Nghiên cứu tổng hợp, cấu trúc và hoạt tính sinh học của các hợp chất tương tự Flavon, có chứa nhân dị vòng

Da thuc hien phan ung ngung tu giua cac san pham chuyen vi Fries a tren v6i cac indol - 3 - andehit hodc v6i cdc andehit day Furan lrong dieu kiCn ciia phan ihig Smith d^ nhan dugc cac

DAI HOC o u 6 c (;f A HA NAI

BAO CAO KfiT QUA THUC HI$N Dfi TAI DAc BlfiT CA'P DHQG: 2001 - 200.1

T«n dt Ml •

SINH HOC COA CAC HOP CHAT TlTONG TV FLA VON,

M&s6 : QG.01-02

Chu i.hi«m d^ m: GS TSKH Nguyin Minh Thdo

Hh n6l- 2003

PHAN MO DAU

MUC LUC

Trang

PHAN Md DAU '

Danh muc cac bang s6 li6u ^

Danh miic c^c hinh ^ TOM TAT NHUNG KET QUA CHINH ^

L Ke't qua v6 mat khoa hoc 4

2 K6t qua phuc vu thuc te 5

3 K6x qua dao tao 5

4 K6'l qua niing cao tiOm luc khoa hoc 6

5 Tmh hinh su dung kinh phi 6

ABSTRACT 7 PHAN N O I DUNG CHINH 8

I DillvAiid^ 8

II Tdng quan cac vA'n de nghien cuu 9

2.1 Ve pli.ln inij.' (.huven vj I rii*s 9

2.2 Ve cac xeton a (3-khong no 10

2.3 Vrti net v6 riavon va flavonoit 11

IIL Phuang phap nghien cuu va Ihuc nghiem 12

3.1 Pliuotig phap xac djnh cau tao do tinh khiet yh hoat tfnh sinh hgc ciia 12

cac hgp cliiit tdng hop dugc

3.2 Tdng hgp cac este ciia phenol va thuc hien phan ung chuyen vi Fries 12

cua chiing

'5-3 HiU(/ng phap chung tdng hgp cac xeton a, \\- khAng no: 14

3.4 Pliuang phap chung tdng hgp cac hgp chat tuong tu flavon 19

.^.5 Hurtrng phap chung (dng hgp cac pira/olin thua nhan di vong: 21

24

4.1 Axetyl hoa c^c phenol vh chuyen vj Fries cua chiing 24

4.2 Tdng hgp cdc xclon a \\- khOng no 25

4.3 Tdng hgp cac hgp chAt tuctng tir flavon co dura nhAn di vong 25

4.4 Tdng hgp cdc hgp chflft kieu pira/olin chi'fa nhrui <li vong 26

4.5 Tinh toan hoa lugng tir 26

4.6 Thdm do hoat tfnh sinh hoc 26

V Ke't luan 30

VI Kie'n nghj 30 TAI LifiU THAM KHAO 31

I H C N G N G U O I THAM (ilA DE TAI

1 Nguyen Minh Thao - GS TSKH - Truong Dai hoc Khoa hoc Tu nhicn- DHQG HN

2 Pham Van Phong - ThS - Trucmg Dai hgc Khoa hgc Tu nhien- DHQG HN

3 M6t s6' hgc vien cao hgc va sinh vien

DANH MUC CAC BANC; SO LI$U Bang I: Cac san phiim phan ihig chuyen vi Irics

Bang 2: Cdc xeton a p- khAng no day agienol va iso(rgicnol (E,.;)

Bang 3: Cac xeton a P- khong no di tir resoxinol (K, s va DKr m)

Bang 4: Cac xeton a P- khong no di ti^ hidroquinon (H,.?)

Bang 5: Cac xeton a, P- khdng-no di ti^ 7- hidroxi- 8- axelylquinolin (Q, 4)

Bang 6: Cac xeton a, p-kh6ng no di lii axit dehidroaxctic ( D H A i n )

Bang 7: Cdc xeton a, P- khdng no di tir 7- hidroxi- 4- metylcumarin (C|.g)

Bang 10: Cdc hop chat tuong lu flavon di lu hidrcxjuinon (F,,, 0

Bang 11: Cac hgp chat luang tu llavon di lu hidroxiquinolin (F,^,^)

Bang 13: Cac pira/t)lin chua lutj) phdn (tgicnol v;i isoofgicnol (IVi (d

Bang 14: Cdc pirazolin chira hgp phAn resoxinol (P,(, ^ va F*,,^^, ,):

Bang 15: Cdc pira/olin chua hgp phdn hidrocpiinon (P,,, 0

Bang 17: Cac pinizolin clura vong tiuinolin (P^i i)

Bang 18: Cac pirazolin chua hgp phan cumarin (Pf,.,)

Haiij^ 10; Kli;i iiAiij; kh;uig khuan \ a 1 liOnji nam cim c:\c x c l o n (X, p- khAng no day

Ffinh 2: Phd khoi lugng cua san pham chuyen vj Fries 8- axetyl- 7- hidroxi- metylcumarin

4-Ffinh 3: Phd cOng huong tu prolon cija xeton a, P- khong no CL

Hinh 4: Phd kho'i lugng cua xeton a, P- khong no Cl

Hinh 5: Phd cong huong tir proton cua hgp chat loai pirazolin P ^

ffinh 6: Phd khA'i lugng cua hgp chat loai pirazolin

IVi-A T NHUNG KEI QUIVi-A CHINH D6 tai: "Nghien ciiru tdng hgp, caiu true va lioiit tinh sinh hoc ciia cac ligp chai tuong lu

Flavon, co chiira nlian cij von^"

Chinh thirc dugc phe duyet la de tai dac biet cap Dai hgc Qudc gia Ha ngi vao Ihdng 05 nam

2001 vdi thdi han 24 thdng (ke tu ngay kf) va ldng kinh phi 60 trieu dAng Den nay, de lai

da dugc lumn lhanh va dai dugi ci\c kei ipid chinh nhu sau:

1 Ke't qua ve mat khoa hoc:

Da nghien cihi phan ung chuyen vi Fries cdc aryl axetat di tu ddn xuat cua quinolin, Ogicnol vii isoogicnol, cdc dihidroxibcn/cn, cdc hidroxi ciia cumarin va quinolon- 2 San phdm cua phan ihig nay la cdc chdt ddu cho cac chuyen hod licp theo

Da thuc hien phan ung ngung tu giua cac san pham chuyen vi Fries a tren v6i cac

indol - 3 - andehit hodc v6i cdc andehit day Furan lrong dieu kiCn ciia phan ihig Smith d^ nhan dugc cac day xeton rx, p - khAng no luong ung co chira cdc nhan di vong (khoang 50 hgp chat mdi)

Claisen-Ti^ cdc hgp chai xclon (/., \\ - khAng no nhan dugc d Iren da cho phan ung cAng hop

vong oxi hod boi lim huynh de lao thanh khoang 40 hgp chai mdi tuong lu Flavon nhung chua nhan di vong hoac cho ngung lu ddng vong vdi phenylhydrazin de lao thanh khoang 50 hop chai niiVi ciia vdng pira/olin

