Nghiên cứu tổng hợp và thử tác dụng sinh học một số dẫn chất acid 3-(benzimidazol-2-yl) propanoic.pdf

B Y T

TRNG I HC DC H NI

ON NGUYN THNH T

NGHIN CU TNG HP V

TH TC DNG SINH HC MT S

DN CHT CA ACID

3-(BENZIMIDAZOL-2-YL)PROPANOIC

KHA LUN TT NGHIP DC S

H NI-2013

B Y T

TRNG I HC DC H NI

ON NGUYN THNH T

NGHIN CU TNG HP V

TH TC DNG SINH HC MT S

DN CHT CA ACID

3-(BENZIMIDAZOL-2-YL)PROPANOIC

KHA LUN TT NGHIP DC S

Ngi hng dn:

PGS. TS. u n n u n

DS. u n T T an Phc

Ni thc hin:

B mn Cn n i p Dc

Trn i c Dc H i

H NI-2013

LI CM N

Trc ht ti xin by t lng knh trng v bit n su sc n thy PGS. TS.

u n n u n, ngi trc tip hng dn, cho ti nhng li khuyn qu

bu, to mi iu kin gip ti trong qu trnh nghin cu v hon thnh kha

lun tt nghip ny.

Ti xin chn thnh cm n cc thy c trong B mn Cng Nghip Dc,

c bit l DS. Nguyn Vn Giang, DS. Phm Th Hin, DS. Nguyn Th Thanh

Phc v CN. Phan Tin Thnh ca T mn Tng hp Ha dc nhit tnh gip

v to iu kin tt nht ti hon thnh kha lun tt nghip ny.

Trong qu trnh thc hin kha lun ti nhn c s gip ca cc

thy c trng i hc Dc H Ni, cn b Phng Phn tch ph- Vin Ha hc-

Vin Hn lm Khoa hc v Cng ngh Vit Nam, Phng Phn tch hu c- Vin

Hp cht thin nhin- Vin Hn lm Khoa hc v Cng ngh Vit Nam cng th

vin Trng i hc Dc H Ni, ti xin chn thnh cm n.

Cui cng, ti xin gi li cm n n b m v bn b, nhng ngi lun

ng vin, khch l ti trong cuc sng v hc tp.

H Ni, Ngy 21 thng 5 nm 2013.

Sinh vin

on Nguyn Thnh t

MC LC

Trang

Danh mc cc k hiu, cc ch vit tt

Danh mc cc bng

Danh mc cc hnh v, th

T VN ... 1

CHNG 1. TNG QUAN................................................................................... 2

1.1. Khi qut chung v benzimidazol v dn cht. 2

1.2. Tng quan v tc dng sinh hc ca benzimidazol....................................... 3

1.2.1. Tc dng khng nm, khng khun............................................................. 3

1.2.2. Tc dng sinh hc khc.. 9

1.3. Xc nh hng ti nghin cu. 14

CHNG 2. NGUYN LIU, THIT B, NI DUNG V PHNG PHP

NGHIN CU. 15

2.1. Nguyn liu v thit b.. 15

2.1.1. Nguyn liu, dung mi, ha cht.. 15

2.1.2. Thit b, dng c . 16

2.2. Ni dung nghin cu. 17

2.3. Phng php nghin cu............................................................................. 18

CHNG 3. KT QU NGHIN CU.. 20

3.1. Tng hp ha hc. 20

3.1.1. Tng hp acid 3-(benzimidazol-2-yl)propanoic (1).................................... 21

3.1.2. Tng hp ethyl 3-(benzimidazol-2-yl)propanoat (2a). 22

3.1.3. Tng hp methyl 3-(benzimidazol-2-yl)propanoat (2b).. 22

3.1.4. Tng hp 3-(benzimidazol-2-yl)propanhydrazid (3a-1). 23

3.1.5. Tng hp ethyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-yl)propanoat

(3a-2) 24

3.1.6. Tng hp ethyl 3-(1-benzyl-benzimidazol-2-yl)propanoat (3a-3). 25

3.1.7. Tng hp methyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-yl)propanoat

(3b-1)

26

3.2. Kim tra tinh khit ca cc dn cht tng hp c... 27

3.3. Xc nh cu trc ca cc cht tng hp c . 29

3.3.1. Kt qu phn tch ph cc cht trung gian (1, 2a, 2b)............................... 29

3.3.2. Kt qu phn tch ph cc cht sn phm (3a-1, 3a-2, 3a-3, 3b-1). 32

3.4. Th tc dng sinh hc. 35

3.4.1. Th hot tnh khng khun. 35

3.4.2. Th hot tnh khng nm. 38

CHNG 4. BN LUN... 41

4.1. V tng hp ha hc. 41

4.2. V tc dng sinh hc 43

KT LUN V KIN NGH 44

TI LIU THAM KHO

PH LC

DANH MC CC K HIU, CC CH VIT TT

1H-NMR Ph cng hng t ht nhn proton (1H nuclear magnetic

resonance)

AcOH Acid acetic

BuOH n-Butanol

CTCT Cng thc cu to

DMF N,N-dimethylformamid

EC50 Nng tc dng 50% (half maximal effective concentration)

ECA Ethylcloroacetat

EtOH Ethanol

g Gam

h Gi

HEPG2 Dng t bo ung th gan ngi (human hepatocellular liver

carcinoma cell line)

IC50 Nng c ch 50% i tng th (half maximal inhibitory

concentration)

IR Ph hng ngoi (infrared)

MeOH Methanol

MIC Nng c ch ti thiu (minimum inhibitory concentration)

MS Ph khi (mass spectroscopy)

MT Mi trng

PC12 Dng t bo pheochromocytoma thng thn chut (rat adrenal

pheochromocytoma cell line)

Rf H s lu gi (retension of factor)

t0

nc Nhit nng chy

TLC Sc k lp mng (thin layer chromatography)

VSV Vi sinh vt

Dao ng ha tr

DANH MC CC BNG

Trang

Bng 1.1 MIC (g/ml) ca cc cht trong nghin cu ca T. Z. Taher 6

Bng 1.2 Cc dn cht 1H-benzimidazolcarboxamidin 8

Bng 1.3 IC50 (mM) ca cc hp cht trn dng t bo HEPG2 v PC12 10

Bng 1.4 Hot ng chng ng kinh trn chut DBA/2 13

Bng 2.1 Danh mc nguyn liu, dung mi v ha cht 15

Bng 2.2 Danh mc thit b, my mc 16

Bng 2.3 Cng thc ca cc cht tng hp c 17

Bng 3.1 Kt qu tng hp ha hc 27

Bng 3.2 TLC ca cc cht trung gian 1, 2a, 2b 28

Bng 3.3 TLC ca cc cht sn phm 3a-1, 3a-2, 3a-3, 3b-1 28

Bng 3.4 Rf v t0nc ca 7 cht tng hp c 29

Bng 3.5 Kt qu phn tch ph hng ngoi ca 1, 2a, 2b 30

Bng 3.6 Kt qu phn tch ph khi lng ca 1, 2a, 2b 30

Bng 3.7 Kt qu phn tch ph cng hng t ht nhn 1H ca 1, 2a, 2b 31

Bng 3.8 Kt qu phn tch ph hng ngoi ca 3a-1, 3a-2, 3a-3, 3b-1 32

Bng 3.9 Kt qu phn tch ph khi lng ca 3a-1, 3a-2, 3a-3, 3b-1 32

Bng 3.10 Kt qu phn tch ph cng hng t ht nhn ca 3a-1, 3a-2,

3a-3, 3b-1

33

Bng 3.11 Kt qu th tc dng khng khun 38

Bng 3.12 Kt qu th tc dng khng nm 40

DANH MC CC HNH V

Trang

Hnh 1.1 5,6-dimethyl-1-( -D-ribofiranosyl)benzimidazol 2

Hnh 1.2 Cu trc vng benzimidazol 2

Hnh 1.3 Hin tng h bin benzimidazol 3

Hnh 1.4 Mt s dn cht benzimidazol c s dung trong iu tr 3

Hnh 1.5 Cc cht benzimidazol-hydrazid c tng hp 4

Hnh 1.6 Cng thc cu to ca N1-alkyl-2-aryl-5(6)-R-1H-benzimidazol

trong nghin cu ca Hakan Goeker

5

Hnh 1.7 Cng thc cu to cc cht trong nghin cu ca T. Z. Taher 6

Hnh 1.8 Dn cht 3-(2-methylbenzimidazol-1-yl)propanhydrazid 7

Hnh 1.9 Cc dn cht trong nghin cu ca Z. M. Nofal 10

Hnh 1.10 Dn cht 2-methylaminobenzimidazol tng hp bi K. Achar 12

Hnh 1.11 1H-pyrrolo[1,2-a]benzimidazol-1-on tng hp bi A. Chimirri 13

DANH MC CC S

Trang

S 3.1 Quy trnh tng hp chung 20

S 3.2 Tng hp acid 3-(benzimidazol-2-yl)propanoic (1) t o-

phenylendiamin

21

S 3.3 Tng hp ester ethyl 3-(benzimidazol-2-yl)propanoat (2a) 22

S 3.4 Tng hp ester methyl 3-(benzimidazol-2-yl)propanoat (2b) 22

S 3.5 Tng hp 3-(benzimidazol-2-yl)propanhydrazid (3a-1) 23

S 3.6 Tng hp ethyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-

yl)propanoat (3a-2)

24

S 3.7 Tng hp ethyl 3-(1-benzyl-benzimidazol-2-yl)propanoat (3a-3) 25

S 3.8 Tng hp methyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-

yl)propanoat (3b-1)

26

S 4.1 Phn ng ng vng benzimidazol 41

S 4.2 Phn ng trng hp 41

S 4.3 Phn ng ester ha xc tc H+ 42

S 4.4 Phn ng tng hp ester xc tc SOCl2 42

S 4.5 Phn ng alkyl ha 42

S 4.6 Phn ng to amoni bc 4 43

1

T VN

Sc khe lun l mt trong nhng vn c ch trng nht trong mi

quc gia. Vic s dng trc tip cc sn phm t nhin cha tr c t lu v

t c nhiu thnh tu, nhng con ng tm kim thuc mi bng phng php

tng hp lun l cn thit khi m m hnh bnh tt ngy cng phc tp. Vic nghin

cu tm ra thuc mi l kt qu kt hp ca nhiu ngnh khoa hc nh bo ch, ha

dc, vi sinh, dc lm sng, trong tng hp ha dc ng vai tr rt quan

trng. Ngy nay, cc thuc c ngun gc tng hp ha hc ngy cng gi v tr

quan trng trong cng tc chm sc sc khe.

