Tổng hợp một số hợp chất hữu cơ có hoạt tính sinh học

dung nghien cufu: - Muc tieu: Tie'n hanh t6ng hop, nghien cuu ca'u tao va thu hoat tinh sinh hoc ctia m6t so dan xu^t ciia axit arylacrylic.. Trong do quan tarn han ca la t6ng hgp m6t s

DAI HOC QUOC GIA HA NOI

TRlrtTNG DAI HOC KHOA HOC TITNHIEN

CHU TRI D £ TAI: Th.S THAN THI THANH VAN

CAN BO THAM GIA: Cac sinh vien phong THHC

HA NOI- 2006

l B A O C A O T O M T A T :

a Ten de tai: "Tong hop mot so hop chat huru ca c6 boat tinh sinh hoc"

Ma so: QT-05-19

b Cbu tri de tai: Th.S Trdn Thi Thanh Van

c Can bo tham gia: Cac sinh vien phong THHC 2

d Muc tieu va no! dung nghien cufu:

- Muc tieu: Tie'n hanh t6ng hop, nghien cuu ca'u tao va thu hoat tinh sinh hoc ctia m6t so

dan xu^t ciia axit arylacrylic Trong do quan tarn han ca la t6ng hgp m6t s6' hidrazit cua axit arylacrylic va chuy^n hoa thanh hidrazon chiia nhan 5-nitrofuranyl c6 hoat tinh sinh hoc cao

- Not dung: Tien hanh phan vtng t6ng hgp cac ch^t huu ca, xac dinh c^u tao san pham nha

cac phuong phap ph6 IR, UV-VIS, MS, 'H-NMR, thu hoat tinh khang khu&,khang na'm cua mOt s6' chat tdng hgp dugc

e Ket qua dat dugc:

• Da tong hgp m6t s6 metyl va etyl este cua axit arylacrylic, tir do t6ng hgp cac hidrazit

va ih cac hidrazit tong hgp cac hidrazon ciia axit arylacrylic

• C^u true cua cac hgp cha't mod nh^n dugc da dugc xac nh^n nhcy cac phuong phap phd h6ng ngoai, ph6 c6ng hucmg ttf hat nhan va ph6 kh6'i lugng

• Hoat tinh sinh hoc cua mot so san phSm dugc thir tren mOt s6 chung n&i va vi khu^n

• V6i ke't qua do da va se cong bo cac c6ng trinh sau day:

Tong hap, xac dinh cdu tao va thi hoat tinh sinh hoc cua mot so dan xud't cua axit arylacrylic, bai giri tap chi Hoa hoc va umg dung, se dang trong nam 2006

• Dua tren de tai nay da gop phin dao tao dugc:

-\- Da gop phin h6 trg 01 hoc vien cao hoc bao ve thanh c6ng luan van cao hoc:

f Tinh binh sii dung kinb phi:

Tong kinh phi dugc ca'p cho viec thuc hien d6 tai la 10 trieu d6ng chu yeu dugc

dung de mua hoa chat nghiem Mot phSn chu yeu khac dugc diing d^ thue mucm chuyen mon va lao dong

KHOA HOA HOC

Hd not, ngayi^ thdng ^ nam 2006

CHU NHllM Dfi TAI

"u-PGS TS Tran Thi Nhu Mai , ThS Tran Thj Thanh Van

S j:>t4ln i^y!n/u'

2 SUMMARY:

a Reaserching Project: "Synthesis of some organic compounds have biological

activity"

Code: QT 05-19

b Director: Tran Thi Thanh Van, M.S

c Members: Some students in Organic Synthesis Group U

d Researching Attitudes and Contents:

- Researching Attitudes: synthesis of, study on structure and test biological activity of

some derivatives of arylacrylic acid

- Researching Contents: Perfoming synthetic reactions of the organic compounds,

determining the constitutions of the products by spectroscopies as IR, UV-VIS, MS, 'H-NMR, test of some biological activity of some compounds