Cau true cua cac iigp chdl mdi nhan dxsac da dugc xac nhan nhd cac phuong phap phd

hdng ngoai, tir ngoai phd cAng hmmg lir hat nhdn va phd khdi lugng

Da van dung cdc plurctng phdp ti'nh Hod lugng lir ti'nh gan dung dc xdc djnh mat dd dien tfch Iren cac vi Iri lrong phan tir xac dinh do dai va nang lugng lien ke't trong phan tir Tren CO sd do da xdc dinh cau h'mh uu tien ciia phAn tif, ddng thdi gdp phdn lam sang ro them ve chieu hudng va co che phan i'mg

khoang 30 hgp chat cd hoat tinh khang khuan vii chdng nam d muc do khac nhau trong dd

cd mot sd chat rat dang chii y va cdn dugc nghien cirii sau hon

Vdi ke'l qua do da cAng bd cdc cong trinh sau dav:

1 Nguyen Minh Thao, Nguyen Oinh Dong,

^Tdng hap vd chuyen hod mat sd xeton a, P- kliong no co chim vong indol vd quinolin \ Tap chi Hod hoc T.3^) so 2, Tr f^O (2001)

2 Nguyen Minh Ihao, Fhani Van Phong,

'Tong hap vd chuyen hod cdc hap chdt tuang tu khan con cd chda vong indndTi T6t^ hap vd chuyen hod cdc hap chat xeton a, p- khdny, no tif cdc 3-fom\lin£n w J^ tuai agienol \

Tuyen tap cdc cong trinh Hoi nghi khoa hoc Idn thu hai Tntang Dai htx KJtau hpc Tu nhien

• DHQGHN, Hd Noi - 2000 Nhd \udt bdn "DHQCHN", Hd Noi - 2(MJI tr I3H • 14J

J Nguyen Minh Ihao liiin V::;i ( h i e n , Pham Van Phong,

veton ce, fi- khong no tii ddn xudt cua isoagienol vd cdc

indol -3- andehit \

Tuyen tap cdc cdng trinh klioa hpc ki niem 45 ndm ngdy thdnh lap Khoa Hod hpc (1956 lOQIh Nhd xudt hdn "DHQGHN" - Hd Noi - 2001, tr 52-55

-4 Nguyen Minh Thao, Pham Vdn Phong

'Xdc dinh cdu hinh cua agienyl axetat vd sdn phdm chuyen vi Fries cua nd bdng phuang phdp tinh Hod luang tu\

Tap chi Hod hpc, T.40, so J, tr 9 (2002)

5 Nguyen Minh Thao, Pham Vdn Phong,

*Xdc dinh cdu hinh cua xeton a, /?- khdng no (td o -axetylagienol vd 3-fomylindol) vd mot

vdi sdn phdm chuyin hod cua nd hdng phuang phdp tinh todn Hod luang td\

Tap chi Hod hpc, T.40, so 2, tr I-10 (2002)

6 Nguyen Minh I hao, Nguyen Van Ndm, l*ham Van Phong,

*Tdng hap vd chuyen hod mat sd xeton a, fi- khdng no ta axit dehidroaxetic vd cdc furfural\

Tap chi Hod hoc, T.40, so 3, tr.43 (2002)

7 Nguyen Minh Thai), Pham Vs^n Phong, Biii Manh Tung, Phi Thi Minh Hai,

'Tong hap vd chuyen hod mot sd xeton a, fi khdng no di tut ddn xudt cua Hidroquinon vd cdc indol- 3- andehit \

Tap chi Hod hoc, T.41 so I tr 6/ (200.^

H Nguyen Minh Thao, Pham Van Phong,

'The quantum calculating application in Fries rearrangement of resorcinol diacetate \ Bdo cdo lai Hdi nghi Khoa hoc Chdu A lan tht'r 10 hop tai lid noi vdo ngdy 21- 24 thdng 10 ndm 2003

9 Nguyen Minh Thao, Pham Van Phong, Nguyen Xuan Tu,

\Synthesis and transformation of some ac, fi unsaturated ketones from coumarine derivatives and indole- 3- aldehydes \

Bdo cdo tai Hoi nghi Klioa hoc Au- A Idn thif VIII hop tai Hd noi vdo ngdy 21- 24 thdng 10 ndm 2003

2 Ket qua phuc vu thuc tc:

Viec tham dd va xac dinh dugc mot loat hgp chat c6 kha nang khang khu an va chdng

nahi da la su dinh hudng ung dung thuc le Hien nay mot vai hgp chat dang chii y dang dugc tie'n hanh thir hoat tinh chdng ung thu va cd the ca chdng HIV Ne'u cd ket qua tdt thi dd se

la cu ddng gdp tdt cho phuc vu thuc tc

Ngoai ra ke't qua dao tao ve mat nao do cung cd the coi nhu la kel qua phuc vu thuc

te

3 Ket qua dao tao:

Dua tren de tai nav da dao t;io duac:

Ig) Ngoai ra ci>n I hgc vien cao hgc khac da hoan t h ^ h chuong trinh hgc tap nhimg chua bao ve luAn van

- Da hudng ddn 08 sinh vien bao ve thanh cAng khoa luan lAt nghiep: Trdn Van Chie'n Nguyen Manh Cudng, Nguyen Van Nam Bui Manh Tung, Hoang Hie Thdng Duong Thi Hd Rii Thi Minh Hai Le Thanh Nghi

- Da hudng d ^ mdt sd sinh vien lam nghien cuu khoa hgc lhu dugc ket qua tdt, Irong

66 cd sinh vien Nguyen XuAn Tir dat ket qua rat tot, dat giai nhi NCKH ciia sinh vien

Trudng DHKHTN va giai khuye'n khfch nghien cmi Khoa hgc Sinh vien cdp Dai hgc Qudc gia Ha ndi nam 2003

4 Ket qua ndng cao tiem lire khoa hoc:

Tren CO sd Ihuc hien de tai da dao lao mol <6 thac si va cu nlmn trong dd co nhi^u

ngudi trd thanh can bA cd nang luc MAl sd sinh vicn sau khi bao vc khoa iuAn tot nghiCp da dugc de nghj chuy^i tie'p cao hoc nhu Phf Thi Minh Hai Ilianh viCn de lai Fliam V.ln Phong sau khi bao ve xua't siic luan vdn thac sT cung dii heu chuan de dugc xet chuye'n tie'p nghien cun sinh

Ve mat thi6^t bi, nhd viec thuc hien de tai vdi ngudn kinh phi dugc cdp ciing da tang cudng mdt sd dung cu cdn thiet cho qua trinh thf nghiem nhu lii dd, bep dien, cac dung cu

ihuy linh di^c biei va dac biei cd ngudn kinh phf dd mua cdc loai hod chdt dac biet phuc vu

qud trinh nghien ci'm

5 Tmh hinh stir dung kinh phi:

Tdng kinh phi dugc cdp cho 2 nam Ihirc liiCn dc tai la 60 trieu ddng (niAi nam 30 trieu ddng) Kinh phi chu ye'u dugc diing dc mua hod chat va dung cu thf nghiem Mot phdn chu

yeu khac disac dung de thue mudn chuyen mdn va lao dong De'n nay da quyet loan dugc

khoang 52 IriCii Cdn hu khoang S Iricu sc dugc qiiycl (odii ngay sau khi nghiem thu de lai