Xu hng nghin cu v pht trin thuc mi thng da vo cu trc ca

cc cht ang c dng lm thuc hoc c trin vng sinh hc tm ra cc hot

cht c th ng dng trong iu tr lm sng.

Nhiu cng trnh nghin cu cho thy dn cht benzimidazol l nhm hp

cht d vng c tc dng sinh hc rt a dng nh: khng khun, khng nm, chng

ung th, chng co git, gim au, chng vim, h huyt p.

gp phn lm phong ph thm cc nghin cu v tng hp v tc dng

sinh hc ca dn cht benzimidazol, chng ti tin hnh thc hin ti: Nghin

cu tng hp v th tc dng sinh hc mt s dn cht ca acid 3-

(benzimidazol-2-yl)propanoic vi cc mc tiu sau:

1. Tng hp v mt s dn cht ester 3-(benzimidazol-2-yl)propanoat vi cc

nhm th khc nhau v tr N1 v tng hp hydrazid

2. Th hot tnh khng khun, khng nm ca hydrazid v mt s dn cht ester

3-(benzimidazol-2-yl)propanoat tng hp c.

2

CHNG 1.

TNG QUAN

1.1. Khi qut chung v benzimidazol v dn cht

Nm 1944, Wooley suy on rng benzimidazol c th hot ng

tng t nh purin th hin tc dng sinh hc [24]. Nm nm sau, Brink

xc nh 5,6-dimethylbenzimidazol l sn phm phn hy ca vitamin B12 v

sau tm thy mt s cc dn xut ca n c hot ng nh vitamin B12 [7].

Hnh 1.1. 5,6-dimethyl-1-( -D-ribofiranosyl)benzimidazol

Cu trc benzimidazol l mt h vng bicyclic m benzen kt hp vi

v tr 4- v 5- ca imidazol. Cc hp cht benzimidazol ni chung, v

benzimidazol carbamat ni ring l nhng cht rn kt tinh vi im nng

chy kh cao v tng i kh tan trong nc [23].

Hnh 1.2. Cu trc vng benzimidazol

Bezimidazol c cha mt nguyn t hydro c gn vi nit 1 v tr

d dng h bin:

3

Hnh 1.3. Hin tng h bin benzimidazol

Hin tng ny cng c tm thy tng t trong imidazol v amidin

[15,25].

1.2. Cc nghin cu v tc dng sinh hc ca benzimidazol

Hnh 1.4. Mt s dn cht benzimidazol c s dng trong iu tr

1.2.1. Tc dng khng nm, khng khun

Nm 2011, Yusuf Ozkay cng cng s tng hp c mt s

benzimidazol-hydrazon (1a 1n); cc dn cht ny th hin tnh khng khun

yu nhng hot tnh khng chng Candida rt ng ch nng khng

c hi [20].

4

Hnh 1.5. Cc cht benzimidazol-hydrazid c tng hp

Cc cht tng hp 1a 1n c th tc dng c ch in vitro vi sinh vt

theo k thut pha long lin tip. Tc dng khng khun c th vi dng vi

khun Gram(+) l: Staphylococcus aureus ATCC (American Type Culture

Collection) 25923, Enterococcus faecalis ATCC 29212, Bacillus subtilis v

Listeria monocytogenes, ng thi th vi vi khun Gram(-) l: Klebsiella

pneumoniae ATCC 13883, Escherichia coli ATCC 35218, E. coli ATCC

25922, Salmonella thyphimurium NRRL (Agricultural Research Service

Culture Collection) B-4420; Proteus vulgaris NRRL B-123 v nm men:

Candida albicans, Candida tropicalis v Candida glabrata ATCC 3658.

Cloramphenicol v ketoconazol c s dng lm thuc i chiu.

Hu ht cc dn cht trn khng c hot tnh chng li cc chng vi

khun, tuy nhin chng vn c hot tnh trung bnh vi E. coli khi so snh vi

cloramphenicol. Tri li vi hot tnh khng khun yu, cc hp cht 1a, 1k,

1l, 1m, 1n c ch mnh vi C. albicans, C. glabrata v C. tropicalis trong

khong MIC= 12,5 400 g/ml. Cht 1k v 1m cho thy hiu lc gp 2 ln

(MIC= 25 g/ml) so vi ketoconazol (MIC= 50 g/ml) i vi tt c cc

chng nm. Bn cnh , hot tnh khng nm vi C. tropicalis ca 1a, 1l, 1n

cng kh cao so vi cc ti liu khc. Cc hp cht khc 1b 1j th hin hot

5

tnh khng nm ngang bng vi ketoconazol. Nghin cu v lin quan cu

trc n tc dng sinh hc (SAR- structure activity relationship) cho thy mt

in t trn vng benzen l yu t quan trng lin quan n tc dng

khng nm ti u. Cc hp cht 1k 1n vi nhm th ht in t (nitro,

triflomethyl, cyano v carboxyl) cho thy tc dng hot tnh khng nm tt

nht [20].

Nm 2009, Hakan Goeker cng cng s tng hp v th cc hot

tnh khng nm Candida in vitro ca mt s N1-alkyl-2-aryl-5(6)-R-1H-

benzimidazol, theo phng php pha long ng. Cc hp cht c th

nghim in vitro cho hot tnh khng nm: C. albicans (ATCC 10231), C.

krusei (ATCC 6258), C. parapsilosis (ATCC 22019), v C. glabrata vi cc

MIC l: 3,12 g/ml; 6,25 g/ml; 12,5 g/ml v 50 g/ml.

R1=-butyl,-propyl,-pentyl

R2=-Cl,-CN,-Br,-F

R3=-Cl,-CN,-F,-Cl,-Br,-NC

R4=-CF3,-F,-Cl,-Br,-I,-CCH,-NO2,-NH2,-

CHO, MeO-N=CH-, CH3CO-, NH2C(N-

OH)CH2-

R5=-Cl,-CN

R5=-F,-OH X,Y,Z= CH, N

Hnh 1.6. Cng thc cu to ca N1-alkyl-2-aryl-5(6)-R-1H-benzimidazol trong

nghin cu ca Hakan Goeker

Kt qu th tc dng sinh hc cho thy cc benzimidazol ny u c

hot tnh tt trn mt s loi Candida. Trong 1-butyl-2-(pyridin-3-yl)-

benzimidazol-5-carbonitril v 1-butyl-2-(pyridin-4-yl)-benzimidazol-5-

carbonitril th hin tc dng ln nht vi gi tr MIC l 6,25 3,125 g/ml

[11].

Nm 2012, T. A. Taher cng cng s tng hp v nh gi kh nng

khng khun, khng nm ca mt s benimidazol-2-yl. Tt c cc cht u

6

c th tc dng in vitro trn cc vi khun Gram(-): Pseudomonas

aeruginosa, Escherichia coli, Salmonella typhi; vi khun Gram(+):

Staphylococcus aureus v nm Candida albicans bng phng php thch

pha long (tobramycin v voriconazol c s dng l thuc i chiu). nh

gi cc hp cht th nghim cho kt qu kh quan, c bit vi vi khun

Gram(-) v Candida albicans vi MIC rt thp (< 0,016 g/ml). Ngc li, vi

khun Gram(+) (Staphylococcus aureus) li c kh nng khng tt c cc cht

th nghim vi MIC > 256 g/ml [22].

Hnh 1.7. Cng thc cu to cc cht trong nghin cu ca T. Z. Taher

Bng 1.1. MIC (g/ml) ca cc cht trong nghin cu ca T. Z. Taher

Hp cht Pseud E.c. Sal. St. Ca.

3a < 0,016 < 0,016 < 0,016 >256 < 0,016

3b < 0,016 < 0,016 < 0,016 >256 < 0,016

3c < 0,016 < 0,016 < 0,016 >256 < 0,016

3d < 0,016 < 0,016 < 0,016 >256 < 0,016

4a < 0,016 < 0,016 < 0,016 >256 < 0,016

7

4b < 0,016 < 0,016 < 0,016 >256 < 0,016

5a < 0,016 < 0,016 < 0,016 >256 < 0,016

5b < 0,016 < 0,016 < 0,016 >256 < 0,016

Tobramycin 1 1,29 - 1 -

Voriconazol - - - - 0,12

Pseud: Pseudomonas aeruginosa, E.c.: Escherichia coli, Sal.: Salmonella typhi,

St.: Staphylococcus aureus, Ca.: Candida albicans.