MS-• The bioactivity of some compounds have been tested

• One reaserching paper has been published and submitted

• The reaserching project has contributed to the graduations of one master

1 Tdng hgp cac metyl va etyl este ciia axit arylacrylic 5

2 T6ng hgp cac hidrazit cua axit arylacrylic 5

3 T6ng hgp cac hidrazon cua axit arylacrylic 8

4 Thir hoat tinh sinh hoc cua mot s6' cha't tdng hgp dugc 10

5 Thuc nghiem 11

6 Ket luan 12

A. L61 M O DAU

Nham gop phSn tim ra nhung chat c6 hoat tinh sinh hoc cao phuc vu cho muc dfch tim ra nhung loai thu6'c m6i ch6'ng lai nhung can benh the ki, chung toi da thuc hien de tai "tdng hgp m6t so hgp ch^t hOu ca c6 hoat tinh sinh hoc" vcd mong muon gop mot phin

nho cho muc dich tren Trong d6 tai chung t6i quan tam han ca den viec tdng hgp mot s6

dan xuit cia axit arylacrylic nhu cac este, hidrazit, hidrazon chiia nhan 5-nitro furanyl da dugc bie't la c6 hoat tinh sinh hoc cao

Cac cha't tdng hgp dugc da dugc xac dinh ca'u tao bang cac phuong phap vat ly hien dai va m5t s6' ch^t da dugc thu hoat tinh sinh hoc tren mot s6' chung vi khuan va na'm

B PHAN N O I D U N G CHINH

1 Tdng hgp cac metyl va etyl este cua axit arylacrylic

Metyl va etyl este cua axit arylacrylic dugc tdng hgp true tiep tir phan ung cua cac ancol va axit arylacrylic trong su c6 mat cua H2SO4 lam xuc tac De tang hieu suat phan

ung chung t6i da dung du ancol va dun nong nhe h6n hgp phan vtng Cac meiyi va etyl este thu dugc a dang tinh th^ hay dang long a dieu kien thucmg, c6 diem nong chay hoac diem

spi xac dinh.^ Ca^u true cua san phim dugc xac dinh bang cac phuang phap phd hong ngoai,

tu ngoai, phd cdng huong tu nhan proton va phd kh6'i lugng

Sa dd phan utig:

R - C H = C H - C O O H + R'-OH ^ " R - C H = C H - C O O R ' + H2O R: C^H^-, P-CH3O-C6H4-, m-N02-C6H4-, m-Cl-C6H4-

277,5 216,5

260,3 203,0 272,4 220,8 303,0

Tren phd hdng ngoai cua cac metyl va etyl este ciia axit arylacrylic cho tha'y cue dai ha'p thu cua nhom -OH axit c6 chan rong (tir 2313-2512 c m ' ) da m^t han, thay vao do

la sir xua't hien cac cue dai hap thu ciia lien ke't C-O-C este a khoang 1200-1300 cm"' (xem

hinh 1 va 2)

2 Tdng hgp cac hidrazit cua axit arylacrylic

Cac hidrazit dugc tdng hgp true tie'p tiJ phan ung cua cac etyl va metyl este cua axit acrylic vdi hidrazin hidrat trong dung m6i etanol hoac metanol Cac phan ung thuc hien tuang dO'i de nhung then gian phan utig thuang keo dai (khoang 12 gid) Cac san pham thu

dugc a dang long hoac tinh the c6 nhiet d6 s6i hoac nhiet do nong chay xac dinh Ca'u triic

ciia cac san ph^m dugc xac dinh bang phuang phap phd hdng ngoai, tu ngoai va phd cong

huong tijf hat nhan proton Ke't qua tdng hgp cac hidrazit dugc cho a bang 2

San ph^m hidrazit tao thanh c6 phd hdng ngoai khac vdi cac este ban dau Tren phd

hdng ngoai xua't hien cac cue dai ha'p thu cua lien ket NH a vung tir 3230-3416 cm"', cue

dai h^p thu cua lien ket C=0 a 1664-1716 cm', nhung cac cue dai hap thu thuang tu,

khOng sac net do c6 hien tugng tao lien ke't hidro giua nhom C=0 cacbonyl va NH2

Bang 2: Ket qua tong hap vd xac dinh cdu tao cac hidrazit R-CH=CH-C0-NH-NH2

nm)

275,4 216,4 309,8

210,8 260,8 206,4 269.2 214,0

1#

Hinh 1: Pho hong ngoai cua este metyl m-cloxinamat

Tren phd c5ng huong tir hat nhan proton, ngoai cac tin hieu cua cac proton trong nhan thom thi tin hieu cua proton trong nhom -CH=CH- cung xua't hien rat ro net va dac

biet la cac pic c6 cucmg do ye'u 6 do chuyen dich hoa hoc 8,0 va 2,lppm dac trung cho proton cua nhom -NH-NH- (xem bang 5)