Hd noi ngdy i^'thdng tenant 2003

XAC NHAN CUA TRUONC; OAI HOC

e and biological activity of the analogs offlavone compounds containing heterocyclic nucleus'*

ABSTRACT The Fries rearrangement reactions of aryl acetates from derivatives of quinoline eugcnole, isoeugenole, dihydroxybcnzenes, hydroxyquinoloncs, hydroxycoumarincs have been studied These products have been used as starting reagents for conscqucnl lransii>rmalit)ns Tlicn, the Fries rearrangement producls have been condensed in the conditions of Claisen- Schmidt reaction with indole- 3- andehydes or furfuraldehydes to give a, P- unsaturated ketones containing heterocyclic nucleus ( about 50 new compounds)

The a, p- unsaturated ketones were cyclo-aditionaly transformed by Sulfur as an oxidizing reagent, forming about 40 new flavone analogs containing heterocyclic nucleus The a P- unsaturated ketones also easily reacted with phenylhydrazine to form about 50 new derivatives of pirazoline ring

The constitutions of the producls have been determined by using IR-, UV-, MS- and NMR- spectroscopies, and the their antibiotic abilities have also been tested Some of them have shown good results and wc have been proposed to enlarge the research in order to dclerminc and developc the resulls

'H-Besides synthetic reactions Chemical Softwares, such as HypcrCiicm 7.0 have also been used lo help determining charge density, binding length, and binding energy of molecularly optimal confonnations and studying mechanisms of the reactions

The anli-bacleria and anli-ycarst abilities of Ihc (X, \\~ unsaturated ketones and pyrazolines

were tested Tlicse synthetic products have showed the biological activities m different levels Some considerable ones need more deeply studying

>an phim thu dugc bang cdc phuong phap pho hien dai : hdng ngoai, tir ngoai, cong hudng tir proton va khdi lugng cung nhu sir dung cac phuong

phap tinh hoa lugng tir gdn dung de xdc dinh mdi d<} dicn tfch, dA dai va nang luong lien k^t

cQng nhu cdc cdu hinh ben ciia phan tir Tir dd cd the gdp phdn lam sang ro them chieu

hudng va co ch^ phan ung

- Ti^n hanh tham dd hoat tfnh khang khudn, chdng ndm va xay duu^ Inrdc ddu mdi

quan he giGa cdu tnic phdn tir vdi hoat linh sinh hgc ciia hgp chat ldng hgj) dugc

De thuc hien 66 tai chiing ldi da sir dung cac phuong phdp thuc nghiem lien lien

trong tdng hgp huu co, cac phuang phap phd hien dai va phuong phdp tinh gan dting cua hoa

lugng tir de xem xet cdu tnic phan tir va phucrng phap tham dd hoat Ifnh sinh hgc theo lieu

c h u ^ trong dugc dien Viet nam

2.1 Ve phdn Umg chuyen vi Fries:^^-'^' ^' '

Phan ling chuyen vj Fries la qud trinh chuyen \'i ngi phdn tir ciia cac phenyl este nhd

su xiic lac ciia axil Lewis (AlCl^, ZnCl2, BF^ ) Phan ung xay ra vd ban chat gidng vdi su

A l ( t ,

li

( I

a.\ylplfc;ni)l

Thong thirdng ti lc cstc: AlCi, khim la 1:1 fmol) Tuy nhien neu trong phdn tir este

chua cdc nhdm cd kha nang tao phuc vdi nhdm clorua thi cdn dimg ti le nhom clorua khan

cao hon

2, dieu kien cd dung mdi vkhi este d Ihe ran va cd nhiet

dd ndng chay cao) hodc khong cdn dung mdi Ca»; dung moi thdng dung !a liilrobenzen, caebon disunfua hodc diclocian Iiong dd liiii'ihcn/m (d mi liie fi*ni' a vt no \ir:i hoa tan nliAm clorua khan, viTa hoa tan este

2.2 Vi cdc xeton a; fi khdng no:

2.2.1 Cdu fuocac xolon a, \\- khong no:

Cdc xeton a, p- khAng no Id cdc hgp chdl hihi at ma trong phan lir ciia chiing cd chira

nhdm vinyl xeton (-CH=CH-CO-) Chi'nh vl vdy ma cdc xeton a, P- khdng no cd kha ndng tham gia nhi^u phan ling dd lao thanh cdc hgp chdt hiru co khdc nhau

Plid hdng ngoai cua xeton a, p- khAng no thudng xudt hien cdc pic ddc liimg cho dao dOng hda trj cua nhdm C = 0 lien hgp trong klioang 1630- 1690cm' ciia ndi ddi lien hop ciing vdi cac ndi ddi cua vdng thom lrong khoang 1550- 16I5rw"' va pic dac tnmg cho dao

ddng bi^n dang khdng phang ciia nhdm trans- vinyl d 960- 990c7« ' ''*'

Hid lir ngoai ciia cdc xclon <x, \\- khdng no Ihuirng cd 3- 4 cue dai ha'p lhu ndm d viing

tir 300«w trd len vdi he sd tdt phdn tir khoang lO'^ dac Irung cho budc chuyen electron

n->7r* 240- 290nm vdi he sd Idt phdn fir khoang 10^ dac Irung cho su chuyen budc chuydn electron n->n* va 200- 2?iOnm dac Inmg cho su chuyen budc chuyen electron K—>7i* cua

nlian benzen''*''

Ngoai ra cdn cd cdc cue dai vdi ^,„;„ nhd hon dac trung cho nhan thom, di vdng

2.2.2 Cdc phuong phap tdng hgp xeton a, P- khdng no:

Cac xeton a P- khdng no cd ihd dugc ldng hgp bang nhidu phuong phdp khac nhau chdng han lx\ng phan ihig ngimg tu ciia ankyltriphenyl photphoclorua vdi andehit piruvic''' bang su quang ddng phdn hda 4- (benzanamino)- 3- melyl- 5- sliryloxazol'"', bdng su phan huy cdc p- aminoxeton''^-'" '", bdng each loai phan tir nudc ciia diaxetoancol''^' va dac biet bang phan ung ngung tu Claisen- Schmidt"^':

2.2.3 Tmh chat ciia cac xeton a, fi- khdng no:

Cac xelon a p- khdng no cd the Iham ;^ia ra<; pluin \sv\)j a i\-)i doi ;ieng biet (cAng bn>m hay oxi hod bdi KMnO,) hojc phdn (m,u tivit nhdm CO iihi du lao ra 2,4-

10

di ca he xelon a, p- khAng no lien hgp de lao thanh cac dJn xuit cua vong pirazolin hoac isoxazolin

2.3 Vdi net ve flavon vd flavonoit:

Flavonoit ndi rieng va flavonoit ndi chung la mgl nlidrn hop chdl rat rdng Idn va phong phii lrong nhien thuc vdi Chiing cd the d dang tu do hodc dang glycozil

