntiteril tivity. Monkey gr (10.0 g) n.l.e.d meiums (10.0 g) in 250.0 ml istille wter n utolve whih is use for preprtion of Petri pltes. The strins were inoulte n inute t 37. The lign n Ts methnoli solutions of 200 n 500 ppm were prepre. The pregnnt iss were soke in test solutions n rie n utolve s well. All the prepre petri pltes were, inute t 37 for 24 h. Insetiil iossy Monomorium minimum, melyug n triolium stneum insets were selete to etermine % toxiity rte s per reporte metho. 15 While in vitro LD 50 vlues were nlyze y Proit sttistil metho. 21 Brine shrimp iossy The lethlity ssys on the Ts were rrie out. LD 50 ws etermine oring to the literture. 24 ESULTS AD DISUSSIS FTI stuy FTI suessfully employe to verify 2:1 molr rtio of etyl hlorie n glyine respetively. The 3500-3100 m -1 region ws remine trnsprent for -H moiety tht is the inition of,protetion of glyine y etyl groups wheres the H ro n ppere t 3000-2600 m -1 n H strething of H 3 of etyl group ourre t 2961 m -1. The importnt υ() sym. υ() sym. υ( ), n υ( ) were oserve in the region s reporte in
22 Ashfq et l. Quim. ov the literture. 24 The retion mong { 2 - (IV)} 2+ /{ 3 (IV)} + n lign ws onfirme y the sene of the ro n of υ(h) t 3000-2600 m -1 showing the e-protontion of free lign n presene of υ( ) in the rnge of 520-400 m -1 given the inition of lign metl omplextion. 25-29 The involvement of the group in the oorintion n e onlue y the shifting of υ() n of the omplexes to lower wve numer s ompre to tht of the free lign. 30 The ifferene etween the υ() sym n υ() sym ns, Δυ() of ientte roxylte group is elow 200 m -1 while unientte roxylte is ove 200 m -1. 31 The hrteristi υ() sym n υ() sym virtions of the roxyli group ppere t 1655 ± 20 n 1490 ± 20 m -l, respetively, for tri-orgnotin(iv) omplexes 4-7. The Δυ() virtions vlues re out 170 ± 15 m -l initing the ovlent oning of the metl-oxygen on. 32 The inresing of symmetri n eresing of symmetri strething vlues of ompouns thn lign while Δυ in the omplexes ws lso lrger thn the Δυ of lign, suggeste tht 3 groups re ientte oorinte to the oxygen of group of DAG whih is lso similr to the reporte generl pttern of oorintion: υ sym(ts) < υ sym(lign) υ sym(ts) < υ sym (lign) Δυ (Ts) > Δυ (lign). 16,33,34 The - strething frequeny t 510, 517, 547, n 540 m -l for enzyl, utyl, phenyl n ylohexyl groups suggeste the presene of ll three orgni groups in the equtoril positions of the polymeri trigonl ipyrmil struture in Figure 1. 34,35 The hrteristi υ() sym. n υ() sym. virtion of monomeri ompouns 1 n 3 ppere t 1620±15 n 1462±8 m -l, respetively, 33-35 while Δυ vlue of ws < 200 m -1 exhiit ientte oning to DAG with trns-otherl geometry (Figure 2). 16,36 Very shrp n t 634 m -1 of ompoun 2 reommen -- - ring imeri networking with eno n exo (IV) toms tht propose the hex oorintion geometry given in Figure 3 n the generl oserve pttern for υ in orne with literture is s follow: υ sym(omp.) <υ sym(lig.), <υ sym(omp.) <υ sym(lig.), Δυ (omp.) >Δυ (lig.). 15,16,36 1 H M stuy The H 3 protons of DAG resonte t 2.30-1.5 ppm n H proton shifte t ownfiel region 11.3 ppm initing the,-protete of glyine. Interestingly no H hemil shift ws oserve in the 1 H M spetr of lign. It is file n more onvenient route tht n e use to protet glyine t site is not foun in the literture. The 1 H M stuy of Ts (1 7) suessfully verifie their synthesis y e-protontion of DAG lign n no hemil shift ws foun t ownfiel for roxyli i proton. All t is given in experimentl prt. The H 2 hemil shifting is foun t 3.71-4.00 ppm while H 2 of enzyl t 2.64-2.87 ppm is seen s reporte. 16,36-39 The proton signl of phenyl, ylohexyl n romti proton of enzyl were foun t rnge 7.32-8.23 ppm. Two molr stoihiometri rtio of DAG ws use to synthesize Ts 1, n 3 re onfirme y 1 H M t n the literture evienes supporte otherl geometry (Figure 2). 