AAT VAN DE 1,3-Benzothiazole va cac dan xuat cua n6 dai dign cho mét nhém cac hop chat dj vong ngung ty dugc céc nha héa hoc trén khap thé gidi quan tam va nghii ciru rat nhieu trong céng nghigp, ndng nghigp vi de bigt trong Tinh vue y duge hoe. Céie din xuat thé vj tri sO 2 ciia benzothiazole 6 tie dung ngin ngira ung thu, chéng khuan lao, chong ndm, chéng ki sinh trang nhw Euglena gracilis, vi khuan dong nhwr Staphyl lococus areus va Bacillius subtilis, mgt vai din xudt c6 hogt tinh giéng nhw auxine va cytokinin trong qué trinh diéu hoa ting trréng the vat [1]. Trén thé gidi, gin day viée nghién ciru,téng hop,danh gid hoat tinh sinh hoc benzothiazole vi din xudt da thu hat sw quan tim manh m@ trong nginh héa durge do hoat tinh sinh hoc da dang cia né. Cac hgp chat cita bezothiazole da duge thit nghigm lim sang va ding lam thuée digu trj cho ngudi. Véi cde hoat tinh tiém nang cua lop chit nay,cde nhi héa hoe trén khap thé gidi quan tim vi nghién cifu rat nhigu béi hoat tinh sinh hoc da dang duge ing dung nhiéu trong cong nghigp, nong nghigp va dic bigt trong linh vue y duge hoc. 6 Vigt Nam,benzothiazole va din xuit iia né da durge quan tim nghién citu.Cé thé ké dén cae eng trinh nghién ciru: Téng hop va nghién ettu edu trie mot s6 din xuit eiia 1,3-benzothiazole [1], Tong hop vi nghién ciru mot s6 din xuat cua benzothiazole [2]. Kha ning khéng khuin cia Ja m6t trong nhiing host tinh sinh hoc tiéu biéu cia benzothiazole vi dan xudtChing c6 thé khang duge cic vi khuan gram m,gram duong,vi khudn Ecoli.Do do, trong bai tiéu lun nay em xin dé cap dén hoat tinh sinh hge tiéu bieu nay.B.NOI DUNG CHiNH Phan 1.Téng quan vé 1,3-benzothiazole va din xuat. 1.Dinh nghia ve 1,3-benzothiazole va din xuat ___1,3-Benzothiazole va cée dan xudt cia né dai dign cho mOt nhém cae hop chit di vong ngung tu.1,3-Benzothiazole e6 céng thite phan tit i CsH;NS, khéi lugng phan tir 1 137, gdm mt vong 6 canh va 1 dj vong 5 canh gém I nguyén tir N va I nguyén tir S. Céng thite edu tao cita 1,3-benzothiazole nhu sau: CO 1,3-Benzothiazole c6 tén IUPAC la 1,3-benzothiazole,la nhét. ft long khong mau, hoi Cée dn xuat ctia 1,3-benzothiazole c6 céng thite cau tao nhur sau: Ry tod f oN. is RY Rj, Rs, Ra 06 thé gidng hoge khae nhau, ¢é thé la nguyén tir hydro, nhém ankyl bac thdp, halogen, nhém ancyl, nhom hydroxyl, nhém nitro, nhém amino va nhém diankyl amino bac thap voi diéu kign 14 cé 2 nhém bat ki trong 3 nhém Ry, Rs, Ry c6 thé két hop véi nhau tao ra dang vong thom chi c6 chia C hoge chira thém 1 nguyén tir N. Rz Ki nguyén tir hydro, nhém acyl, hog I nhém e6 eéng thire nhur sau: i Re Ne Ry R;, Rs c6 thé gidng hoge khéc nhau,la nguyén tir hydro hoe la nhom ankyl bac thap.Rs Ki mt nguyén tir hydro. Rg li m6t nhém c6 e6ng thite nhur sau: x \-sonv Khi X la 1 nhém CO hoje 1 nhém CH; va ¥ la m@t nhém ankyl bae thip hoac Y cé céng thite céu tao: NO = N