Chung cd Ihe dugc tdng hgp bang nhidu phuofng phap khac nhau (Jhiing han:

Tdng hgp theo Koslaneski- Robinson" *':

(CMiCO),0

^ o - -c:,,H5

Cdc Idc gia [15] da long luyi") dugc day flavon khi khudy trdn hdn hgp ddng phdn tir

gam ciia o- axelylphenol vdi benzandehil trong dung dich NaOH 0,1N d nhiet dc> 37"C sudt

48- 216 g i d \ d i hieu sudi cao

U VA T H U C N G H l f e M :

3.L Phuang phdp xdc dinh cdu tao dp tinh khiet vd hoat tinh sinh hpc cua cdc hap

chdi tong hap duac:

- Sdc kl lop mdng dugc thuc hien tren ban mdng trdng silicagel He dung mdi etyl

axetat: clorofom = 1 : 4 Hien hinh bang hoi idt hoac d\ia\ dnh sdng tir ngoai

- Phd hdng ngoai dvxoc ghi dudi dang cp vien vdi KBr tren may P I - IK 1801 Shimadzu

tai vien Khoa hgc Hinh su- Bg cong an, Trung ldm Hod inAi trudng va phat tricn bdn vung, may Nicolet 760 E S P Trung tdm Hod dau, mdy Nicolet Avatar 360 Sl - IR eP ciia phdng thi nghiem VH-I Trudng Dai hgc Khoa hgc tu nhien- Dai hgc Qudc gia Ha ndi

- Phd tu ngoai ciia cac hgp chdt dugc ghi Iren may Spectrophotometer UV- 2001 trong dung mdi etanol tai Phdng may- Bg mon Hod Vo co- Khoa Hod hgc- Trudng Dai hgc Khoa ligc lu nhien- Dai hgc QuAc gia Ha noi

- Phd cAng hudng tir proton cua cac hgp chdt dugc ghi Iren may BRUKER AVANCE 500 MHz trong dung mAi DMSO- d^, vdi chdt ndi chuan IMS tai phdng Hod cdu true Trung tarn Khoa hgc Tu nhien va CAng nghe Qudc gia

- Phd khdi lugng ciia cdc h(;p chdt dmc ghi tren may 5989 BMS tai phdng hoa cdu tnic

Trung tam Khoa hgc Tu nhien va Cong nghe Qudc gia

~ niir lu)al Ifnh khang khuan \l\ chdng nam diroc Ihuc hicn lhc(^ phuiyng phdp ghi trong dugc die'n Viet nam (Idp kluiiig sinh dC)) tai Phdng ihi nghiem Hoa sinh XMzuh \ ien 19-8 B(>

cdng an va lai Medilalec Co Ltd (38 Chau Long- Ha ngi)

3.2 Tdng hap cdc este cda phenol vd thuc hien phdn iaig chuyen vi Fries cua chiing:

3.2.J Tdng h(/p cac aryl axetat WsXa cda cac phenol):

Dun si\\ hdn hgp phciu>I \d\ juhldiil ;i\clit (ti Ic mol 1:1 \ai monophcnol vd 1:2 vdi

dihidroxiaren) vdi sued mat ciia Iml a\il photpiioric dac ldm xiic tac lrong sudt 3- 5 gid Cai

loai axil axetic tao ra lrong phan ung va anhidrit a:<ctic du Tach lay Idp huu ca, rira bang

dung dich NaOH loiing rdi nra lai nhieu Idn bdng nuoc lam khd rdi cat lay cstc d dp sudt thdp (trong trudng hgp cd dung mdi de chicl thi trudc khi cat Idy este phai cdt loai dung nidi trudc)

Vdi cac dihidroxibcn/cn thuinig chi diing axil sunfuric dixc h\m xiic lacva chi cdn khuay trdn hon hgp plu'ui iuv^^ d nhiel dd phdng sO (hu dugc cstc thudng d trang thai rdn

Dudi day la cdc este khdi ddu tdng hgp: duac:

- Qgienyl axetat: t", 163- l67"C/23minHgi"' Hieu suat 53%

- MYM/gicnyl axelal: I',„ 78- 8(r'C Hieu sudi Ky/v

- Resoxinyl diaxelal; i'\ 278"C (Theo lai lieu ' " ' I'; 278"C) Hieu sudt 70%

- Hidr(K|uinyl diaxelal: t"„ I22'C (Theo lai lieu ' " ' t',„ I22'C) Hieu sudt 84%

12

Icumarin: C,., 150- 15r'(: n i i c o lai lieu " " ' t",, I51"C) Hieu sudt 90%

3-2.2 Thuc hien phan utig chuyen vj Frits este cua cac phenol:

Dun ndng hdn hop este ciia phenol vdi AICL khan Ihco li le mol I: 2 hay I: 3 luy theo

este hodc diesie (cd Ihe' khong dung dung moi hoac dimg dung mAi iiitiol)en/eu) d 180"C sudt 3 gid Sau dd phan huy hdn hgp bang nudc da va axil clohidric dac San ph^m d dang ke't tinh dugc lgc hiit rira vu lam khd ngoai khAng khf (in)ng trudng hgp dimg nitrobenzen lam dung mdi thi phai cdl loai nitrobenzen bdng chung cdt Idi cudn hoi nudc)

170-Cac san ph£m phan ung chuyen vi Fries duac ghi trong bang I

Bdng I: Cdc sdn phdm phdn ifng chuyen vi Fries

3.3 Fhuang phdp chung tdng hap cdc xeton a, /A khdng no:

a Trong su lam lanh ben ngoai bang nuc'jfc dd, khuay trdn hdn hgp ddng tl le mol ciia

cdc hop chdt kieu o- hidroxiaxclophciioii (c;ic s;in phiim chuyen vi Fries- Bang I) vdi cdc

andehit day indol hoac furan lrong etanol vd cd mat xiic tac la dung dich NaOH 30- 60% Sau dd de yen hdn hgp phan ung d nhict do phdng 120 gid Tie'p theo pha loang hdn hgp phan ling bang nU('/c dd de'n gdp doi the tfch ban dau rdi trung hoa bdng lugng axit axetic

dugc linh sdn den phan ung trung tfnh Lgc hut ket tiia tdch ra, dc khd ngoai khong khf va

cd the ket tinh lai tijrdung dich etanol- nudc

h D6i vdi cac hgp chat la axil dehidio axclic hay axctylcumarin thi thuc hien phan

i'rng bdng each dun ndng hdn h(;p ddng li lc mol ciia hai chdt phan ung lrong clorofom vdi vai gigt piperidin lam xiic lac lrong sudt 3- 5 gid San phdm o dang ket tiia dugc tach ra bang lgc hiit va do khd ngoai khdng kin'

Ke't qua dugc gidi thieu d cac hang 2 3 4, 5 6 vd 7

14

*n

3,4 Phuang phdp chung long hap cdc hap chdt tuang tu flavon:

Dun sAi hdn hgp theo ll le mol i: I cua xclon (x, |1- khAng no vdi luu huynh trong xilen sudt 6- 8 gid San phim tach ra d dang linh Ihe dugc Igc hiit va de khA ngoai khdng

kill ( O diO'' kci linh lui lir dtiiif; ilii h rlaiiol: tiuac

K6i qua dugc gidi thieu trong cac bang 8, 9, 10, 11, 12

/?a/ig 8: Cdc hap chdt tuang tu flavon di tit agienol vd isoagienol (Fp,^)

Rf

0.60 0,35 0.54 0.55 0.36 0.54

, 1

Hi6u suat

-

-Tim 4.38 4.34 3.72 3.57

1245 1174.1247 1175.1260 1043; 1265 1037; 1267

Phd tGrngoa

KJnm)(}QE)

241(4.19); 257(4.10); -; 294(4,42) 243(4.45); 264(4.51); -; 301(4,54) -; 255(4.71);-; 312(4.41) 244(4.40);-;-; 298(4.43)

-

150-151 105-106 20!> ?0(J 21S-216

161-162 242-243

'; Cdc hap elicit tuang tu

R,

1.54 0.70 0.45

0.63 0.48 O.Mi 0.73

0,52 0.50

Hi6u sunt

4.81 3.81

4.95 3.54 Ei.)2 6.12

-

1170; 1257 1084; 1243

\\yf VM

1161; 1243

1125; 1210 1175; 1245

Phd tiJr ngoai X^(nm) (tge)

210(3.71); 250(3.46); -; 407(3.60) -; 256(3.90); 364(3.68) 204(3.94); 245(3.71); 266(3.59);

302(3.55) 2(Xi(3.64); -, 258(3,37); 362(3.62)

?2:'H3.75) 253(3.39) 412(3.58)

210(3.83); 240(3,75); 263(3,56);

314(3.65) 209(3,65); 245(3.31); 300(3,34)

0.63

ac hap

Hieu suai (%)

4.81

3,97 4.81

3.81

Tim 5.21

4.91

3.75 4.88

303(4.28) -208(4.76); 259(4.54); 303(4.16);

364(4,12) -

Bdnn 11: Cdc hap chat luang tu flavon di tir hidroxiquinolin (FQI,^)

251 252 102-103

R

0,49 0.43 0.42 0.46

Hieu

s u ^ {%) 7a,

80

69

72

%N hnt)

8.9 8.6 7.2 6.9

Tim

9.1 8.2

1 U 5 1245 1174;1244

V M I

3167

3266

3128 -

Ptid turngoai

X ^ ( n m ) ( l 9 E )

241(4.58); 256(4.48); 294(3.94) 241(4.46); 263(4.31); 300(4.45) -; 256(4.62); 312(4.35) 242(4.48);-; 298(4,40)

Bdng 12: Cdc hap chdt titang tu flavon di tir axit dehidroaxetic (Ff),f^ ,.12)

212-m

2/4-2/5 207-209 215-216 247-248 259-260 185-186 173-174 119-120 158-159

1 ^

0,40 0.47 0,56

0 4 / 0.54 0.42 0.5C 0.57 0,59 0.44 0.35 0.65

nm

5.03

4 M j 4.31 3.81 4.59 3.67 -

3.a3 -

- •

4.19 4.32 4.01 -

Pttd tiong rejoai ( c m ' )

V c o

1695; 162a 1695; 1528 1716; 1647 1714.1041 1713; irvt?

1722.1060

1718 1540 3,97

-4.81 1 4.65

• 1

-1720:1660 1685; 1666 1728; 1640 1718; 1641 1719-154((

2 0 9 : 2 4 1 ; - ; 383 209; 255; -; 381 209;251;35G;;«'.9 210; 23a 3 1 7 ; - 201; 2 4 8 ; - ; 393

2 0 1 2 2 5 : 3 0 8 : 3 6 4 201; 2 3 1 ; - ; 356

20

J.J rnuangpnap chung tdng hgp cac pirazolin chua nhdn di vdng:

Dun sAi h6i luu hAn hgp theo ti le mol I: 1 ctia xclon r/, p- khong no v(5ri phenylhidrazin trong etanol vi su c6 mat vai gigt axil axetic liim xiic tac suAt 3- 5 gi5 San pliiim tach ra (V dang ke't tua dugc Igc hut va de khA ngo^i khAng khi

K^t qua dugc gidri thieu 6 cdc bang 13, 14, 15, 16, 17 va 18

Bdnz 13: Cdc pirazolin chita hgp phdn agienol vd isoagienol (PEL 6)

107-109

R,

0.71 0.65 0.83 0,77 0.56

0,53

Ht^suat (%)

-Tim 9,64 9,33 8.25 8.50

^

-Phd hdng ngoai Vc^cm')

Ddng 14: Cdc pirazolin chda hgp phdn resoxinol (Pjf,,^ vd PoRf,.9)

Hi6usuat (%)

Tim 11.10 10.85 9,30 11,17 9.33 13.12 12.50 -1^50

Phd hdng ngoai

V ^ J o n ' )

3432 3381 3118,3380 3150.3138

3311 4448.3312 3400.3388

-250(4.05);-; 340(4.21) 230(3.69); 291P.36); 337(3,52) 230(3,66); 266(3.24); 346(3.33)

223(3,48); 291(3,11); 365(3.15)

-21

J.J rnuungpnap cnung long nap cac pirazolin chua nhdn di vong:

Dun sAi h6i luu hAn hgp theo (i le mol 1: 1 ciia xeton a, ^~ khong no voi

phenylhidrazin trong etanol \h su co mat vai gigt axil axetic lim xiic lac suol 3- 5 gicr San

pliiim tdch ra (V dang ke't tua dugc Igc hiit va de khA ngoii khAng khi

K^t qua dugc gidri thieu 6 cac bang 13, 14, 15, 16, 17 va 18

107-109

R,

0.71 0.65 0.83 0.77 0.56

-Tim 9.64 9.33 8.25 8,50

-Phd hdng ngoai Vc^cm')

R,

0.56 0.67 0.74 0.71 0.78 0.57 0.62 0.66 0,75

-Tim 11.10 10.85 9.30 11.17 9.33 13.12 1Z50

-12,80 12.50

Phd hdng ngoai V.„{rm')

3432 3381 3418,3380 3150,3138

3311 4448.3312 3400.3388

-

-250(4.05);-: 340(4.21) 230(3.69) 291P.36); 337P.52) 230(3.66); 266(3.24); 346(3.33)

-223(3.48); 291(3,11); 365(3.15)

2J

15: Cdc pirazolin chiia hgp phdn hidroquinon (Pfn-s)

Rr

0.61 0,66 0.46 0,53 0.44

HiOusuJt (%)

Inn 11.50 11.20 9.29 10,78 9.00

Phd hdng ngoai Vo„(an')

3425 3383 3414.3372

3283

3314 3288.3230

Phd hJT ngoai:

A,«("m)(k|c) 225(3.93): 310(3.85); 340(3.95) 227(3.48); 316(3.45); 344(3,55)

222(3.90); 294(3.37); 368(3.40)