Nghin cu ca Afaf H. El-masry cng cng s trong vic tng hp v

nh gi tc dng ca cc dn cht 3-(2-methylbenzimidazol-1-

yl)propanhydrazid (nm 2000) trn chng vi khun Gram(+) (Bacillus

cereus), Gram(-) (Escherichia coli), nm men (Saccharomyces cerevisae) v

nm mc (Aspergillus niger), thc hin theo phng php khuch tn a

(gentamycin, ampicillin c dng l cht i chiu) [10].

Hnh 1.8. Dn cht 3-(2-methylbenzimidazol-1-yl)propanhydrazid

Kt qu cho thy 6a l cht c hot ng rt mnh chng li vi khun

Bacillus cereus, nhng c tc dng yu trn Escherichia coli. Cc hp cht

6c, 6d hot ng tt chng li Bacillus cereus, trong khi hp cht 6b, 6g ch

c tc dng yu trn Bacillus cereus. Nhng tt c hp cht c th

nghim cho thy khng c tc dng chng li Saccharomyces cerevisae v

Aspergillus niger [10].

8

Nm 2012, nhn thy t l khng thuc ca cc cu khun Gram(+)

bao gm c Staphylococcus aureus khng methicillin (MRSA), t cu

Coagulas khng methicillin (MR-CNS), Pneumoniea khng penicillin, v

Enterococcus khng vancomycin (VRE) tip tc tng [21], trong ng ch

l S. aureus khi nhiu trng hp chng ny khng li methicillin [12],

Hacer Karatas cng cng s tng hp 1 dy cc cht 1H-

benzimidazolcarboxamidin v nh gi tc dng khng khun, khng nm in

vitro trn Staphylococcus aureus ATTC 25923, Candida albicans ATTC

10231, Candida krusei ATCC 6258, MRSA ATTC 43300 (Staphylococcus

aureus khng methicillin) theo phng php pha long.

Bng 1.2. Cc dn cht 1H-benzimidazolcarboxamidin

CTCT Cht R R

7a H

7b H

7c H

7d n-butyl

7e n-butyl

7f n-butyl

7g p-Cl-benzyl

7h p-Cl-benzyl

9

8a 1-naphtyl NHEt

8b Phenyl NHEt

8c p-Cl-phenyl NHEt

8d p-Cl-phenyl NH-isopropyl

8e p-Cl-phenyl NH(Me)2

9a Cl H

9b Cl Cl

Kt qu th nghim cho thy 8a, 8c, 8d, 8e, 9a, 9b c hot tnh khng

khun tt: chng MRSA (MIC < l g/ml), hp cht 9a, 9b c hot tnh va

phi chng li nm Candida. Cc cht cn li 7a 7h, 8b cho thy tc dng

yu hoc khng c tc dng khng nm, khng khun.

Th nghim cn cho thy nhm amidin thm (trong 9a, 9b) ca 1H-

benizimidazol ng vai tr quan trng trong hot ng trong hot ng khng

khun [16].

1.2.2. Tc dng khc ca benzimidazol

Nm 2011, Z. M. Nofal cng cng s tng hp c 1 dy cc dn

cht ca 1-(1H-benzimidazol-2-yl)-3-R-2-propen-1-on v th hot tnh chng

ung th trn HEPG2 (dng t bo ung th biu m gan), PC12 (t bo ty

thng thn chut). Di y l mt s dn cht thuc nhm ny:

10

Hnh 1.9. Cc dn cht trong nghin cu ca Z. M. Nofal

Kt qu nghin cu tc dng in vitro ca cc hp cht 10 15 c ch s

pht trin ca 2 dng t bo ung th ngi c trnh by bng 1.3. Nghin

cu cho thy, cht 11 c trin vng tc dng cao i vi c PC12 (IC50= 2,4

mM) v HEPG2 (IC50= 0,268 mM), trong khi cht 10a, 10b, 14, 15a, 15b

ch hot ng duy nht trn t bo PC12 v c hot tnh in vitro yu chng li

HEPG2 nng thp. Nghin cu cng ch ra ,-ceton khng no 10a l

yu t tch cc nht chng li dng t bo PC12 (IC50= 0,103 mM), dn xut

isoxazol 11 ca n cho hot ng kp trn c 2 dng t bo ny. Cc dn xut

acetohydrazid c hot tnh r rng trn dng PC12 v hot tnh yu trn

HEPG2, trong 15a cho thy hot tnh r rng nht trn PC12 (IC50= 0,251

mM) do c s hin din ca lu hunh trong chui nh km bn [19].

11

Bng 1.3. IC50 (mM) ca cc hp cht trn dng t bo HEPG2 v PC12

Hp cht IC50 (mM)

HEPG2-24h PC12-24h

10a >30 mM 0,103 mM

10b >30 mM 5mM

11 2,4 mM 0,268 mM

12 >30mM 18 mM

13 >30 mM 3 mM

14 >30 mM 0,954 mM

15a >30 mM 0,251 mM

15b >30 mM 1,5 mM

Nm 1982, trung tm nghin cu dc phm ti Kanebo (Japan)

pht trin 1 dy dn cht 2-(2-pyridinyl)benzimidazol t 55 hp cht v th

tc dng gim au, chng vim. Kt qu cho thy, 2-(5-ethyl-2-

pyridinyl)benzimidazol (KB-1043) l hp cht c hot ng chng vim,

gim au h st tt hn phenylbutazon v tiaramid. Hn na, hp cht ny c

tc dng kch thch tiu ha thp hn v ch s iu tr cao hn 2 3 ln so vi

nhm hp cht cng nghin cu [14].

Nm 2010, mt dy cc dn xut 2-methylaminobenzimidazol c

tng hp bi Kavitha Achar v c sng lc tc dng gim au, chng vim.

12

Hnh 1.10. Dn cht 2-methylaminobenzimidazol c tng hp bi K.

Achar

Tc dng gim au c nh gi theo phng php gy au bng acid

acetic. Gn nh tt c cc hp cht th nghim u cho thy tc dng gim

au mnh khi so snh vi thuc chun nimesulid. Trong , cht 16-g cho

thy tc dng gim au r rt (89%, 100 mg/kg th trng). Cn li hp cht

16-b, 16-d, 16-f, 16-g, 16-h, 16-i, 16-j v 16-k cng cho thy tc dng tt.

Trong h thng vng 2-methylaminobenzimidazol, ngi ta nhn thy rng s

c mt ca -Br, -Cl trn vng benzimidazol v -Br, -Cl, methyl, methoxy trn

phn anilin ti cc v tr khc nhau lm tng cng tc dng gim au. Ngoi

ra cc dn cht trn cng c nghin cu tc dng chng vim. Kt qu cho

thy hp cht 16-a, 16-b c kh nng chng vim tt [6].

Nm 2001, Alba Chimirri cng cng s tng hp mt s dn cht

1H-pyrrolo[1,2-a]benzimidazol-1-on v th c tnh chng co git trn chut

DBA/2 [18]. S liu c tnh ton theo phng php ca Litchfield v

Wilcoxon.

13

Hnh 1.11. 1H-pyrrolo[1,2-a]benzimidazol-1-on tng hp bi A. Chimirri

Bng 1.4. Hot ng chng ng kinh trn chut DBA/2

Cht EC50 (mol/kg)

Pha co git Pha co cng

18 24,1 17,9

19 52,7 27,4

21 23,9 17,0

22 104 79,0

23 46,4 31,7

24 63,8 54,4

Cis-25 63,8 56,9

Trans-25 39,1 25,6

Cis-26 80,3 63,8

Trans-26 43,2 29,1

27 29,2 27,0

28 18,2 9,26

29 27,2 18,5

14

Trong cc hp cht c thay th methyl v tr R2 (18, 19, 21), s c

mt ca fluor v tr C6 (cht 21) khng lm nh hng n tc dng, nhng

nu thay bng clor (cht 19) th li lm gim tc dng. Trong cc hp cht

thay th bng phenyl R2 (22, 23, 24) th hot ng mnh nht l dn cht th

6-Cl (cht 23). Hiu ng co git cng tng ln khi c mt nhm methyl C2

(25 v 26), ng phn trans hot ng mnh hn so vi cis. Cui cng, tc

dng c tng cng mnh khi thay p-tolyl v tr R2 (27, 28, 29), c bit

s kt hp ca nhm th 6-Cl v p-tolyl (cht 28) cho thy hiu qu chng co

git mnh nht [9].

1.3. La chn hng tng hp v th tc dng sinh hc cho ti

T cc ti liu tham kho c chng ti nhn thy rng cc hp cht

ca benzimidazol th v tr C2 v N1 u c nhiu tc dng sinh hc nh:

khng nm, khng khun, chng ung th, virus, chng co git, gim au,

chng vim.[6,9,11,19]. Cc benzimidazol hydrazid cng c cc tc dng

sinh hc ng k, c bit l chng nm [20]. V th hng nghin cu ca

chng ti d kin l tng hp cc dn cht ca benzimidazol-2-propanoat, bao

gm: cc hp cht th v tr N1 v tng hp mt s hydrazid, ng thi th

tc dng khng nm, khng khun ca chng.

15

CHNG 2.

NGUYN LIU, THIT B, NI DUNG

V PHNG PHP NGHIN CU

2.1. Nguyn liu v thit b

Thc hin kha lun ny chng ti s dng mt s ha cht, dung

mi v thit b ca phng th nghim Tng hp Ha dc- B mn Cng

nghip Dc.