Dai hoc Ouoc gia

3 Tong hgp cac hidrazon cua axit arylacrylic

Thuc hien phan iJng ngung tu cac hidrazit vcd furan-2 andehit the thu dugc cac hidrazon khac nhau Tren phd hong ngoai cua hidrazon khOng tha'y xua't hien dao dong hoa tri ciia lien ke't N-H cua nhom NH2 trong khoang 3416-3230 c m ' ma thay vao do la lien ke't C-H cua vong furan 6 khoang 3199-3016 c m ' va C-O-C a 1348-1184 cm' va dac biet d viing 1684-1600 cm"' xua't hien them nhieu dinh dan xen nhau, dieu do cho tha'y lien ke't C=N da dugc hinh thanh (xem bang 3)

Bang 3: Ket qua tong hgp vd xac dinh cdu tao cac hidrazon

326.6 277,0 221,8 376,6 281,0 214,8 324,0 228,0 204,0 380,8 323,4 316,8 260,4

Phd kh6'i lugng cua cac hidrazon cho cac ion phan tu dung vcd du kien Lien ket 0=C-NH- ciia cac hidrazon kh6ng ben, de bi cat dut va nhung hidrazon chiia Cio trong nguyen tir c6 xua't hien ion dong vi (xem so do phan manh)

CI ^O^CH=

o

II

CH-C-NH-N=CH M"" 319/321

O'

NO-NH-N=CH m/e 139 O

So d6 phan manh ciia 5-nitro fufuryUden p-clo xinamoyl hidrazon

Bang 4 Phdkhdi luang cua mot so chat tdng hgp duac

204(5), 161(100), 133(45), 118(15), 107(30), 94(25), 77(30), 67(40) 319/321(50), 304(23), 273(35), 257(5), 165/167(60), 139(100), 125/127(65), 103(70), 77(30)

285(15), 239(5), 131(100), 103(45), 77(30)

Bang 5: Phd cong huong tit hat nhan proton cua mot so chat tdng hgp duac

2H, -CH2)

6,8(d, J=15,5Hz, IH, H'); 7,81(d, J=4Hz,

IH, H'); 7,5(d, J=2Hz, IH, tf); 7,55(d, J=15,5Hz, IH, H'); 8,0(q,J-l,0Hz, IH, H');

6,0(d, J=:2,0Hz, 2H, H')

4 Thiif boat tinh sinh hoc cua mot so chat tdng hgp dugc

Tien hanh thir hoat tinh khang khudn, khang n^m cua m5t s6' este, hidrazit va hidrazon Ke't qua cho tha'y miu T2, T4, T7, T8 c6 tac dung doi vci chung S.A, S.B, P.A Cac mau Tl den T5 deu c6 tac dung vci na'm men Dac biet miu T4 c6 tac dung vci ca 4 chung tren Ke't qua thu hoat tinh sinh hoc th^ hien a bang 6

Chung S.A: Staphylococus Aureus (Tu cSu vang thu6c c^u khuan gam (+))

Chung P.A: Pseudomonas Aeraginosa (Mii xanh thuCc true khudn gam (-))

Chung B.A: Bacillus Subtilis (ThuOc gam (+))

Na'm men: Candida albicans

10

Bang 6: Ket qua thu hoat tinh sinh hoc cua mot so dan xudt cua axit arylacrylic

Co tac dune

Co tac dune

Co tac dung

Co tac dung

Co tac dung

Khong tac dung

5 Thuc nghiem

Diem chay cua cac san phSm duoc do bang phuang phap mao quan

Phd hdng ngoai dugc do tren may AVATAR 760-FnR cua hang NICOLET

Phd tu ngoai do tren may UVCP39 hang SHIMAZU

Phd kh6'i lugng dugc do tren may HP.4989B

Phd c6ng huong tir hat nhan dugc do tren may 500MHz

Hoat tinh sinh hoc dugc thu tai Khoa Hoa Sinh Vien 19-8 B6 Cong an

• Cac metyl va etyl este cua axit arylacrylic dugc tdng hgp true tiep tir axit tuang utig va metanol, etanol Dun hoi luu each thuy hdn hiap axit arylacryhc, rugu va axit sunfuric trong 5 gia Thay sinh han de ca't loai bdt rugu du, d^ nguOi roi chiet la'y lap dlu, trung hoa Icfp d^u bang Na2C03, lam lanh bang da mu<5i Thu san pham va ket tinh lai trong etanohnudc