R,

0,60 0,70 0,63 0.66 0.75 0,69 0.47 0.66 0.38 0.40 0,52 0.50 0.49

Hi&usuat (%)

lim

7.32 6,70 5,68 7.31 6.07 12.50 10.72

Phd hdng ngoai (cm') Vc,,

22

uuriK M /_ \.u% yuu4,olin chita vdng quinolin (PQI^)

i7&-ieo

Rr

0,58 0.64 0.76 0.61

Tim

13,6 13.2 11.4 11.2

Phd hong ngoai (cm')

Pho tu ngoai X_(nm)(lgr)

221(4.21) -; 340(4.32) 238(4.81): 303(3,92); 341(3,82) 236(4,43); 297(3.92); : -: 341(4.45)

Bang 18: Cdc pirazolin chUa hgp phdn cumarin (Pci.9)

*: PhA l i l - N M K cS/7>//;: 2.4()(CI1,); >,7() va 4 U) (CII.); 5.SO (IIC); i 1,10 (HO);

12,10 (HN): 6,20 - 7,70 (cac H nhiin therm)

MS: 435 (M'')

23

IV I HAU LUAN KEI QUA:

4.1 Axetyl hod cdc phenol vd chuyen vi Fries cua chung:

•J* Ddi vdri cac monophcnol day benzen va quinolm chiing lAi thuc hien phan ling axetyl

ho^ nhom hidroxi bing anhidrit axetic trong su co mat cua mgl ft axil axit pholphoric l^m

xiic uic DA'i vdi c«ic phenol dihidric (hidrotiuinon \a rcs(>:\inol) hoac hidroxicumarin cluing

t6i thuc hien phan ling tuong lu nhinig thuiifng dung axit sunluric lam xiic tac

(Zac este nh$n dugc co nhiet dA nong chay phu hgp voi du kicn trong tai lieu tham khao tren phd hong ngoai cua chiing deu khong con pic dac trung cho dao dAng hoa tri cua nh6m OH phenol, trong khi do xua't hien pic dac trung cho dao dAng hoa tri cOa nhom cacbonyl este 0 khoang 1650- 1720c/?/'

• Cac ddn xuat axetyl cua phenol dugc chiing lAi dua vao phan ling chuyen vj Fries nhim tao ra cac chft't d^u ihuAc loai 1- axetyl 2- hidroxiaron Phan ung dugc thuc hien vdi lugng

AICI3 khan lam xiic tac theo ti le mol vdi este 2: I hay 3: 1 tuy theo monoeste hay dieste a

nhiet dA 160- 180"C trong dung mAi nitrobenzen hoac khAng co dung mAi

San p h ^ ciia phan iimg chuyen vi Fries deu la chat rdn va co di^m chay ro rang, cung nhu c6 gia tri R, tren s;1c ki ban mong khac vcri csle ban ddu Tren pho hong ngoai ciia chiing deu xua't hien tra lai pic dac trung cho dao dong hoa tri cua nhom hidroxi phenol trong khoang 3200- 3400c7/7'' va pic dac lrung cho nhom CO axetyl, thudng vdi sd sdng nho hon cua nhdm CO este PhA cong hudng tir proton cua cac san pham chuyin vj Fries deu xuat ihen cac tin liicu cua uhdiu C l i r C O , cua hidro trong nhdm OH va cac tut hieu khac phu hgp vdi cau triic pham tir (hinh 1) Pho khAi lucmg cua chiing deu cho pic ion phan lir phii hgp vdi phan lu khA'i (hinh 2) va cho su phan manh phii hgp vdi ca'u tao phan

lir IIH^ du: DAi vdi sin phfim chuytin vj h'ries la H- axetyl- 7- hidroxicumarin cd su phan

manh nhu sau:

CM

O ^ "^Ctb

190

24

I I

CJ

CO

l-l r-1

IV I HAU LUAN KET QUA:

4A Axetyl hod cdc phenol vd chuyen vi Fries cua chung:

• D6i vdi cac monophcnol day benzen va quinolin chiing tAi thuc hien phan umg axetyl

ho^ nhdm hidroxi bing anhidrit axetic trong su cd mat cua mAt ft axit axit pholphoric lim xiic uic DAi vdi cac phenol dihidric (hidrcKpiinon va resoxinol) hoac hidroxicumarin chiing tAi thuc hien phiui ung tucnig tu nhimg Ihmmg diing axil sunluric lam xiic uic

Cac este nhan dugc cd nhiet dA ndng chay phu hcfp vdi du kien Irong lai lieu tham khao tren pho hong ngoai cua chiing deu khong con pic dac trung cho dao dAng hod tri ciia nhdm OH phenol, trong khi dd xuat hien pic dac trung cho dao dAng hoa tri ciia nhdm cacbonyl este d khoang 1650- 1720C77/'

•> Cac dan xuat axetyl cua phenol dugc chiing toi dua vao phan dng chuyen vj Fries nhlun lao ra cac chai dau thuAc loai 1- axclyl 2- hidr<)\iarcn Phan ihig dugc thuc hien vdi lugng AlCl^ khan lam xiic lac theo ti le mol vdi este 2: 1 hay 3: 1 luy theo monoeste hay dieste d nhiet dA 160- 180"C trong dung mAi nitrobenzen hoac khAng cd dung moi

San p h ^ ciia phan img chuyen vi Fries deu la chat ran va cd di^m chay ro rang, cung nhu cd gia tri R, tren sac kf ban mdng khac vdi csle ban dau Tren pho hdng ngoai cua chiing deu xuat hien trd lai pic dac Irung cho dao dong hoa tri ciia nhdm hidroxi phenol trong khoang 3200- 34000??' va pic dac trung cho nhdm CO axetyl, thucmg vdi sd sdng nhd hon ciia nhdm CO este PhA cong hudng tir proton ciia cac san pham chuyen vi Fries deu xuat iiien cue tin iiicu cua iihum ClI^-CO cua hidro lrong nhdm OH va cac tut hieu khac phil hgp vdi cau triic pham lu (hinh 1) Pho khAi lugng ciia chiing deu cho pic ion phan lir phil hgp vdi phan tu khdi (iiinh 2) va cho su phan manh phii hgp vdi ca'u tao phan

lir, Ilii du: DA'i vdi san ph«am chuy(!n vj hrics la 8- axclyl- 7- hidroxicumarin cd su phan

manh nhu sau:

I W

24

CM

4.2 Tdng hgp cdc xeton a, fi khong no:

Cac xeton a, P- khAng no dugc lAng hgp bang phan ung ngung lu Claison- Schmidt giu'a cac metyl xeton vdi cac andehit di vdng theo ti lc mol 1:1 lrong trudng hgp ciia cac metyl xeton binh thudng va cac indol- 3- andehit phan ung dugc thuc hien Irong dung mAi clanol vdi dung djch kiem dac (NaOH 60'/r) Ifun xiic tac Cdn trong Irudng hcrp cac metyl xelon cua axit dehidroaxetic ho;]c cumarin hay vdi hgp phan andehit ciia day fufural thi phan dng dugc thuc hien bang each dun soi trong clorofom vdi pipcriddin lam xiic lac Tren phd hdng ngoai ciia cac xclon a, (i- khAng no deu cd cac pic dac trung cho dao

dAng hoa tri cua nhdm CO lien hgp trong khoang 1600- {GHOctn' va dao dAng bien dang khAng ddi xihig ciia nhdm frari.s- vinyl irong khoanu *?50- 1000(7// ^ Ngoai ra con cd cac

pic dac trung cho cac nhdm chuc khac trong phan tir

Pho tir ngoai cua cac xeton a, f>- khong no ndi chung cd 3- 4 cue dai ha'p lhu nam

va n->7r* ciia timg doan mach lien hgp va ciia mach iicn hgp keo dai loan phan lir