2.1.1. u n li u, dun mi v a c t

Bng 2.1. Danh mc nguyn liu, dung mi v ha cht

STT Tn ha cht Xut x

1 Acid acetic 99,8% Merck- c

2 Acid hydrocloric Trung Quc

3 Acid monocloroacetic Trung Quc

4 Acid sulfuric Trung Quc

5 Anhydrid succinic Trung Quc

6 Benzyl clorid Trung Quc

7 Cloroform Trung Quc

8 Dicloromethan Trung Quc

9 Ethanol tuyt i Vit Nam

10 Hydrazin hydrat Trung Quc

11 Kali carbonat khan Trung Quc

12 Methanol Trung Quc

13 Natri acetat Trung Quc

14 n-Butanol Trung Quc

15 Natri carbonat Trung Quc

16 Natri hydroxyd Trung Quc

16

17 N,N-dimethylformamid Trung Quc

18 Natri sulfat khan Trung Quc

19 O-phenylendiamin Merck- c

20 Thionyl clorid Merck- c

21 Xylen Trung Quc

2.1.2. T it b dn c

Bng 2.2. Danh mc thit b, my mc

STT Tn thit b/ dng c Xut x

1 Bn mng Silicagel GF254 70-230 mesh c

2 B lc ht chn khng Buchner Buchi- Thy S

3 Cn k thut XB 320 Precisa- Thy S

4 n soi UV sc k CN6 Vilber Lourmart- c

5 My ct quay chn khng Buchi CH 9230

Model: R-210; No 0700012009

Buchi- Thy S

6 My khuy t gia nhit Wisd Wise stir MSH-20A

Daihansci- Hn Quc

7 My to kh N2 Nitrox UHP N0751

Model UHP N0751E-SIN 9900774

Domnick Hunter Ltd- Anh

8 T hotte Unilab

Model TH 1300

Jinan Unilab Instrusments. Co.

Ltd-Trung quc

9 T lnh Toshiba- Nht

10 T sy Wisd Wiseven

Serial No: 0409300124T002

Daihansci- Hn Quc

11

Bnh cu, bnh sc k, bnh 2 c, bnh nh mc 25 ml,pipet, cc c m, ng nghim, a thy tinh.

Lenz- c

17

- Ph hng ngoi (IR) c ghi trn my Perkin Elmer- USA ti b mn Ha

vt liu- Khoa Ha- Trng i hc Khoa hc t nhin H Ni v my

Impact- 410 Micolet ti Vin Ha hc- Vin Hn lm Khoa hc v Cng

ngh Vit Nam.

- Ph khi lng (MS) c ghi bng my o ph khi 1100 series LC/MSD

Trap Agilent ca Vin Ha hc v Vin Ha hc cc hp cht thin nhin-

Vin Hn lm Khoa hc v Cng ngh Vit Nam.

- Ph cng hng t ht nhn (1H-NMR) c ghi bng my Bruker AV-

500 ti Vin Ha hc- Vin Hn lm Khoa hc v Cng ngh Vit Nam.

2.2. Ni dung nghin cu

- Tng hp cc hp cht theo s sau:

Bng 2.3. Cng thc ca cc cht d kin tng hp

Cng thc Danh php

Acid 3-(benzimidazol-2-

yl)propanoic (1)

18

Ethyl 3-(benzimidazol-2-

yl)propanoat (2a)

Methyl 3-(benzimidazol-2-

yl)propanoat (2b)

3-(benzimidazol-2-

yl)propanhydrazid (3a-1)

Ethyl 3-(1-ethoxy carbonyl

methyl-benzimidazol-2-

yl)propanoat (3a-2)

Ethyl 3-(1-benzyl-benzimidazol-

2-yl)propanoat (3a-3)

Methyl 3-(1-ethoxy carbonyl

methyl-benzimidazol-2-

yl)propanoat (3b-1)

Kim tra tinh khit v xc nh cu trc ca cc cht tng hp c.

Th tc dng khng khun, khng nm ca cht 2a, 2b, 3a-1, 3a-2, 3a-3,

3b-1.

2.3. Phng php nghin cu

2.3.1. Tn p a c v kim tra tin k it

S dng phng php tng hp ha hc, da trn phn ng:

Phn ng ng vng to dn cht ester 3-(benzimidazol-2-

yl)propanoat.

Phn ng tng hp ester bng tc nhn SOCl2.

Phn ng hydrazid ha ethyl 3-(benzimidazol-2-yl)propanoat.

19

Phn ng th N1 ca ester 3-(benzimidazol-2-yl)propanoat.

Dng TLC theo di qu trnh tin trin ca phn ng.

Kim tra tinh khit ca sn phm bng TLC v nhit nng chy.

2.3.2. Xc n cu trc

Cc cht tng hp c c xc nh cu trc bng cc ph: ph hng

ngoi (IR), ph khi (MS), ph cng hng t ht nhn (1H-NMR).

* Ph hng ngoi (IR): ph hng ngoi c ghi ti Khoa Ha, Trng i

hc KHTN H Ni, trn my Perkin Elmer v my Impact- 410 ca Vin Ha

hc- Vin Hn lm Khoa hc v Cng ngh Vit Nam, vi k thut vin nn

KBr trong vng 4000- 400cm-1

. Cc mu rn c phn tn trong KBr sy

kh vi t l khong 1: 200 ri p di dng film mng di p lc cao c

ht chn khng loi b hi m [1,3].

* Ph khi lng (MS): ph khi lng cc cht c ghi ti Vin Ha hc

v Vin Ha hc cc hp cht thin nhin- Vin Hn lm Khoa hc v Cng

ngh Vit Nam, my o LC/MSD Trap Agilent hoc Agilent 6310 vi ch

o ESI hoc LC-MS [5,13].

* Ph cng hng t ht nhn (1H-NMR) c ghi trn my Bruker AV-500

ti Vin Ha hc- Vin Hn lm Khoa hc v Cng ngh Vit Nam dng

DMSO, MeOD lm dung mi [2,17].

2.3.3. T tc dn sin c k n nm, k n k un

Th tc dng sinh hc tin hnh trn 5 vi khun Gram(+), 5 vi khun

Gram(-) v 4 vi nm, thc hin ti b mn Vi sinh- Sinh hc ca Trng i

hc Dc H Ni.

Tt c cc cht tng hp c em th hot tnh theo phng php

khuch tn trn thch v sau o kch thc vng v khun. Chn cht i

chiu l penicillin v streptomycin vi khng khun. Chn intraconazol l

cht i chiu vi phng php khng nm.

20

CHNG 3

THC NGHIM, KT QU NGHIN CU

3.1. Tng hp ha hc:

Sau khi tham kho cc ti liu v da vo iu kin phng th nghim,

cc ha cht cho php, chng ti tin hnh tng hp mt s dn cht ester

3-(benzimidazol-2-yl)propanoat v tng hp hydrazid theo s sau:

S 3.1. Quy trnh tng hp chung

Tc n n v iu ki n: a) anhydrid succinic, xylen, 1400C, 3h; b) EtOH, SOCl2,

800C, 2h; c) MeOH, SOCl2, 80

0C, 2h; d) hydrazin hydrat, EtOH, 90

0C, 4h; e) ECA,

DMF, K2CO3, 250C, 12h; f) Benzyl clorid, DMF, K2CO3, 25

0C, 2h; g) ECA, DMF,

K2CO3, 250C, 4h.

21

3.1.1. Tng hp acid 3-(benzoimidazol-2-yl)propanoic (1)

- Cht acid 3-(benzimidazol-2-yl)propanoic c tng hp theo quy trnh:

S 3.2. Tng hp 3-(benzimidazol-2-yl)propanoic (1) t o-phenylendiamin

Ha tan hn hp gm: 5,4g (0,05mol) 1,2-phenylen diamin v 30ml

xylen trong bnh cu 250ml. Thm tip 10g (0,1mol) anhydrid succinic.

Lp sinh hn v un hi lu, kt hp khuy t trong 3h.

Kim tra phn ng bng TLC vi pha ng n-BuOH: AcOH: H2O = 9:

2: 2,5.

X l: hn hp phn ng sau khi kt thc c lm lnh, gn ly ta.

Ha tan ta thu c trong 60ml HCl 1M ( 600C). Lm lnh, lc ly

dch qua phu lc Buchner. Dch lc c thm 1g than hot, dng a

thy tinh khuy 600C trong 10 pht. Lc qua phu lc Buchner, ra 2

ln vi 10ml nc nng. Dch lc c vo cc c m, lm lnh v

trung ha dch lc bng natri acetat n pH= 6 th xut hin sn phm

(1) mu trng. trong 12h ta ht sn phm. Lc qua phu lc

Buchner, ra ta 3 ln vi 10ml nc lnh, thu c 6,65g sn phm

th. Kt tinh li sn phm trong EtOH 700, thu c tinh th trng, hnh

kim, nh.

Kt qu:

Hiu sut: 70% (6,65g).

Cm quan: tinh th mu trng, hnh kim, nh.

T0nc: 229-2300C

Rf = 0,67 (n-BuOH: AcOH: H2O = 9: 2: 2,5)

22

3.1.2. Tng hp ethyl 3-(benzimidazol-2-yl)propanoat (2a)

- Quy trnh tng hp:

S 3.3. Tng hp ester ethyl 3-(benzimidazol-2-yl)propanoat (2a)

Thm 30ml EtOH tuyt i vo bnh cu 2 c 100ml, lm lnh n 50C,

va khuy va thm t t 0,36ml (4,9mmol) SOCl2, sau thm tip

1g (4,9mmol) acid 3-(benzimidazol-2-yl)propanoic. Lp sinh hn, un

hi lu trong 2h. Sc kh N2 trong sut qu trnh phn ng.