Rio Ro, Rio ¢6 thé giéng hodic khac nhau, la nguyén tit hydro, nhém ankyl bac thip, halogen, nhém ankoxyl bac thdp, nhém rugu bac thdp hoa nhom diankyl Bl 2.Tinh chit vt Ii cia benzothiazole. Benzothiazole la mét chat long hoi nhét,khong mau,nhiét dO néng chay la 2°C,nhigt d6 sOi la 227-228°C.Khéi lugng rigng la 1,644 g/ml, khoi lugng phan tir la 137,19g/mol.Benzothiazole khong duge str dung tai hd gia dinh va nd duge sit dung trong cng nghiép va nghién eiru [4] . 3.CAc phwong phap tong hop din xuat ciia benzothiazole Do benzothiazole va din xudt ¢6 hoat tinh sinh hc phong phi, nén cdc phuong php tong hgp cac dn xuat benzothiazole chiém mét vi thé dang ké trong cae cOng trinh nghién ctu nganh héa durge hign nay. Cac phuong phap cé dién tng hop dan xuat benzothiazole déu lién quan dén phn tng ngung tu ciia o- aminothiphenols véi aldehyde, acyl clorua, axit cacboxylic hodc este, nitriles. Cac phuong phap khac duge sir dung cing due str dung, phé bién nhat la Pd/ Cw Mn/ chloranil xite tic tao vong v6i o-halothioformanilides [5] Sau day li mét vai phuong php théng thudng téng hop dn xuat cia benzothiazole 2.1.Phin ting ngung ty cita o-aminothiophenol véi aldehyde.La phan tng téng hop din xudt cia 2-benzothiazole dua trén phan img ngumng ty ciia o-aminothiophenol véi aldehyde. Phong php nay durge thye hign rit thinh céng bi nha khoa hoc Umesh R.Pratap (Umesh et al 2009), Xiie tée phin it Jip xép theo thir ty tira t6i £ [5]. 15 5 io cn Sass 010 Co

[SSS as geese So dé 2: Téng hop dén xudit bezothiazole dua trén phan img ngung tu ctia o- aminothiophenol vai axit. 2.3.Phiin tng tgo vong eta thioformanilindes véi chat xtc tae khie nha Hop chat thé thioformanilindes cé thé chu déi thanh = 2- aminobenzothoazole théng qua vige tao lién két ndi phan tir C-S, C-H nhé sy c6 mat cia chat xtic tic Cw/Pd. Lién két C-S duge hinh thanh gitta hgp chat nhan thomchia halogen va thioformanilindes.Phuong phap nay duge m@t nha khoa hoc An D6 thuc hién (Khokra et al.,2011).Xiic téc phiin ting sip xép tira toi ¢ [5]. z x 8 CL oe Cals (ato) Cx NR N So dé 3: Tong hop dan xudt bezothiazole dya trén phan ing tao vong cia thioformanilindes voi chdt xite ude Khdie nhau a.Cu, 1-10 Phenathroline, CSCOs, dun hdi lu. b. Manganese tricatate ©. CS:COs, Dioxane 4d. Tao vong quang héa boi chloranil e.Pd(PPh3)«/ MnO, duéi oxi khong khi, Phan ting ghép ndi tao vong gitta thiophenos va benzennitriles tao ra aryl benzothiazole.Phan ting sir dung xiic tac 1a ceric ammonium, higu suét cia phin img rit cao.Phin img duge thye hign boi nha khoa hoc Khokra (Khokra et al.,201 1) (5). CAN (2 equi) NaHCO, : MeGNRTO She” aa So dé 4: Téng hop din xudt aryl bezothiazole diea trén phan tng tao vong ctia thiophenos va benzennitriles 2.4,Plurong phap tong hgp di tir aniline Hugerschoff da ting hop 2-amino benzothiazole bing cach cho din xuat ctia aniline déng vong voi KSCN trong méi trong brom va chloroform tao ra 2-amino benzothiazole ( Hugerschoff 1901).Br, CHCI, KCSN aT So dé 5: Téng hop dan xudt bezothiazole dwa trén di tit aniline Khokra cing thyc hign phn dng twong ty di tir aniline nhung xtc tée hoi khae motchit 46 la véi sy c6 mat ctia axit axetic bang [5] . 