PhA cdng hudng lir proton da cho thay cac Im hieu ung vdi cac prolon lrong phan tir, dac biet rd net la lin hieu ciia hai proton trong nhdm vinyl d dang 2 vach ddi cd hieu ung mai nha va hang sd tuong tac spin- spin J= 15- 16Hz, ma dieu nay ndi ien nhdm vinyl cd

ca'u hinh trans- (hinh 3)

Vh6 khA'i hrgng ciia m(Vl sd xclon </ \)- khAng no cung cho pic ion phan lir triing vdi

phan tir khdi ciia chat (hinh 4J

4.3 Tdng hop cdc hop chat tuang tu flavon cd chira nhdn di vdng:

Cac hgp chat tucmg tu Haven cd chua nhan di \ong indol hoac furan dugc long hgp bang phan inig cAng hgp ddng vdng de hidro hoa bdi luu huynh Phan ling dugc thuc hien

bang Cclch dun sAi \\6\ luu suA'l 5 K gid hAn hgp ihco ti lc mol I: 1 giua xclon a, P- khAng

no vdi luu huynh trong dung mdi xilen

San pham la cac hgp chat ddang ket tinh thudng co man sSni, cd nhict do nc')ng chay rd rang va cd gia tri R, ticn sac ki han mong khac \di R, ciia xclon (x (J- khAng no khdi d^u

Ph(5 hdng ngoai \l\ tir ngoai ciia cac hop chat luong tu flavon thudng khong khac nhieu

so vcri phA ciia cac xclon a, p- khong no tuo'ng ung 7 iiy nhicn tren pho hAng ngoai cua cac hgp cha'l imnig (u llavon da lh;Vy mat di pic dac lrung cho dao ddng hoa Iri ciia nhdm OH

phenol va dao ddng bie'n dang cua nhom trans- vinyl, lrong khi do lai xuat hien cac pic dac

25

t- ]

1 / 1 r-

:

1

1

11^

lrung cho dao dAng ciia nhdm ete vdng d khoang 1130- 1160 va 1240- 1280cm"^ Cac dCJ

kien nky phii hgp vdi dU kien ve ph6 ciia cac hgp chat tircmg tu cd trong tai lieu tham khao

4.4 Tong hgp cdc hgp chai kieu pirazolin chua nhdn di vdng:

Chung ldi da tien hanh phan ii'ng ngung tu ddng vdng ciia xeton a, P- khdng no vdi phenylhidrazin de nhan dugc cac hgp cha't pirazolin cd chira di vdng indol, furan, quinolin

vk cumarin Phan dng dugc lie'n hanh bang each dun hdi luu hdn hgp cua xeton a, P- khAng

no vdi phenylhidrazin trong etanol vdi vai gigt axit axetic lam xiic tac

Cdc san phim pirazolin ddu la cac chat ran d dang tinh the, cd nhiet dA ndng chay va gia tri R, tren sdc kf ban mdng khac vdi R^ cua xeton a, P- khAng no khdi dSu

Tren ph6 hdng ngoai cua chiing da thay mat di dao ddng hoa tri cua nhdm CO lien hgp, nhung vSn cdn pic dac Irinig cho dao dAng ciia nhdm OH phenol va ciia cdc nhdm chi'rc khac

Phd lir ngoai cua cac pirazolin da khac hin ve sd lugng va vi tri cac cue dai ha'p thu,

cung nhu v6 dang phcl Sd di vay vi khi tao vdng pirazolin, mach liCn hgp toan phan lit da bj

dut gay

Vh6 khdi lugng va ph6 cdng hucmg tir proton cua mAt sd pirazolin cung cho pic ion

phan tiJr phii hgp vdi phan lu khAi va tin hieu cdc hidro phii hgp vdi su chuyen dich hoa hgc ciia cac proton lrong phan tir (hinh 5, 6)

Cdc dii" kien ve ph6 da xac dinh cau true cua cac pirazolin nhan dugc la diing

4.5 Tinh todn hod lugng tu:

v a n dung phuofng phap linh gAn diing bang phan mem HyperChem- 4.5'^" chung tdi da

xic dinh mat dd dien lich, nang lucmg lien kel va nang lugng loan phan cua cac phan tir va

tiirdd xac dinh ca'u hinh uu tien ciia cac phan lir tdng hgp dugc

Tren ca sd tfnh hoa lugng lir cho cac trang thai chuyen tie'p trong phan irng chuyen vi

Fries, san phim chuyen vj xeton (x, P- khAng no, flavon va pirazolin da nit ra nhung k^t

luftn hgp ll, lam sang rd ihem chieu hudng va ca che pijan tmg cdng nhu ciiu hinh Wn ciia cac hgp chat i6ng hgp duac

4.6 Thdm do hoat tinh sinh hoc:

Viec thir nghiem hoat tmh khang khuin va cho'ng na'm dugc thuc hien d phdng Hoa sinh benh \'ien 19/8- Bg Cong an \'a Medilalec Co l.mt theo phuorng phap dugc ghi lrong

76

' '

dugc diln Viet nam (nhd chat thir nghiem d ndng do thich hgp tren thach da nuAi ca'y vi

khu^ r6i do dudng kinh vdng vA khuan) Ke'l (|ua dugc gidi ihieu a cac phiin dudi day:

4.6.1 Hoat tinh sinh hoc cua cac xeton a, p- khong no:

Qic thi nghiem cho thay cac xeton a, P- khong no chiJa hgp phdn hidroquinon va

resoxinol deu cd kha nang khang cac loai khu^n Citrobacter fr., E coli, true khuan mil

xanh va na'm Candida allncal vdi muc dA khac nhau d ndng dA 5mglmi (bang 19)

Bane 19: Khd ndng khdng khuan vd chdng ndim cua cdc xeton a, fi khong no ddy

(Tic xeton a, p- khAng no day cumarin cung deu the hien kha nang khang cac loai true

khuin mu xanh (Pseudomonas aureus- gram am) va khang k h u ^ tu ciu vang (S epidermidis- gram duong), cung nhu chdng nam Candida albical vdi mirc do cao d ndng do

khac nhau Thir nghiem dugc dung vdi 50/// (mAt so trudng hgp sir dung vdng 2, lire la vdi 100///) vdi ndng dA xeton a, p- khAng no khac nhau trong dimetylfomamit (bang 20)