31,40 = n-utyl,enzyl, phenyl n ylohexyl Figure 1. Polymeri trigonl ipyrmil struture of tri-orgnotin(iv) omplexes (4-7) n In se of ompouns 2 the eno- n exoyli (IV) enters were iffiult to ientify s reporte in literture euse there is no istint signls of utyl group tthe to eno- n exoyli tin(iv) enters giving the equl sttus to eno n exo tin(iv) enters. 16,17,41,42 It is oviously ue to six oorintion sites of eh eno n exotin(iv) tom with hemilly equivlent nture. Hene it might e purpose tht imer hve ler topology with sinusoil view from one unit to other tht linke with eh other through oxygen tom of roxylte of one unit to (IV) tom of other unit s we reporte previously n shown in Figure 3. 15,31 For triorgnotin(iv) ompouns (TTs) 4-7, the 1 H M spetr (t n e seen in experimentl prt) show the hemil shift tht verifying the tetrherl struture in Dl 3 solvent n estlishe the oorintion of oxygen of roxyli group to tin(iv) enters (Figure 4) with support of literture s well. 41,42 13 M stuy Figure 2. therl geometry of monomer 1, n 3 =(H 3 ) 2 H 2 - The 13 M spetr of DAG t n e seen in experimentl prt. Aoring to Sheme 1, ll the ron toms 1, 2, 3, 4 were resonte t the speifie hemil shifts s reporte in the literture. 16,17,31 The -1of H gve 13 signl t 169.22 ppm n wheres the -4 of H 3 t 21.68 ppm is onfirming the synthesis of DAG. All the Ts hve vlues t own fiel up to 173.73 ppm s well onfirme roxylte ron (-1) oning to tin(iv) tom. The 13 hemil shift of utyl, phenyl, enzyl n ylohexyl (-, -, -, -, -e) were oserve t rnge 13.55-27.13, 130-140 n 22-30 ppm, respetively. 16,17,41 Figure 3. Sinusoil view of ompoun 2 exhiiting wekly one two imer units = n-utyl, enzyl, phenyl nylohexyl Figure 4. Tetrherl geometry of triorgnotin(iv) omplexes (4-7)
Vol. 39, o. 1 Synthesis n iologil tivity of new series of orgnotin(iv) esters with,-ietylglyine 23 119 M stuy The 119 hemil shifts of the trienzyl-, triutyl-, triphenyl-, n triylohexyl-tin(iv) roxyltes were t -142.71, 123.7, -99.29, n 71.21 ppm initing tetrherl environment. 43,44 While iutyl- n ienzyl-tin(iv) omplexes exhiite 119 hemil shift t -190.35 n -238.32 ppm respetively onfirming the trns otherl rrngement (Figure 2). 45 While pir of 119 resonne peks of equl intensities t -210.4 n -216.2 were onfirming the eno- n exo-yli sttus of tin(iv) respetively tht sustntite the sinusoil view of ompoun 2 given in Figure 3. 15,23 Mss spetrl stuy Moleulr ion pek t m/z 159 is the tul mss of lign DAG is true eviene of existene of two moles of etyl groups t terminl of glyine is the most importnt step towr synthesis of DAG through this new n file route to protet terminl. In the orgnotin(iv) erivtives mjor frgmenttion ws oserve ue to the loss of the lign moiety from the tin(iv) erivtives. Suessive loss of groups (, Bz, Ph) uring frgmenttion ws hppene until the 4+ ion ws resulte. In n lterntive route, groups were eliminte first n next one moleule of 2 remove s per revele in literture. 23,46 Further, the remining sustituents were efrgmente on sme pttern s given in Shemes 3 n 4. Antiteril tivity The results relte to ntiteril tivity is given in Tle 1. The Ts 4, 5, 6 n 7 (500 ppm) is promising more thn two fol tivity thn the stnr ntiioti enoxin (1000 ppm). The ompouns 1, 2 n 3 reflete goo tivity t 500 ppm ose wheres the DAG is too less promise s given in selete petri plte of E. oli (Figure 5) n the omprtive zone of inhiition of Ts 1-7 versus teril strins is given in Figure 6. It is ovious tht promising property of Ts (4, 5, 6 n 7) is ue to tetrherl geometry of tin(iv) tom tht ers oxygen free for oorinte with orresponing metl ions of enzymti system of strins s well the tin(iv) metl ions hs more vnt oorintion site to lok the metolites to protein synthesis long with riosoml su units of teril strins. 