2-aryl benzothiazole ciing cé thé téng hop nhé phan img gitta hop aniline va nitrobenzoyl chloride trong méi trudng pridin. Sn véi chlorobenzen, sau dé tgo vong v din xudt benzothiazole [5] . phim duge tigp tuc phan ting -yanide tao ra Pyriding Cl) : “Retlu NH No: Chlorabenzene KiFatCNe a. Mate “S R ol LLawesson's reagent nee ey ‘NO: So dé 6: Tang hop dan xudt aryl bezothiazole dya trén phan ting hop aniline va nitrobenzoyl chloridePhan 2. Téng hgp céc din xuat benzothiazole c6 hoat tinh khang khuan LPhan teng tong hop dan xudt cia 2-[(I-pheny/aryl) azo] methyleneimino-6 chlorobenzothiazole. 2-Aminobenzothiazole va cae din xuat ctia né da duge bio céo c6 nhigu hoat tinh sinh hoc khée nhau nhu chéng ung thu, khang u, khang viém va gid dau. Khéc, hat nhdn formazan 1a mt hat nhan ¢6 nhiéu téc dung duge ly trong tw nhién, Dieu nay dy kién cde din xuat benzothiazole chita nhan formazan st di cutng hoat tinh sinh hge. Vi vay cée nha khoa hoc An Dé tong hop dan x pheny/aryl) azo] methyleneimino-6 chlorobenzothiazole va dinh gid kha ning khang khuan cia ching, N Nib NH,NH)H,0. SY SOC we ame CS cr s ca 8 4(a-0) 3erd) So dé 7 : Téng hop tg tong hop dén xudt cia 2-[(1-pheny/aryl) azo] methyleneimino-6 chlorobenzothiazole Xuit phat tir 6-chloro-2-aminobenzothiazole (1) tie dung voi hdrazine hydrat véi xiic tae 1a axit clohydrie lanh cho 6-chloro-2-hydrazinobenzothiazole (2). Sau 46 tiép tye cho (2) phin tg véi axit thom tao ra din xuit chia vong thom 6- chloro-2-hydrazinobenzothiazole (3).Tiép tue cho (3) thye hign phan img diazo héa voi tie nhan la axit chohydric tai nhigt d6 tir 0-5 °C cho san phim cudi cing 1a 2- [(1-pheny/aryl) azo] methylene-imino-6 chlorobenzothiazole. Danh gid kha nang khéng khuan: Tat ca cic hop chat tng hop moi duge sing loc cho hoat dong khang khuan chéng Igi E.coli, Pseudomanas, S.aereus, Bosubtilis, va khdng nam Aspergillus.Flavus va Candida albicans (Bang 1),Bang 1: Dit liéu vat li ctia dén xudt nhén thom (6-chloro-1,3,-benzothiazole-2-yl) Iydrazone (3a-d) va 2-[(I-phenyl) (aryl) azo] methylenemino-6-chloro benzothiazole (4a-o) Chat Ri MP (°C) Higu suat 3a <<) 205 3b 7 210 on 3c 175 a \ ons 3d ee 195-200 4a <) “Y 174 4b <<) tS 117-118 4e N 215 ‘ 4d oo! 4 S-o 89-92 ow de <\ Se 185 4f2999 99:99 AR 9 2s AA + = $ = = &2. Téng hop dén xudt pyrimido benzothiazole. Nhu chiing ta da biét,cde din xudt pyrimino benzothiazole ¢6 hoat tinh sinh hoc rit ding quan tim nhu: khdng khudn, khing ndm...d%c bigt la kha ning khing khuan, Be R Rs &, Ry 4 R s I yan Noon x é Rs Rs >< ee a Ry oH Re i Rs ky ke So dé 8 : Téng hop din