Phn ng c theo di bng TLC vi pha ng n-BuOH: AcOH: H2O

= 9: 2: 2,5.

X l: hn hp phn ng sau khi kt thc c c thu hi dung mi

di p sut gim. Lm lnh bng , thm 30ml nc lnh v trung

ha bng Na2CO3 n pH= 6 th s xut hin sn phm (2a) mu vng

nht. Lc thu ta qua phu Buchner. Ra ta 2 ln vi 10ml nc, ht

kit v sy kh.

Kt qu:

Hiu sut: 70,6% (0,81g)

Cm quan: cht rn mu vng nht.

T0nc= 136-138oC

Rf = 0,3 (CHCl3: MeOH= 20: 1)

3.1.3. Tng hp methyl 3-(benzimidazol-2-yl)propanoat (2b)

- Quy trnh tng hp:

S 3.4. Tng hp ester methyl 3-(benzimidazol-2-yl)propanoat (2b)

23

Thm 30ml MeOH vo bnh cu 2 c 100ml, lm lnh n 50C, va

khuy va thm t t 0,36ml (4,9mmol) SOCl2, sau thm tip 1g

(4,9mmol) acid 3-(benzimidazol-2-yl)propanoic. Lp sinh hn, un hi

lu trong 2h. Sc kh N2 trong sut qu trnh phn ng.

Phn ng c theo di bng TLC vi pha ng n-BuOH: AcOH: H2O

= 9: 2: 2,5.

X l: hn hp phn ng sau khi kt thc c c thu hi dung mi

di p sut gim. Lm lnh bng , thm 30ml nc lnh v trung

ha bng Na2CO3 n pH= 6 th s xut hin sn phm (2b) mu trng.

Lc thu ta qua phu Buchner. Ra ta 2 ln vi 10ml nc, ht kit v

sy kh.

Kt qu:

Hiu sut: 62% (0,66g)

Cm quan: cht rn mu trng lp lnh.

T0nc= 144-1460C

Rf = 0,24 (CHCl3: MeOH= 20: 1)

3.1.4. Tng hp 3-(benzimidazol-2-yl)propanhydrazid (3a-1)

- Quy trnh tng hp:

S 3.5. Tng hp 3-(benzimidazol-2-yl)propanhydrazid (3a-1)

Ha tan hn hp gm: 1g (4,58mmol) ethyl 3-(benzimidazol-2-

yl)propanoat v 17ml EtOH tuyt i trong bnh cu 100ml. Sau

thm 8ml (82,4mmol) hydrazin monohydrat 50%. Lp sinh hn, un

hi lu v khuy trong 4h.

Phn ng c theo di bng TLC vi pha ng CHCl3: MeOH = 9: 1

24

X l: lnh trong 15 pht s xut hin ta sn phm (3a-1) mu

trng, lc qua phu Buchner, ra ta 2 ln vi nc lnh.

- Kt qu:

Hiu sut: 77% (0,73g).

Cm quan: cht rn mu trng.

T0nc= 265-2680C.

Rf = 0,16 (CHCl3: MeOH = 9: 1)

3.1.5. Tng hp ethyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-

yl)propanoat (3a-2)

- Quy trnh tng hp:

S 3.6. Tng hp ethyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-

yl)propanoat (3a-2)

Ha tan hn hp gm: 0,2g (0,9mmol) ethyl 3-(benzimidazol-2-

yl)propanoat v 7ml DMF khan trong bnh cu 2 c 50ml. Thm tip

0,13g (0,9mmol) K2CO3 khan, cui cng thm t t 0,11ml (1,0mmol)

ECA vo hn hp trn. Lp dng c lm khan (c gn CaO), sc kh N2

trong sut qu trnh phn ng, khuy nhit phng trong 12h.

Phn ng c theo di bng TLC vi pha ng CHCl3: MeOH= 20: 1

X l: hn hp phn ng sau khi kt thc c lc loi b mui v c,

ra bng CH2Cl2, thm 20ml nc lnh ri chit 2 ln vi CH2Cl2. Gp

dch chit v lc dch chit vi dung dch NaOH loi sn phm b

thy phn. Dch CH2Cl2 c lm khan v ct thu hi dung mi p

sut gim. Cht rn (3a-2) c kt tinh li trong nc, trong t lnh

1 ngy. Lc thu ta qua phu Buchner.

- Kt qu:

25

Hiu sut: 72% (0,2g)

Cm quan: cht bt mu trng.

T0nc= 65-670C.

Rf = 0,7 (CHCl3: MeOH= 20: 1)

3.1.6. Tng hp ethyl 3-(1-benzyl-benzimidazol-2-yl)propanoat (3a-3)

- Quy trnh tng hp:

S 3.7. Tng hp ethyl-3-(1-benzyl-benzimidazol-2-yl)propanoat (3a-3)

Ha tan hn hp gm: 0,25g (1,15mmol) ethyl 3-(benzimidazol-2-


0,16g (1,15mmol) K2CO3 khan, cui cng thm t t 0,13ml (1,2mmol)

benzyl clorid vo hn hp trn. Lp dng c lm khan (c gn CaO),

sc kh N2 trong sut qu trnh phn ng, khuy nhit phng trong

1h30 pht.




dch chit dicloromethan, lc dch chit vi dung dch NaOH 10%

loi sn phm b thy phn. Dch CH2Cl2 c lm khan bng Na2SO4

khan v ct thu hi dung mi p sut gim. Cht rn (3a-3) c kt

tinh li trong nc, trong t lnh 1 ngy. Lc thu ta qua phu

Buchner.

- Kt qu:

Hiu sut: 46,0% (0,16g)

Cm quan: cht rn mu nu.

T0nc= 85-880C.

26

Rf= 0,68 (CHCl3: MeOH= 20: 1)

3.1.7. Tng hp methyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-

yl)propanoat (3b-1)

- Quy trnh tng hp:

S 3.8. Tng hp methyl 3-(1-ethoxy carbonyl methyl-benzimidazol-2-

yl)propanoat (3b-1)

Ha tan hn hp gm: 0,2g (0,98mmol) methyl 3-(benzimidazol-2-


0,14g (0,98mmol) K2CO3 khan, cui cng thm t t 0,13ml

(1,18mmol) ECA vo hn hp trn. Lp dng c lm khan (c gn

CaO), sc kh N2 trong sut qu trnh phn ng, khuy nhit

phng trong 4h.




dch chit dicloromethan, lc dch chit vi dung dch NaOH 10%

loi sn phm b thy phn. Dch CH2Cl2 c ra, lm khan v ct thu

hi dung mi p sut gim. Cht rn (3b-1) c kt tinh li trong

nc, trong t lnh 4 ngy. Lc thu ta qua phu Buchner.

- Kt qu:

Hiu sut: 64,2% (0,18g)

Cm quan: tinh th mu trng, hnh kim, nh.

T0nc= 103-1040C

Rf= 0,48 (CHCl3: MeOH= 20: 1)

27

Nh vy, chng ti tng hp c 7 cht. Sau y l bng tm tt kt qu

tng hp ha hc:

Bng 3.1. Kt qu tng hp ha hc

STT Cht CTCT Cm quan T0nc

Hiu

sut

(%)

Rf

1 1

Tinh th mu

trng, hnh

kim.

229-

2300C

70% 0,67

2 2a

Cht rn mu

vng nht.

136-

1380C

70,6% 0,30

3 2b

Cht rn mu

trng lp lnh.

144-

1460C

62% 0,24

4 3a-1

cht rn mu

trng.

265-

2680C

77% 0,16

5 3a-2

Cht rn mu

trng.

65-

670C

72% 0,69

6 3a-3

Cht rn mu

nu

85-

880C

46% 0,68

7 3b-1

Tinh th mu

trng, hnh

kim, nh

103-

1040C

64% 0,48

3.2. Kim tra tinh khit

Chng ti kim tra tinh khit ca cc cht tng hp c bng

sc k lp mng v nhit nng chy nh sau:

- TLC c tin hnh trn bn nhm trng sn silicagel GF254 70-230 mesh,

quan st di n t ngoi bc sng 254 nm.

28

- Dung mi ha tan: EtOH 960.

- H dung mi: n-BuOH: AcOH: H2O (9: 2: 2,5); cloroform: methanol (20: 1)

v cloroform: methanol (9: 1).

Bng 3.2. TLC ca cc cht trung gian (1, 2a, 2b)

TLC

Vt o-ph 1 1 2a 1 2b

H dung mi

n-BuOH: AcOH:

H2O (9: 2: 2,5)

CHCl3: MeOH (20: 1) CHCl3: MeOH (20: 1)

Ghi ch: o-ph: o-phenylendiamin

Bng 3.3. TLC ca cc cht sn phm (3a-1, 3a-2, 3a-3, 3b-1)

TLC

Vt 2a 3a-1 2a 3a-2 2a 3a-3 2b 3b-1

Dung

mi

CHCl3: MeOH

(9: 1)

CHCl3: MeOH

(20: 1)

CHCl3: MeOH

(20: 1)

CHCl3: MeOH

(20: 1)

29

- o nhit nng chy cc cht.