• Cac hidrazit cua axit arylacrylic dugc tdng hgp true tie'p tu cac este va hidrazinhidrat ViTa khua^y va dun each thuy hCn hgp phan tog trong 12 gicf ca't loai bcft etanol sau do dd true tiep hdn hop vao cdc nude da, lam lanh ve 0-5*'C Ket tinh lai trong etanol

• Cac hidrazon dugc tdng hgp bang each dun h6i luu each thuy trong khoang 6 giof hdn hgp hidrazit va fufurol trong dung moi etanol Ca't loai het etanol sau

do lam lanh hdn hgp den 0-5^C Ket tinh lai san ph&n trong etanol

11

6 Ket luan

1 Da tdng hgp dugc 6 este, 5 hidrazit va 5 hidrazon ciia axit acrylic the San pham dugc kidm tra do tinh khie't bang sac ki ban mong, tach tinh khiet bang sdc ki cot tren he dung moi thich hgp

2 Xac dinh c^u tao ciia cac san pham ran bang phuang phap phd hong ngoai, tir ngoai, phd cong huong tir hat nhan proton va phd khoi lugng

3 Mot s6 cha't duoc thu hoat tinh sinh hoc tren mot so chung vi khu^n va na'm

C.TAI LIEU THAM KHAO

1 American Medical Association (1994), 'Drug Eva/uarian "chapter 73

2 Dimmock J.R., Taylor U.G (1984), ''Synthesis and physical propeties of substituted 4-dimethylaminomethyl-l-phenyl-l-nonen-3- ones possecing antitumor propeties'\ J Pharm.Sci, Vol 63, N°l

3 Stephen Gillespie (2004), ''Medical Microbiology illustrated", Butterworth

Heinemnn

4 Kirrk Othmer (1994), "Encyclopedia of Chemical technology", John Wiley

and sons, NewYork, Vol.13, 3^^ ed

12

TOM T A T CAC CONG TRINH NCKH CUA CA NHAN Nganh: Hoa hoc Chuyen nganh: Hoa Huu ca

1 Nguyen Dinh Trieu, Phan Dinh Long, Trfo Thi Thanh Van, Doan Manh Chat, Tran

Thi Phuong Thao

Tdng hgp, xac dinh ca'u tao va thir hoat tinh sinh hoc cua mot so dan xua't

5-aryl-2-mecapto-1,3,4-oxadiazol

Bao cao 6 Hoi nghi khoa hoc Trucmg Dai hoc Khoa hoc Tu nhien, tr 129-133

2 Nguyen Dinh Trieu, Doan buy Tien, Trkn Thi Thanh Van

Phd hdng ngoai ciia mot so fomazan chu:a di vong quinolin

Bao cao 6 Hoi nghi khoa hoc Truong Dai hoc Khoa hoc Tu nhien, tr 134-137

3 Trdn Thi Thanh Van, Vu Van Ha, Nguyen Dinh Trieu

Tdng hgp, nghien curu ca'u tao va su tao phiic cua mot so dan xuat fomazan c6 kha

nang tan trong nu6c

Bao cao 6 H6i nghi Hoa hoc toan quo'c nam 2003

4 Trfo Thi Thanh Van, Dang Ba Dung, Dang Tni Tuyet Anh, Nguyen Dinh Trieu

Nghien curu tdng hgp m6t so fomazan chtia di vong pirol, tdng hop phuc ciia

fomazan chiia di vong pirol va 4,5-dimetylthiazolyl fomazan vdi mot so ion kim loai

chuyen tie'p

5 Nguyen Dinh Trieu, TrSn Thi Thanh Van ^ Tinh hang s6 b6n ciia phiic fomazan chura di vong vdi m6t so ion kim loai chuyen