xudt pyrimido benzothiazole Phuong phap tong hgp din xuat pyrimido benzothiazole duge thé hién & hinh 2. Phuong phip tng hop nay dya trén sy lién hgp cla nguyén tir nito imino cua hgp chat pyrimino benzothiazole(5) ti nguyén tir B-carbon ciia axit acetylenic(6)v6i su c6 mit cia butanol tgo ra hgp chat (7).Sau dé la cfc phan ting chuyén vi dign tich, dng _vong va loai HO cho din xuat 2H- pyrimido-bezothiazole. .Higu suit cua cde phan ing duge thé hién tai bing 1. Phuong phap nay duge thye hién bai cc nha khoa hoc An Dd cong bé nam 2009. Dinh gid kha nang khing khudn: Theo cde két qua sang loc v8 kha nang Khang khuan thi hop chat 10a,11a c6 higu luc t6t vi cde chiing khudn nhu E.coli, Enterobacter; 10c va 11b ¢6 kha ning khang tt voi _khuin tu cdu vang Staphylococus. Ngoai ra, cae hop chat 10b,10¢ c6 higu Ive vita phai voi cde khuan E.coli, Enterobacter. Tuy nhién cde din xuat nay it hofe khong c6 kha ning hing lai tit ca cde dong vi khudn (Bang 2) Bang 2: Dit ligu vat li ctia céc dan xudt pyrimido benzothiazole. Hop chat RI R2 R3 R4 RS Hiéu suat 10a H a H H Ph 62 10b H H Br_| H Ph 6 10¢ H Me H_| Me Ph 4 Ha Me Me H H_|_L-pent R lb H C4H4 C44 H I-penty 68 3. Tong hop dan xudt 2-mecapto-1,3-benzothiazole. Theo cae tai ligu céng bé nim 2009 ciia cde nha khoa hoc Italy din xudt trong Iugng phan tir thép 2-mecapto bezothiazole c6 kha nang khang lai cée ching vi Khuan nhw E.coli, B.subtilis,P.typhii va S.aureus. That vay, theo cdc két qua nghién ctru trong phong thi nghiém thi cac din xuat 14(a-f) chéng lai cde dong vi khudn Gram 4m va Gram duong rat tt va hién nay da duge str dung lam thuéc dang lu ‘hanh trén thi truéng. Phuong phép téng hop chung dan xuat thé 1,3-bezothiazole-2-thiols 13(a-f) di tir cdc dan xuat aniline c6 sin trén thi trong va kali ethyl xanthate (PEX).Phan img thyc hign 6 160°C trong dung mi dimethylformamide (DMF).Day la mot phan tmg kha don gin cho higu suat cao tir 71-98% tity theo nhém R.a § DMF, 16g Jor Tae ys Br R s RX Let) Met) >. OCH, wr ance. br, Bet, pans, thclciion 38 13,14(a-f) : R= a-CH(CH})x b-Cl; c-CH3; d-O CH3; e-CF 3; f-F. 4.Téng hop cdc dan xudt ctia N-2-benzothiazolythiourea. Dn xudt N-2-benzothiazolythiourea c6 kha nang te vi khuan Gram am nhu Staphylococus, Pseudomonas, E.coli va cée vi khuan Gram duong nh P.acuruginosa,CH; Cone HCHO, Brin CHC, NHS > NH 6 7 PP -chloraacstophendne caxitaxeti bang tromoasctaphenane why ' : "ala ON: a Vige tong hgp dan xuat N-2-benzothiazolythiourea xuat phat p-toludine (16) tic dung voi NELSCN trong mdi truéng HCI va H,O,dung cach thiy trong 22h cho p- tolyl thiourea (17).Tir hgp chat (17) théng qua phan tg déng vong voi su co mat cua Br/CHCl; tgo ra 2-amino-6-methyl benzothiazole(18),sau dé tao ra N-2- benzothiazolythiourea (19) bing phan img amonithiocyante. Tiép tue di tir N-2- benzothiazolythiourea phan img véi hydrazine hydrate trong etylen gycol cho din xuat S-4 cia N-2-benzothiazolythiourea (20). Tir $-4 ta 6 the tng hgp cae din xuat $-5(21),S-6(23),S-7(22) ciia N-2-benzothiazolythiourea,Theo nhiing két qui nghién ctu trong phong thi nghiém ca cdc nha khoa hoc An thi $-5 c6 kha nfing khéng lai rit t6t P.aeuruginosa trong khi S-6 thi khang lai rit t6t B.coli.S-7 e6 kha nang khang khudn trung binh v6i P.aeuruginosa,E.coli, S.aureus. 