47-50 From this stuy following tren of Ts my e onlue for the ntiteril inhiition: TTs (lkyl) > TTs (ryl) > imer > monomer > lign.. [ [ 3 2 / ].+ 2. / [ 3 ] + 2 2 / ] +. 2 [ 2 / ].+ [ 2 ] +...,./ [ / ] +. [] + [ ] + Sheme 3. Frgmenttion pttern of triorgnotin(iv) omplexes. [ ( [ 2 ( 2 / ) 2 ].+ 2 [ 2 2 / ] + 2 / ) 2 ] + / 2 Insetiie tivity The Ts 4 n 5 hve exellent tivity ginst M. minimum n T. stneum ut remine insignifint ginst Mely ug. The LD 50 vlue n the results re given in Tle 2. ytotoxiity stuy 2 2 [ 2 / ( 2 / )].+ [ 2 / ].+ 2 2./. [ / 2].+.,./ =, Bz, Ph, y [ 2 / ] + 2.. [ / ] + [] + [ / ] + ytotoxiity ws evlute using rine shrimp lethlity ssy (Tle 3). LD 50 of ll ompouns were rrie out ginst rine shrimp lrve using stnr sttistil proeure Proit nlysis. Ts 4, 5 n 7 were foun to e tive../ =, Bz, Sheme 4. Frgmenttion pttern of iorgnotin(iv) omplexes Tle 1. Antiteril iossy ompouns (500 ppm) E. oli P. eruginos K. pneumonie S. typhi Inhiition (mm) esults Inhiition (mm) esults Inhiition (mm) esults Inhiition (mm) esults DAG 10 + 8 + 7 + 9 + 1 18 ++ 15 ++ 13 ++ 14 ++ 2 22 +++ 18 ++ 16 ++ 15 ++ 3 15 ++ 13 ++ 12 ++ 14 ++ 4 25 +++ 22 +++ 20 ++ 19 ++ 5 39 ++++ 33 +++ 29 +++ 28 +++ 6 35 ++++ 30 +++ 27 +++ 30 +++ 7 32 ++++ 31 ++++ 23 ++ 25 ++ *Stnr 28 +++ 29 +++ 30 +++ 34 ++++ where - = no result, + = insignifint, ++ = signifint, +++ = more signifint, ++++ = most signifint. *enoxin = 1000 ppm oze.
24 Ashfq et l. Quim. ov Figure 5. Selete experimentl petri pltes ginst E. oli Figure 6. omprison of ntiteril tivity Tle 2. Insetiil iossy Type of insets (% Deth) μg/mg *ompouns Monomorium minimum Triolium stneum Mely ug 1000 700 400 100 10 LD 50 esult 1000 700 400 100 10 LD 50 esult esult DAG 10 10 10 - - - - 10 10 - - - - - - 1 80 70 60 40 30 140.48 + 80 60 60 40 20 100.00 + - 2 100 100 80 70 20 28.18 ++ 60 60 40 40 30 350.80 ++ - 3 80 80 80 80 40 35.48 ++ 90 90 60 60 10 79.43 ++ - 4 100 100 90 80 60 6.60 ++ 90 80 70 70 40 35.48 ++ - 5 100 100 90 70 50 1.00 +++ 100 100 80 60 30 28.18 +++ - 6 90 90 60 30 30 39.81 ++ 70 70 50 50 20 141.48 ++ - 7 90 80 80 80 30 39.81 ++ 80 70 50 40 20 100.00 ++ - * ompouns n flour re in w/w % rtio; where: - = no result, + = insignifint, ++ = signifint, +++ = more signifint, ++++ = most signifint. Tle 3. Brine shrimp LD 50 iossy % Deth t ose (μg/mg) ompouns 1000 700 400 100 10 DAG 20 20 10 - - - + 1 40 30 20 20 20 - ++ 2 90 80 70 70 60 7.94 ++++ 3 30 30 10 10 10 - ++ 4 90 80 80 80 60 3.16 ++++ 5 100 100 100 90 70 3..98 ++++ 6 100 100 70 70 50 10.00 ++ 7 90 90 90 90 60 3.16 +++ where: ++++ = more signifint, +++ = signifint = no tivity. LD 50 esults LUSIS A new series of monomeri orgnotin(iv) esters 1, 3 imeri orgnotin(iv) esters 2 n triorgnotin(iv) esters 4-7, were synthesize with,-ietylglyine. All the omplexes were more tive thn the lign n some were even more tive thn stnr use. The following tren my e onlue for the ntiteril inhiition; Ts (lkyl) > Ts (ryl) > monomeri orgnotin(iv) esters > monomer orgnotin(iv) esters > ligns, the teril strins were inhiite s: E. oli > P. eruginos > K. pneumoni > S. typhi. While the rte of toxiity n LD 50 vlues hve following orer: T. stneum > M. minimium > Melyug in otton plnt. LD 50 ginst Brine Shrimp lrve were foun to e tive for imer n intive for monomer while Ts esters hve very nrrow rnge of LD 50 vlues of 3-10 μg/mg. AKWLEDGEMETS The uthors re thnkful to Deprtment of hemistry (Inorgni Ph. D. L) The Islmi University of Bhwlpur-Pkistn for proviing ll reserh filities. HEJ eserh Institute, University of Krhi for spetrosopi nlysis n Qui-e-Azm Meil ollege Bhwlpur for ntiteril tivities re grtefully knowlege. Gilro iver Sánhez wish to thnk the finnil support reeive from the omisión e perión y Fomento e Ativies Aémis (FAA-Instituto Politénio ionl),
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