tiep

Tap chi Phan tich Ly Hoa Sinh, so 2, tap 10, tr 31-36, 2005

6 Trdn Thi Thanh Van, Nguyen Dinh Trieu

Tdng hgp va nghien cuu ca'u tao mot so hgp cha't fomazan chiia di vong furan,

thiophen va pirol

Tap chi Hoa hoc, so 3, tap 43, tr 302-306, 2005

7 Nguyen Dinh Trieu, Trdn Thi Thanh Van, Dang Ba Dung, Dang Thi Tuyet Anh

Nghien ciJu tdng hgp mot so difomazan chua di vong

Tuyen tap cac cong trinh hoi nghi khoa hoc va cong nghe hoa huu co, tr 177-180,

2005

8 Trdn Thi Thanh Van, Nguyen Hai Doan, Nguyen Dinh Tneu

Tdng hgp, xac dinh ca'u tao va thir hoat tinh sinh hoc cua mot so dan xu£t ciia axit

arylacrylic,

Bai giri tap chi Hoa hoc va ling dung, se dang trong nam 2006

13

3 Managing Institution: Hanoi University of Science

4 Implementing Institution: Faculty of Chemistry

5 Key implementors: - Tran Thi Thanh Van, M.A - Director

6 Duration: 12 months since January, 2005

1 Budget: 10 millions VND

8 Main results:

- Results in science and technology

- Results in practical apphcation

- Results in training

- Publications

Result in science and practical application:

Several of methyl, ethyl este hidrazides and hidrazones of arylacrylic acid have been synthesized

The constitutions of the products have been determined by using 1R-, UV-VIS, MS- and ^H-NMR- spectroscopies

The bioactivity of some compounds have been tested

Result in training: The reaserching project has contributed to the graduations of a

master

Publication: One reaserching paper have been reported

Tran Thi Thanh Van, Nguyen Hai Doan, Nguyen Dinh Trieu, Synthesise, establish structure and bioactivity of some derivatives of arylaerylie acid, Journal of Chemistry

and using (submitted)

9 Evaluation grade

14

PHIEU DANG KY KET QUA NGHIEN ClJtJ KH-CN

Ten de tai (hoac du an): "Tdng hgp mot so phufc hgp chat huru ca c6 hoat tinh sinh hoc"

Ma so: QT- 05-19

Co quan chu tri de tai (hoac du an): Khoa Hda-Trudng DHKHTN

Dja chi: 19 Le Thanh Tong Ha noi

Tel: 04 8 533 503

Co quan quan ly de tai (hoac du an): Trudng Dai hoc Khoa hoc Tu nhien

Dia chi: 334 Nguyen Trai- Thanh Xuan-Ha noi

Tel:

Tdng kinh phi thuc chi: 10 000 000 dong (Mudi trieu dong)

Trong do: - Tuf ngan sach Nha nude: 0

- Kinh phi cua trudng: 10 000 000 dong

- Vay tin dung: 0

- Von tuco: 0

- Thu hoi: 0 Thoi gian nghien cufu: 12 thang

Thdi gian bat dau: 1/2005

Then gian ket thuc: 12/2005

Ten cac can bo phdi hgp nghien cum:

Cac sinh vien phong THHC 2

a Phd bien rong rai: 0

b Phd bien han che: D

c Bao mat: D

Tom tat ket qua nghien curu:

• Da nghien cuu phan vcng tdng hgp mot so metyl, etyl este, hidrazit, hidrazon ciia

axit arylacrylic

• ca'u true cua cac hgp chat mdi nhan dugc da dugc xac nhan nhd cac phuong phap phd hong ngoai, phd cong huong tu hat nhan va phd khoi lugng

• Mot so cha't tdng hgp dugc da dugc thir hoat ti'nh khang khuan, khang nam

Kien nghi v^qliT^^i^T^ ddi tugng ap dung nghien cuu;

Chu nhieni de tai Thu truong caquan

Vt(^'^

16

Hi) Noi ngay 07 thdng 03 lulm 200()

GIAY CHONG NHAN

T a p chi H o a hoc va U"ng d u n g chilng n h a n bai bao: "TONC

HOP, XAC DINH CAU TAO VA THL HOAT TINH SINH HOC CUA MOT

SO DAN XUAT CUA AXIT ARYLACRYUIC" ciia tac gia Trdn Thi

Thanh Van, Nguyin Hai Doan v a Nguyin Dinh Trieu Toa