5.Téng hop dan xudt 7-chloro-6-fluoro-2-choroacetamidobenzothiazole. Phan img ting hgp din xuit 7-chloro-6-fluoro-2-choroacetamidobenzothiazole durge thé hign trong so dé sau day: NH, Ne ‘cHcooHT F cl 23 CICH,A con| DMF, MW N | Qu N OH = alleles I F s H F 8 H a a 26 2s HO OO Op H H H H Ri Ry Ry R NO, NO2 a OO 3 H H H Rs Re Ry Rs ‘ut phat tir din xudt 3-chlor-4-fluoroaniline (23) thye hién phan img dong voi KSCN, xiie the Bro trong sur c6 mat ciia axit axetic bang tao din xuat 7-chloro- 6-fluorobenzothiazole-2-amin (24).Tiép tue tao din xudt 7-chloro-6-floro-2- choloroacetamidobenzen (25) bing céch cho din xudt (24) tie dung voi CICH2COC! loai di mot phan tir nude trong dung méi DMF bing phuong php vi séng.Sau dé thay thé nguyén tir -Cl trong dan xuat (25) bing cde din xuat aminthom ta thu duge ce din xua zole cé hoat tinh khing kh ¢ din xuat c6 hoat tinh Tuy thude vio timg nhém -R khie nhau ma ta khéng khudn khdc nhau, Dan xudt chira nhom -R, khang yéu véi S.typhi va E.coli va khong khing duge S.aureus va B.subtilis.-R> c6 khin nang khing khudn tot tuong ty nhw norfloxaxin nhumg yéu hon penixilin.-Ry,R, Rs tuong tw nhu R>: khdng Iai tit cd cae dong vi khuin tuong ty norfloxaxin nung yéu hom amphixilin. -R, khong ¢6 kha nfing khang lai B.subtilis nhumg c6 kha ning khang yeu voi S.typhi E.coli ,S.aureus. 6.Téng hop dan xudt benzothiazole chita vong 1,3,4-oxadiazole 1,3,4- oxadiazole va din xuat la hé théng di vong cé nhiéu hoat tinh sinh hoc da dang nhu khang khuan,khang ndm,chéng ung thu...Benzothiazole cing 1a mt hé di vong cing c6 nhiing tinh chat tuong ty. Vi vay dé tao ra m6t chat cd kha nang khang khuan manh céc nha nghién citu da tim cach téng hop cac din xuat cia benzothiazole c6 chita vong 1,3,4- oxadiazol: OC : Y—cooess Hs een I 4 7 Nis A $ » |r tees ye 30s “On oe cr NH SONG, 304 Bé ting hop din xudt chia vong 1,3,4-oxadiazole cua benzothiazole ngudi ta cho o-aminophenol(27) phan ting diethyl oxalate to ra ethyl-2-benzothiazolecarboxylate (28),Sau d6 din xudt (28) phan tmg_véi hydrazine trong 8 h va lam mit & nhigt 46 phong cho 1,3-benzothiazole-2-carboxyhydrazine (29). (29) tiép tue phan ting déng ving 1,3,4-oxadiazole véi axit thom va xiie tie OCI; tgo thinh ede din xuit cia benzothiazole chita vong 1,3,4-oxadiazole. Cf din xuat mdi 30(a-j) c6 kha nang khang lai tot cdc ching vi khuan Gram am va Gram dong nhur khudn Bacillus subtilis, Baccilus pumilus, E.coli va P.aureginosa. Ngoai ra, kha nang khang khudn cia nhém hop chit nay manh hon so véi ciprofloxacin. 