Gi tr Rf v nhit nng chy (t0

nc) ca cc cht c tm tt trong bng

Bng 3.4. Rf v t0nc ca 7 cht tng hp c

Cht H dung mi khai trin Rf T0nc(

0C)

1 n-BuOH: AcOH: H2O (9: 2: 2,5) 0,67 229-230

2a CHCl3: MeOH (20: 1) 0,30 136-138

2b CHCl3: MeOH (20: 1) 0,24 144-146

3a-1 CHCl3: MeOH (9: 1) 0,16 265-268

3a-2 CHCl3: MeOH (20: 1) 0,70 65-67

3a-3 CHCl3: MeOH (20: 1) 0,68 85-88

3b-1 CHCl3: MeOH (20: 1) 0,48 103-104

Nhn xt:

- Kt qu TLC trn c 2 h dung mi thu c 1 vt sn phm, gn, r

di nh sng n t ngoi bc sng 254nm, khng c vt l.

- Nhit nng chy ca cc cht dao ng khong hp t 2 40C.

S b kt lun cc cht tng hp c l tinh khit.

Tin hnh o ph xc nh cu trc cc cht tng hp c.

3.3. Xc nh cu trc ca cc cht tng hp c

3.3.1. Kt qu phn tch ph cc cht trung gian (acid 1 v ester 2a, 2b)

a. Ph hng ngoi (IR)

30

Bng 3.5. Kt qu phn tch ph hng ngoi ca 1, 2a, 2b

Cht CTCT S sng (cm-1) ng vi cc dao ng

maxNH maxC=O maxC=C maxC-N

1

3177 1636 1557 1218

2a

3443 1728 1545 1272

2b

3149 1728 1537 1204

Nhn xt: Cc cht u c s sng ng vi cc dao ng ca cc nhm

lin kt, trong dao ng ca nhm C=O l dao ng mnh. 2a, 2b nhm

C=O r v cao hn acid 1.

b. Ph khi lng (MS)

Bng 3.6. Kt qu phn tch ph khi lng ca 1, 2a, 2b

Cht Cng thc cu to m/z

1

M=190,07 189,0 [M-H]

-

2a

M=218,11 218 [M]

+

2b

M=204,09 205,06 [M+H]

+

Nhn xt: T cc d liu phn tch ph bng 3.4 v ph (ph lc

8 10) chng ti u thy c pic phn t c s khi ng bng s khi d

kin vi cng mnh.

c. Ph cng hng t ht nhn proton (1H-NMR)

31

Bng 3.7. Kt qu phn tch ph cng hng t ht nhn 1H ca 1,2a,2b

Cht Cng thc cu to S liu phn tch 1H-NMR

1

1H-NMR (500MHz, DMSO, ppm):

2,80 (2H, t, C2H2); 3,04 (2H, t, C3H2);

7,11 (2H, d, C5H + C6H); 7,46 (2H, d,

C4H + C7H)

2a


1,21 (3H, t, CH3); 2,91 (2H, t, C2H2);

3,19 (2H, t, C3H2); 4,12 (2H, q,-CH2-);

7,20 (2H, dd, C5H + C6H); 7,50 (2H,

dd, C4H + C7H)

2b


2,88 (2H, t, C2H2); 2,06 (2H, t, C3H2);

3,59 (3H, s, O-CH3); 7,07-7,13 (2H, m,

C5H + C6H); 7,41 (1H, d, C4H); 7,51

(1H, d, C7H); 12,21 (1H, s, NH)

Ghi ch: : chuyn dch ha hc (ppm); s: singlet; d: doublet; t: triplet; q: quartet;

m: multiplet

Nhn xt: da vo kt qu phn tch ph bng 3.5 v cn c vo ph

(ph lc 15 20) chng ti nhn thy:

- S lng proton, dch chuyn, bi ca tn hiu l ph hp vi cng

thc cu to ca 3 cht. Cc cht u c cc proton ca khung benzimidazol

nm trong vng dch chuyn t 7,1 7,5. Cht 1, 2b u c proton ca NH

vng 12; ring cht 2a khng hin proton ca NH l do o trong dung mi

MeOD.

- Kt hp vi kt qu ph IR, ph MS c th khng nh 3 cht 1, 2a, 2b

chng ti tng hp c c cng thc cu to nh d kin.

32

3.3.1. Kt qu phn tch ph cc cht sn phm (3a-1; 3a-2; 3a-3; 3b-1)

a. Ph hng ngoi (IR)

Bng 3.8. Kt qu phn tch ph hng ngoi ca 3a-1, 3a-2, 3a-3, 3b-1

Cht CTCT

S sng (cm-1) ng vi cc dao ng

max

C-H

max

C-N

max

C=O

max

C=C

max nhm

c trng

khc

3a-1

2853 1175 1655 1534 3274 ( NH)

3a-2

2993

2937 1174 1733 1519

3a-3

2926

2863 1176 1728 1509

3b-1

2959

2886 1170 1736 1515

Nhn xt: Cc cht u c s sng ng vi cc dao ng ca cc nhm

lin kt. Trong dao ng ca nhm NH l dao ng mnh, c trng cho

3a-1. Dao ng ca nhm C=O c trng cho cc sn phm 3a-2, 3a-3, 3b-1.

b. Ph khi lng (MS)

Bng 3.9. Kt qu phn tch ph khi lng ca 3a-1, 3a-2, 3a-3, 3b-1

Cht Cng thc cu to m/z

3a-1

M= 204,10 204 [M]

+

33

3a-2

M= 304,14

305,13 [M+H]+

3a-3

M= 308,15

309,13 [M+H]+

3b-1

M= 290,13

291,09 [M+H]+

Nhn xt: T cc d liu phn tch ph bng 3.7 v ph (ph lc

11 14) chng ti u thy pic phn t c s khi ng bng s khi d kin

vi cng mnh.

c. Ph cng hng t ht nhn proton (1H-NMR)

Bng 3.10. Kt qu phn tch ph cng hng t ht nhn 3a-1, 3a-2, 3a-3, 3b-1

Cht Cng thc cu to S liu phn tch 1H-NMR

3a-1


2,55 (2H, t, C3H2); 3,01 (2H, t, C2H2);

4,16 (2H, s, NH2); 7,05-7,11 (2H, m,

C5H + C6H); 7,37 (1H, d, C4H);

7,48 (1H, d, C7H); 9,06 (1H, s, O-

NH); 12,15 (1H, s, NH)

3a-2


1,17 (3H, t, CH3); 1,22 (3H, t, CH3);

2,86 (2H, t, C2H2); 3,03 (2H, t, C3H2);

4,07 (2H, q, O-CH2); 4,18 (2H, q, O-

CH2); 5,21 (2H, s, N-CH2); 7,14-7,19

(2H, m, C5H + C6H); 7,47 (1H, d,

C4H); 7,55 (1H, d, C7H)

34

3a-3


1,15 (3H, t, CH3); 2,87 (2H, t, C2H2);

3,08 (2H, t, C3H2); 4,05 (2H, q, O-

CH2); 5,50 (2H, s, N-CH2); 7,12-7,15

(4H, m, 4CH); 7,26-7,28 (1H, m, CH);

7,31-7,33 (2H, m, 2CH); 7,44-7,46

(1H, m, CH); 7,56-7,58 (1H, m, CH)

3b-1


1,22 (3H, t, CH3); 2,89 (2H, t, C2H2);

3,03 (2H, d, C3H2); 3,61 (3H, s,

OCH3); 4,18 (2H, q, OCH2); 5,12 (2H,

s, N-CH2); 7,14-7,19 (2H, m, C5H +

C6H); 7,47 (1H, d, C4H); 7,56 (1H,

d, C7H)

Ghi ch: : chuyn dch ha hc (ppm); s: singlet; d: doublet; t: triplet; q: quartet;

m: multiplet

Nhn xt: da vo kt qu phn tch ph bng 3.8 v cn c vo ph

(ph lc 21 28) chng ti nhn thy:

- S lng proton, dch chuyn, bi ca tn hiu l ph hp vi

cng thc cu to ca 4 cht d kin. Cc cht u c cc proton ca khung

benzimidazol nm trong vng dch chuyn t 7,1 7,6. Cht 3a-1 vn c 1

proton ca NH v tr 12 do khng th vo v tr N1 ging nh 3a-2, 3a-3,

3b-1. Cht 3a-3 c 9 proton vng dch chuyn t 7,1 7,6 do trong phn t

c 2 vng benzen.

- Kt hp vi kt qu ph IR, ph MS c th khng nh 4 cht 3a-1,

3a-2, 3a-3, 3b-1 chng ti tng hp c c cng thc cu to nh d kin.

35

3.4. Th tc dng sinh hc

Vi mc ch tm kim cc cht c hot tnh sinh hc cao, c trin vng

trong s dng lm thuc, chng ti tin hnh th tc dng sinh hc ca cc

dn cht tng hp c. Da vo mt s kt qu nghin cu v hot tnh sinh

hc ca benzimidazol-2-yl v benzimidazol hydrazid nh: khng nm, khng

khun, chng ung th, virus, chng co git, gim au, chng vim.

[6,9,11,19], chng ti nh hng thm d tc dng khng khun, khng

nm ca cht 2a, 2b, 3a-1, 3a-2, 3a-3, 3b-1.

3.4.1. Nguyn tc, cch tin hnh th hot tnh khng khun

3.4.1.1. Cc vi sinh vt s dng trong nghin cu

Th tc dng khng khun c thc hin i vi 5 vi khun Gram(+)

v 5 vi khun Gram(-) sau:

Vi khun Gram(+) gm: Bacillus cereus ATCC 9946 (Bc),

Bacillus pumilus ATCC 10241 (Bp),

Bacillus subtilis ATCC 6633 (Bs),

Sarcina lutea ATCC 9341 (SL),

Staphylococcus aureus ATCC 1128 (Sta).