Bdng 20 Khd ndng khdng khuan vd chdng nam cda cdc xeton oc, fi khdng no ddy

16

18 15**

-s* 'llur vdng I (vdi 50///), dudng kinh \ong \ 6 kh;:aii la \5rnm\

Thir vdng 2 (vdi 100///), dudng kmh vong vo kJiufin deu la 25mm;

4.6.2 Hoat tinh sinh hgc ciia cac hgp chat (uorng tu flavon:

Sir thir nghiem hoat ti'nh sinh hgc cac hgp chat luofng tu flavon cua day axit dehidroaxetic cho thay ca 5 hgp chai ma d vj trf 2 chira vdng furan vdi nhdm the d vi trf 5

va brom (Ftj,,^?) deu cd hoat lmh khang nam Candida alhical vai muc dA cao Nhung chi cd

Irung hinh kha

28

Co 3 hgp ch^t ki^u flavon chda vdng quinolin va vdng indol d vj iri 2 (FQ,, FQ2 va FQ4)

cd kha nang khang khu^n Escherichia Coli, Pseudomonas aureus (true khudn mu xanh) va

Staphylococcus epidermidis a misc 66 cao vdi nhieu ndng do khac nhau

2,5- di hidroxiaxetophenon vdi indol- 3- andehit cd hoat tinh khang k h u ^ mil xanh dang chu

y-4.6.3 Hoat tinh sinh hgc cua cdc hgp chdt kieu pirazolin:

Chung tAi chi tie'n hanh tham dd hoat tinh sinh hgc ciia mAt day pirazolin chd'a vdng

cumarin va th^y rang 6 hgp chat cd kha nang khang khuan S epidermidis (tu ciu vang- gr duong) va Pseudomonas aureus (true khuan mil xanh- gr am), cung nhu chA'ng na'm

Candida albical vox muc dA cao va a nhieu nong do khac nhau (bang 21)

Bdne 21: Khd ndng khdng khuan vd chong nam cua cdc pirazolin ddy cumarin

Du6ng kinh vdng v6 khu^n (mm)

V KCT LUAN:

1 Da nghien ciiu phan ung chuyen vj Fries de tren ca sd dd tong hgp cac chat ddu cho

cac chuyen hoa tie'p theo

2 Bang phan ung ngung lu Claisen- Schmidt da tdng hgp dugc hon 50 hgp chai xeton a,

P - khAng no cd chda cac nhan dj vdng indol hoac furan IhuAc cac day ogienol va isoogienol, axil dehidroaxetic, ipiinolin, hidro(|uinol, resoxinol va cumarin Tir dA da chuye'n hoa cac xeton a, p - khong no thanh hon 40 hgp cha't luong tu flavon va gan

50 hgp chat kie'u pirazolin tuong litig

3 Da cung ca'p cac hang sd vat li, cac du kien phA hdng ngoai, tir ngoai, phd cAiig

hudng tiir hat nhan va pho khdi lugng ciia cac hgp chat long hgp dugc Tren co sd dd

da xac djnh dugc cau lao ciia chiing

4 Da van dung cac phuong phap ti'nh tfnh gan diing de' tfnh loan hoa lugng tir cho cac hgp chat leing hgp dugc 1 u do da lam sang ro ihem dieu kien, chieu hudng va co che

niAl sd phiui ung, tUng nhu \AC dinh c(n\ hinh hen ciia tiic san pham

5 Da Iham dd hoat Ifnh sinh hgc cua cac day chat long hgp duac va xac djnh dugc cd

35 hgp chat lhuoc cac day xelon (x, (i - khong no, flavon va pira/olin cd klui nHng

khiing khuan va chA'ng nam khac nhau, trong dd cd mgl sd cha'l ra'l dang chii f Ke't

qua nay se la lien de cho su nghien ctru sau rgng hon ve hoat tfnh sinh hgc, dac biei nghien cuu kha nang chdng ung thu va chdng HIV trong tuong lai ciia cac hgp chat

ma chiing tdi da ldng hgp dugc

VI, KlfeN N ( ; H I

Vdi kinh phi va lluri gian cd han, cluing tdi da cd gdng hoan thanh mijc lieu, nAi dung, nhiem vu cua de tai va da Ihti dugc ket qua lot Rieng phdn hoat tfnh sinh hgc mdi dirng lai d miirc tham do djnh linh klui nang khang klman va chdng naiii, Vi vay chiing tdi

mong mudn dc tai nay duac tiep tuc nghien cuu, v.v^ rong va phat tr'Cn dugc chuyen ca'p cao hon de' c6 the nghien cihi sau hon vc iiial hoai ii'iih sinh-hgc nh«im dtra den nlntng ung dung

thuc te'

30

TAI LIEU THAM KHAO

1 Phan litig mang ten

2 O.A Reutop, ^Theoretical principles of organic chemistry', MIR Moscow- 1970, pp

602- 604

3 Dang Nhu Tai, Ngo Thi Thuan, 'Tong hgp Hod hpc Him ca (bdn dich) ", Tap 1, NXB

KHKT., Ha ndi-^ 1982, trang 207- 210

4 Hoang Van Hoan, Ludn dn phd tien si Hod hpcy DHSP HNN 1991

5 Nguyen Dinh Trieu, "CAC phuang phdp phdn tich Vdt ly vd Hod lf\ Tap 1, NXB

KHKT, Ha nAi- 2001, Tr 55

6 Nguyen Hiru Dinh, Tr^n Tlij Da, *Ung dung mot sd phuang phdp phd nghiin cmi

cdu true phdn tti\ NXB *Giao diic\ Ha ngi- 1999, tr 140- 142

7 Rainer B., Hanst T., Dieter 1., Mikhael K., Ulrich S (1994), ''Unsaturated ketones'\

(BASF A_G) Ges Offen De 3 402 732; C.A., Vol 104, No 4, 34065f (1986)

8 Rao v , Vang J i a n / h o u , Xuccheng X U (1987), "'Synthesis of the new tannining

agents: 4,4- dimethyl oxazolidine and 3- hydroxy- ethyloxazolidine", pige kiji (7)

11-13(ch): C.A., Vol 109, No 13, 110300z (1988)

9 KoanoB H c , UJMaHaM r c , /iraAneHKO n.0., "AHTpaueHBbie

npoM3BOAHbie 6eH30 [ f ] xnHonnHa CMHTea M cneKpanbHO /iH)MMHecueHTHbie xapaKTepMCTMKM" x i c , NO, 1 1 , c 1 5 3 6 ( 1 9 8 5 )

1 0 K03/10B H C , r y c a k K H , jxanr Htbi Taw, "CnHTes M

cneKpanbHbie xapaKTepucrnKM aueHa({)TeHOBbix 6eH3o [ f ] XMHO/iMHa" X r C N O 8 , C 1 1 0 8 ( 1 9 8 6 )

11 Nguyen Thi Lien, *Khod luan tdt nghiep\ Trudng DHTH Ha ngi- 1974, trang 7

12 CeMeHOB A f l , KyMKOsa K n , CTbiHaran E n , '*npoM3BOAHbie MHAO/ia V CKaTM/iM/teHaueTOH B peaKunn MMxaa/iji", X r C , No