7.Tong hop 7 dan xudt méi ctia benzothiazole Alang et al da tong hop 7 din xudt méi cia benzothiazole 6 khan ning khang rat tt cae ching vi Khuin Gram durong (S.aureus, S.epidermisdis),Gram am (E.coli .P.aureginosa). So dé qui trinh tong hgp duge thé hién trong so 46: cH s, wate ee > TNHSCN “Tso, NH Ni He ri | NH-NH 1 ">s CHO HC a pa v a4 a n& “CH: He. . DNR > Need 38 Scr R= 2-flouroacetophenone, — R=4’-flouroacetophenone, R=? flouroacetophenone, R=4'- flouroacetophenone, Rs=p-hydroxyacetophenone, Re= 2'-hydroxyacetophenone, R=2,5-Dihydroxyacetophenone.Tuong tu nhu téng hop cdc dn xuat trén,Alang et al di tir p-toluen anilin (31) thuc hién phan img déng vong voi KSCN tao ra din xuat 1,3-benzothiazole (33).Din xudt (33) phan ting véi hydrazine trong dung méi ethylen glycol tao ra din xuat (34).934) tiép tue phan img véi cdc dan xuit flouro/chloro acetophenone tao ra caed dan xuat c6 hoat tinh khang khuan (35).Day la mét phuong phap méi duge Alang thure hign va céng bé nam 2010. 8.Téng hop dén xudt pyridin cé hoat tinh khéng khudn bang phan ing gitta 4- thiazolidinones va benzothiazole. Pyridin la hé vong co sé, xudt hién rat nhiéu trong cdc hyp chat thién nhién.Pyridin va din xuat cua n6 c6 nhiéu hoat tinh sinh hoc da dang nhu: khang HIV, chéng co gidt, chéng viém...Cac din xuat cua pyrindin duge img dung nhiéu trong cong nghiép, néng nghiép, duge phim.Thiazolidinones cing la mét din xuat co nhiéu hoat tinh tuong ty pyridin: chéng viém,khdng HIV... Tuy nhién trong mt vai nim 16 Iai day vige chimg minh duge bezothiazole ¢6 duge ly t6t hon pyridin nur Khang u,chéng vim va nhigu hoat tinh khie ntta da thdi thie cde nha khoa hoc Iran tng hop mét dan xuat chita ca nhdn benzothiazole,pyridin, thiazolidinones dé tao ra mot din xuat két hop da dang cdc hoat tinh sinh hoc hon.CONHNH [ N. Nv NX 9 |» 7 p 40 ‘NO> NO; A.L.SOCI2.2.Hydrazine, chloroform, triethylamine, DMF, 1-2 got avi avetie bang. B. Andehit thom, DMF, 1-2 gict axitaxetic bang, CThioglycolic axit, ZnC12, T-diovane, 12-14h ib R=2-Cl, ¢ Re4-Ci, dR: -NO2, ¢ ;R=3-NO2, £:R=4-OH, g:R-4-OCH3, h-R=3- 102, R=C4H30( Fury) So d6 téng hop dan xuat pyridin duge thé hién tai so d6 (8). Di tir din xuat 2- ino-6-nitro benzen (36) téc dung véi 2-chloro-pyridin-3-carboxylic (37) tao ra At 2-(6-nitrobenzo{d]thiazol-2-ylamino)-nicotinic axit (38).Tiép tuc cho (38) phan tmg véi SOCh va hydrazine trong dung mdi DMF va xiic téc vai gigt axit axetic bang tao ra din xuat 2-nicotinohydrazin (39).Sau dé hgp chat hydrazin (39) tac dung véi cdc axit thom khae nhau trong dung méi DMF,xtic tac axit axetic tao ra din xuat N’-benzylidene/furan-2-nicotino hydrazine (40). Hop chat (40) tic dung v6i thiogluconic axit voi xte tae ZnCl (phuong phap Shift) cho din xudt cudi cing ctia 4- thiazolidinones. Dainh gi hoat tinh khing khudn: Cie hgp chit 40(2-j) e6 