Vi khun Gram(-) gm: Escherichia coli ATCC 25922 (EC),

Proteus mirabilis BV 108 (Pro),

Pseudomonas aeruginosa VM 201 (Pseu),

Salmonella typhi DT 220 (Sal),

Shigella flexneri DT 112 (Shi).

Khng sinh i chng: Streptomycin: 14 g/ml

Penicillin: 27 UI/ml

3.4.1.2. Mi trng th nghim

Mi trng th nghim trong nghin cu c thnh phn nh sau:

36

Thnh

. phn

MT

NaCl

(%)

Cao

tht

(%)

Pepton

(%)

Thch

(%) Nc pH

Canh thang

nui cy VSV 0,5 0,3 0,5 0 Va

100ml

7,0 7,4

Thch thng 0,5 0,3 0,5 1,6

3.4.1.3. Nguyn tc

Th tc dng khng khun tin hnh theo phng php khuch tn trn

thch. Mu th (c cha hot cht th) c t ln lp thch dinh dng

cy vi sinh vt kim nh, hot cht t mu th khuch tn vo mi trng

thch s c ch s pht trin ca vi sinh vt kim nh to thnh vng v

khun.

Php th c thc hin ti b mn Vi sinh- Sinh hc, Trng i hc

Dc H Ni.

3.4.1.4. Tin hnh

- Mu th c pha vo dung mi thch hp (EtOH) vi nng l 100

g/ml. Cc khoanh giy lc v trng v c sy kh c tm 3 ln vi

dung dch mu th gm: mu cht 2a, 2b, 3a-1, 3a-2, 3a-3, 3b-1, sau mi ln

tm cc khoanh giy lc c cha mu th u c sy nhit thp hn

600C n kh ht dung mi.

- Chun b mi trng v cy VSV kim nh:

VSV kim nh c cy vo mi trng canh thang, ri nui cy cho

pht trin trong t m 370C trong thi gian 18 24 gi n nng 107 t

bo/ml (kim tra bng pha long v dy dch chun). Mi trng thch

37

thng v trng (tit trng 1180C/30 pht) c lm lnh v 45 500C v

c cy ging VSV kim nh vo vi t l 2,5 ml/100 ml. Lc trn VSV

kim nh phn tn u trong mi trng thch thng, ri vo a petri v

trng vi th tch 20 ml/a v cho thch ng li.

- t khoanh giy lc: khoanh giy lc c tm cht th v x l nh trn

c t ln b mt mi trng thch thng cha VSV kim nh theo s

nh sn.

- cc a petri c mu th c t nh trn trong t m t0 = 370C trong

18 24h, ri sau ly ra c kt qu, o ng knh vng v khun nu c

(s dng thc kp Panmer chnh xc 0,02 mm).

- nh gi kt qu: da trn ng knh vng v khun v c nh gi theo

cng thc:

2

1 1

( )

1

n n

i i

i i

D D D

D sn n

D : ng knh trung bnh vng v khun

iD : ng knh vng v khun th i

s: lch thc nghim chun c hiu chnh

n: s th nghim lm song song (n = 3).

3.2.2.4. Kt qu th nghim

38

Bng 3.11. Kt qu th tc dng khng khun

Mu ng knh vng v khun [mm] ( D , s)

Bc Bs Bp SL Sal EC Shi Pro Pseu Sta

2a - - 12,05

0,69

10,29

1,25

9,13

0,60 - - - -

10,12

0,46

2b - - 11,34

0,14 - -

12,11

1,17 -

9,42

0,66 - -

3a-1 15,42

0,79 - - - - - - - - -

3a-2 - - - - 10,97

0,68

9,59

0,46 - -

10,59

0,84 -

3a-3 - - 13,78

0,37 - -

10,47

0,72

11,03

0,45

11,10

0,52 -

10,91

0,34

3b-1 12,10

0,43 - - - - - - - - -

Peni 19,38

0,37

20,47

0,70 -

12,91

0,47 - - - - -

11,42

0,67

Strep 21,50

0,66

20,16

1,21 -

12,73

0,41

13,73

1,50

13,20

1,05

12,07

0,89

15,53

0,81

17,37

0,67

17,37

0,12

Ghi ch: Peni: penicillin; Strep: streptomycin

Kt lun:

- Mu 3a-1, 3b-1 c tc dng vi 1 vi khun th.

- Mu 2b, 3a-2 c tc dng vi 3 vi khun th.

- Mu 2a c tc dng vi 4 vi khun th.

- Mu 3a-3 c tc dng vi 5 vi khun th.

3.4.2. Nguyn tc, cch tin hnh th hot tnh khng nm

3.4.2.1. Cc vi sinh vt s dng trong nghin cu

39

Vi sinh vt kim nh: + Candida albicans (Ca)

+ Aspergillus niger (As)

+ Saccaromyces ceravitiae (Sa)

+ Penicilium sp. (Pe)

Cht i chng: Intraconazol 50 g/ml

3.4.2.2. Mi trng th nghim

Mi trng th nghim trong nghin cu c thnh phn nh sau:

Thnh

. phn

MT

Glucose

(%)

Pepton

(%)

Thch

(%) Nc pH

Sabouraud

nui cy 2,0 1,0 0

Va

100ml 7,0 7,4

Sabouraud

th nghim 2,0 1,0 1,6

3.4.2.3. Nguyn tc

Nguyn tc tng t php th khng khun.

3.4.2.4. Tin hnh

- Tin hnh tng t vi phng php khng khun. Mt s ch trong php

th khng nm:

+ Mu th c pha vo EtOH vi nng 100 g/ml.

+ Nm kim nh nui cy trong t m 28 300C, thi gian 18 24h.

+ Cc a petri c mu th c t trong t m t0= 28 300C, trong

24 48h, ri sau ly ra c kt qu, o ng knh vng v nm nu c.

- nh gi kt qu: da trn ng knh vng v nm v c nh gi theo

cng thc:

40

2

1 1

( )

1

n n

i i

i i

D D D

D sn n

D : ng knh trung bnh vng v nm

iD : ng knh vng v nm th i

s: lch thc nghim chun c hiu chnh

n: s th nghim lm song song (n=4).

3.2.2.4. Kt qu th nghim

Bng 3.12. Kt qu th tc dng khng nm

Mu ng knh vng v nm [mm] ( D , s)

Ca As Sa Pe

2a 9,73

0,31 -

11,16

0,61 -

2b - - - -

3a-1 - - - -

3a-2 Ht mu

3a-3 - 10,05

0,59

8,67

0,68 -

3b-1 8,15

0,76 -

10,21

0,46 -

Intra 16,33

2,01

15,26

0,41

9,73

0,43

12,39

0,75

Ghi ch: Intra: intraconazol

Kt lun:

- Cc cht 2a, 3a-3, 3b-1 c tc dng vi 2 vi nm th, khng c cht

no c tc dng vi Penicilium sp.

- Cht 2b, 3a-1 khng c tc dng vi tt c vi nm th.

41

CHNG 4.

BN LUN

4.1. V tng hp ha hc

Qua vic tng hp cc cht, chng ti c nhn xt sau

- Phn ng ng vng benzimidazol: gia o-phelylendiamin v anhydrid

succinic thc hin theo phng php ca Bibhucharan Chatterjee [8], xy ra

vi hiu sut kh cao. Phn ng c th xy ra 2 giai on nh sau:

S 4.1. Phn ng ng vng benzimidazol

Mt s yu t nh hng n hiu sut phn ng l:

+ Nhit phn ng: chng ti thy nhit ti u ca phn ng l

140 1450C (nhit xylen bt u si, to s hi lu). Nu nhit thp,

phn ng xy ra chm v khng hon ton. Nu nhit cao qu s to ra

nhiu tp do s trng hp hoc amin b oxy ha. Cc giai on s trng hp

nh sau:

S 4.2. Phn ng trng hp

+ Lng HCl 1M dng loi acid succinic. Nu dng t th s khng

loi b c ht acid succinic, cn khi dng nhiu qu th s lm sn phm

kh kt tinh. Chng ti nhn thy ch cn thm t t HCl 1M v un nng n

khi ta tan ht, lnh l loi c acid succinic.

42

- Phn ng tng hp cc ester: phn ng to ester gia acid carboxylic v

EtOH; MeOH xc tc H+

(H2SO4, HCl kh) c hiu sut khng cao do phn

ng thun nghch (H= 46%). C ch phn ng nh sau:

S 4.3. Phn ng ester ha xc tc H+

Chng ti nhn thy khi s dng tc nhn SOCl2 to ra cht trung

gian l acyl clorid th thu c ester vi hiu sut cao nht, phn ng xy ra

hon ton. Tuy nhin khi s dng SOCl2 cn phi lm khan dng c [2].

S 4.4. Phn ng tng hp ester tc nhn SOCl2

- Phn ng alkyl ha : to dn cht th v tr N1 thc hin theo phng

php gin on trong gio trnh K thut sn xut dc phm tp I, xy ra

theo c ch SN [4]:

S 4.5. Phn ng alkyl ha

Hiu sut phn ng thng thp. Cc iu kin phn ng sau cn c ch :

+ Nguyn liu l cc ester, trong mi trng base (K2CO3) d b thy

phn. V th, trnh thy phn ester phn ng cn lm khan tuyt i: sy

43

dng c trc khi dng, lm khan dung mi DMF v K2CO3, lp b dng c

lm khan (c CaO) loi hi m. Ngoi ra phn ng trnh un nng, ch cn

khuy nhit phng.