khiing tét cde chiing vi khudn Gram dm vi Gram durong ngodi ra cin ¢6 te dung khing nam. Cée hgp cht 40 b.c,d.g,hij) Khang t6t S.aureus.40j khing tét Pyogenes.Céc hop chat 40(a,b,c,e) khang t6t dén trung binh E.coli.40((b,j) khang tét P.aeruginosa.Cac hop chat 41(a-j) c6 khan ning khang khuan vira phai véi cde ching khuan trén,9.Téng hop dan xudt -lactam ctia 2-benzothiazole-6-cacboxylic axit. -lactam la mét thudc khang sinh str dung phé bién trong y hgc.Cée thude Khang sinh duge sit dung rong rai hign nay nu penixilin, cephalosporin, catumonam, aztreonam...déu chira vong -lactam.Tuy nhién do duge siz dung lam thude khing khudn di Mu nén cae ngay cang xudt hién nhiéu nhém vi khudn méi khang Iai -lactam.Gan day, vige phat hign kha ning khing khudn manh mé cia nhém benzo thiazole da ggi ¥ cic nhi khoa hoe An BO téng hop mét loai khding sinh mdi c6 thé két hop duge ca nhan benzothiazole va -lactam.Diéu nay sé thie day tim ra mot chat khang khuan méi diét duge cée dong vi khuan da quen thude khang sinh -lactam Qui trinh téng hgp dn xudt duge thé hign 6 so dé 9. Ban dau xuat phat tir 2-benzothiazole-6-cacboxylic axit(42) téc dung véi chloroacetyl chloride trong dung méi chloroform véi sy cé mat ciia KxCO; trong 12h tao ra din xudt 2-(2-chloroacetylamino) benzothiazole-6-cacboxylic axit (43), Tiép tye cho (43) phan img véi hydrazin hydrat trong ethanol trong tao ra dan xuat 2.(2-hydrazin acetylamin) benzothiazole-6-cacboxylic axit (44).(44) lai cho te dung véi céc anhdehit thom véi xite téc vai gigt axit axetic bang trong dung méi ethanol tao ra hgp chit 2-{ 2-[N’-(arylidene) hydrazino} acetymino} benzothiazole- 6-cacboxylic axit (45).Hgp chat (45) tiép tuc phan img véi chloroacetyl chloride trong su cé mit ciia triethylamin tao ra din xudt cudi cing (46).N cen N 9 , ————o NH-C—CH,CI SOQ ag poneeen coor ‘coo s 3 7 © NHN HO N, 2 hy D-NH-C-C-N-NED cooHl s LH 44 1, O= CL R 2axitaxetic bang N o H I a Cet yay, COOH _ 45 O @ HS) cca - cl sh Nous No Rhy DONHC-C-NN-C-H COOH s R R= 4a,Sa: 3-BrCgH, ; 4b,5b: 4-OHC Hy 4e,5e: CoH; 4d,5d: 4-OCH CH 4e,5e: 2-CICGHy ; 4f,5f: 4-CICGH, 5 4g,5g2 3-NO2CqH,; 4h, Sh: 4- NOCH, HSN, Danh gia kha nang khing khudin 46(¢,g,h,f) va 45(¢,g,0) 6 khin nang khang khuén manh v6i S.aureus va E.coli, 45(g,h)e6 hoat tinh cao véi P.aeruginosa, C: con Iai khdng khuan vita phai hoc hoi khang khudn hoge khdng khang khuan, 10.Téng hop mudi 2-styryl benzothiazole. Tir lau, mét sé din xudt cia benzothiazole c6 cdu trac day-kéo (nhém cho-nhém nhn.Vd: mudi 2-styryl benzothiazole) dugc tmg dung rat tot lam thudc. Sé di c6 digu nay vi cic mudi 2-styryl benzothiazole cé kha nang digt khuin rit higu qua. Ching ¢6 phé tée dung rong trén cde khuin Gram duong. Chinh vi vay cie nhkhoa hoc Slovakia da tim cach téng hop cac dan xuat cé hoat tinh sinh hoc nay.Cau triie clia mudi benzothiazodium : oe | &x So dé téng hop:Z=5-NO> ; 6-NOx; 5-NHAc; 6-NHAc. R= methyl, allyl, proparglyl. Br. Y=-N(CH))2 ,-O-CH3 ,-OH ,-N-piperidin. So dé téng hop mudi benzothiazidium duge thé hién 6 trén. Dau tién ta di tong hop cae nguyén ligu ban déu la dan xuat nitro va acetymino cia 2-methyl benzothiazole (52).Ban dau cée nha khoa hoc Slovakia tong hgp din xuat 5-nitro- 2-methyl benzothiazole (48a) bing phn tng nitro héa 2-methyl benzothiazole. Tuy nhién dan xudt 6-nitro-2-methy! benzothiazole (48b) lai khong thé thye hién bang phuong phap nay ma phai di tir din xudt m-nitro-anilin thong qua cde phan img brom héa, acetyl héa, khir héa dé thu duge din xuit 48(b).Tuong tw mun tng hop dan xuit acetymino ta di tir cde dn xudt nitro vira thu durge khit héa sau 6 acetyl héa li thu duge cde din xuit theo yéu céu (51).Dan xuat (52) phan img véi R-X theo co ché tin cdng electrophil tao ra din xuat (53).Nguyén tit N bie 4 trong (53) kich hoat hydro ciia nhém 2-CH; tao than hydro linh dng dé phan ting ngung ty véi andehit thom tao ra mudi benzothiazidium (54). 11.Tong hop dan xudt 2-azetidinone benzothiazole. Cé thé coi cdc loai Khang sinh B-lactam khéc nhau la din xudt ciia azetidinone. Tir bd khung ccr ban cita azetidone ngung ty véi cic dan xuat khic nhau cho cdc logi thudc khang sinh khac nhau nhu: penixilin,carbapenem,3-chloro-monocyclic f}- lactam ciing 1a m@t din xuat dang chit y cia B-lactam vi né ¢6 nhieu hoat tinh sinh hoc thi vi nhw: khéng viémkhang khudn manh,chéng co gidtjchéng déng kinh.... Benzothiazole ciing c6 nhiing tinh chat tuong ty nh vay.Diéu nay goi ¥ cde nha khoa hoe An Dé téng hgp cae din xuat moi chtra b6 khung B-lactam va nhan benzothiazole cé hoat tinh manh hon cae dan xuat ban dau,x Ds Nea Ss 7 fc peer rt cae NHN=CHAr 58 (en) ‘cl a) Ar= an: 2-CICiHy 3-CICSHy 4-CICHy 2-BrCgHy 3-BrCcHy 4-BrCcHy, 2- OCH;CsH,, 3-OCH;CoH 5 4-OCH;CoH 5 2-NO:CsH 3-NO2C6H,, 4-NO2C6H, , 4,4-(CHy) CH Téng hop dan xuat 2-azetidinone benzothiazole so dé 11. Xudt phat tir dn xudt 2- mecaptobenzothiazole (55) cho phan img vi hydrazine hydrat tao ra 2-hydrazino benzothiazole (56).Tigp tue cho (56) tic dung voi adehit thom (mét trong cae andehit tir a-n) tao ra dan xudt 57(a-n).Dan xudt 57 (a-n) tigp tue phan img véi chloroacety chloride trong dung méi trietylamin tgo ra din xuat 58(a-n). Danh gid kha nang khang khuan: 57 (a-n) va 58 (a-n) c6 kha nang khang lai céc khuan: Bacillus subtilis, E.coli, S.aureus ngoai ra ching cdn tac dung khang nm.Tai ligu tham khao [1]. Hé Xuan Dau, Tigu Tuan Kigt, Trin Thj Thu, Ngo Thj Hanh (2009), Téng hop va nghién ctu cau tric m6t s6 din xuat cla 1,3-benzothiazole, Tap chi Khoa hoc DHSP TP. HCM, $6 18 nim 2009. [2]. Ho Xuan Dau, Tran Thj Tiru, Lé Thi Bich (1994), Nghién ciru tong hop din xudt benzothyazole, dé tai cdp BO ma s6 B19-30-06 nghiém thu 1995, Trudng Dai hoc Su pham TP. Hé Chi Minh. [3]. Abe et al. : U. S. pat, 4,929,623 (1990). (4).