+ Dung mi s dng l DMF, kh loi khi x l v th lm sn phm

kh kt tinh, lm gim hiu sut.

+ T l mol gia benzimidazol v tc nhn th. Nhn thy t l mol

benzimidazol: tc nhn th = 1:1,1 l tt nht. Nu dng lng tc nhn th t

hn th phn ng khng hon ton; nu dng nhiu qu th c th to ra mui

amoni bc 4 ti N3 nh sau:

S 4.6. Phn ng to amoni bc 4

- Phn ng hydrazid: gia ethyl ester v hydrin hydrat c hiu sut kh cao.

Phn ng nhanh, x l n gin nn d dng thu c sn phm.

4.2. V tc dng sinh hc

- Cc cht ester: ethyl ester (2a) c tc dng tt (th hin trn 4 vi khun:

Bacillus pumilus, Sarcina lutea, Salmonella typhi, Staphylococcus aureus v

2 vi nm: Candida albicans, Saccaromyces ceravitiae); trong khi dn cht

methyl ester (2b) c hot tnh yu hn (3 vi khun: Bacillus pumilus,

Escherichia coli, Proteus mirabilis, khng c tc dng trn cc vi nm th).

- Cc dn cht th N1: dn cht th vi benzyl clorid (3a-3) cho thy tc dng

tt nht (c vng v khun trn 5 vi khun: Bacillus pumilus, Escherichia

coli, Shigella flexneri, Proteus mirabilis, Staphylococcus aureus v 2 vi nm:

Aspergillus niger, Saccaromyces ceravitiae). Trong cc dn cht th vi

ECA: cht 3a-2 tc dng tt trn vi khun (Salmonella typhi, Escherichia coli,

44

Pseudomonas aeruginosa), 3b-1 tc dng tt trn vi nm (Candida albicans,

Saccaromyces ceravitiae).

- Dn cht hydrazid cho thy tc dng yu: khng c hot tnh trn vi nm v

ch c tc dng trn 1 vi khun th (Bacillus cereus).

T kt qu th hot tnh ta thy: khi chuyn ester (2a, 2b) thnh

hydrazid (3a-1b) th mt tc dng trn tt c vi khun th v vi nm, nhng

li xut hin hot tnh trn chng Bacillus cereus. Khi gn thm cc nhm

akyl vo N1 th c th mt hot tnh trn 1 s chng, nhng li xut hin hot

tnh trn cc chng khc; c bit nhm benzyl (3a-3) cho thy tc dng trn

nhiu chng vi khun, vi nm.

45

KT LUN V KIN NGH

Kt lun

1. tng hp c cc cht nh d kin, trong cc hp cht 3a-2, 3a-3, 3b-1

cha thy cng b trong cc ti liu tham kho c. Bao gm:

- Acid 3-(benzimidazol-2-yl)propanoic (1)

- Ethyl 3-(benzimidazol-2-yl)propanoat (2a)

- Methyl 3-(benzimidazol-2-yl)propanoat (2b)

- 3-(benzimidazol-2-yl)propanhydrazid (3a-1)

- Ethyl 3-(1-methoxy carbonyl methyl-benzimidazol-2-yl)propanoat (3a-2)

- Ethyl 3-(1-benzyl-benzimidazol-2-yl)propanoat (3a-3)

- Methyl 3-(1-methoxy carbonyl methyl-benzimidazol-2-yl)propanoat (3b-1)

Da trn c s phn tch TLC, o nhit nng chy, d liu phn tch ph IR,

ph MS v ph cng hng t proton 1H-NMR chng ti xc nh c cu

trc ca cc cht tng hp ph hp vi cu trc d kin.

2. th tc dng khng nm, khng khun ca 6 cht: 2a, 2b, 3a-1, 3a-2, 3a-3,

3b-1. Cc cht u c hot tnh khng khun hoc khng nm nhng tc dng

khng cao.

xut

tip tc pht trin kt qu ca kha lun ny, chng ti a ra mt s xut

1. Tip tc nghin cu phn ng tng hp dn cht ca ester 3-(benzimidazol-2-

yl)propanoat vi nhm th v tr N1 hoc tng hp lm di thm mch ester.

2. Tip tc th nghim cc hot tnh sinh hc trin vng vi cc dn cht mi ca

ester 3-(benzimidazol-2yl)propanoat nh: tc dng chng ung th, tc dng

gim au chng vim, tc dng h huyt p, gp phn vo vic tm ra nhm

dn cht mi c tc dng sinh hc trin vng.

TI LIU THAM KHO

Ting Vit

1. Trn Mnh Bnh (2003), Phn tch cu trc cc hp cht hu c, B mn

Ha Hu C, Trng i Hc Dc H Ni, trang 4-29.

2. Trn Mnh Bnh, Nguyn Quang t (2007), Ha hc hu c tp I, Nh

xut bn Y hc, H Ni, trang 92-96, 112-130.

3. Nguyn Hu nh, Trn Th (1999), ng dng mt s phng php ph

nghin cu cu trc phn t, Nh xut bn Gio Dc, H Ni, trang 27-99,

296-320.

4. T Minh Kong (2007), K thut sn xut dc phm tp I, Nh xut bn Y

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5. Nguyn nh Triu (2005), Cc phng php phn tch vt l v ha l tp

II, Nh xut bn Khoa hc v K thut, H Ni, trang 61-204.

Ting Anh

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225-232.

25. Wright John B. (1951), "The Chemistry of the Benzimidazoles", Chemical

Reviews, 48(3), pp. 397-541.

PH LC

Ph lc 1: Ph hng ngoi IR ca cht 1

Ph lc 2: Ph hng ngoi IR ca cht 2a

Ph lc 3: Ph hng ngoi IR ca cht 2b

Ph lc 4: Ph hng ngoi IR ca cht 3a-1



Ph lc 7: Ph hng ngoi IR ca cht 3b-1

Ph lc 8: Ph khi lng MS ca cht 1

Ph lc 9: Ph khi lng MS ca cht 2a

Ph lc 10: Ph khi lng MS ca cht 2b

Ph lc 11: Ph khi lng MS ca cht 3a-1



Ph lc 14: Ph khi lng MS ca cht 3b-1

Ph lc 15: Ph 1H-NMR ca cht 1

Ph lc 16: Ph 1H-NMR m rng ca cht 1

Ph lc 17: Ph 1H-NMR ca cht 2a

Ph lc 18: Ph 1H-NMR m rng ca cht 2a

Ph lc 19: Ph 1H-NMR ca cht 2b

Ph lc 20: Ph 1H-NMR m rng ca cht 2b

Ph lc 21: Ph 1H-NMR ca cht 3a-1

Ph lc 22: Ph 1H-NMR m rng ca cht 3a-1





Ph lc 27: Ph 1H-NMR ca cht 3b-1

Ph lc 28: Ph 1H-NMR m rng ca cht 3b-1

Ph lc 1: Ph hng ngoi IR ca cht 1

Ten may: GX-PerkinElmer-USA Resolution: 4cm-1

BO MON HOA VAT LIEU-KHOA HOA-TRUONG DHKHTN

Nguoi do: Phan Thi Tuyet MaiTen mau: F-esteDate: 4/5/2013

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.0

0.0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100.0

cm-1

%T

3443

3058

2981

2903

2846

2741

2687

2635

1728

1623

1592

1545

1451

1428

1375

1353

1333

1272 1189

1152

1116

1054

1031

936

887

791

745

618

Ph lc 2: Ph hng ngoi IR ca cht 2a

Ph lc 3: Ph hng ngoi IR ca cht 2b

Ten may: GX-PerkinElmer-USA Resolution: 4cm-1

BO MON HOA VAT LIEU-KHOA HOA-TRUONG DHKHTN

Nguoi do: Phan Thi Tuyet MaiTen mau: HydrazitDate: 4/5/2013

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600.0

0.0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100.1

cm-1

%T

3327

3274

3081

3051

3016

2974

2939

2853

2737

2661

1768

1655

1602

1534

1481

1451

1432

1366

1326

1312

1273

1243

1223

1175

1158

1109

1022

1000

929

888

778

765

748

737

698

666

616


Ph lc 7: Ph hng ngoi IR ca cht 3b-1

Ph lc 8: Ph khi lng MS ca cht 1

Ph lc 9: Ph khi lng MS ca cht 2a

Ph lc 10: Ph khi lng MS ca cht 2b


M= 204

Ph lc 14: Ph khi lng MS ca cht 3b-1

Ph lc 15: Ph 1H-NMR ca cht 1

Ph lc 16: Ph 1H-NMR ca cht 1 (m rng)

Ph lc 17: Ph 1H-NMR ca cht 2a

Ph lc 18: Ph 1H-NMR ca cht 2a (m rng)

Ph lc 19: Ph 1H-NMR ca cht 2b

Ph lc 20: Ph 1H-NMR ca cht 2b (m rng)

Ph lc 22: Ph 1H-NMR ca cht 3a-1 (m rng)

Ph lc 27: Ph 1H-NMR ca cht 3b-1

Ph lc 28: Ph 1H-NMR ca cht 3b-1 (m rng)

Documents

Nghiên cứu tổng hợp và thử tác dụng sinh học một số dẫn chất acid 3-(benzimidazol-2-yl) propanoic.pdf