Nghiên cứu bán tổng hợp định hướng các dẫn xuất EUGENOL có tác dụng kháng nấm C ALBICANS

BO GIAO DUG VA DAO TAO
TRU'O'NG
OAI
HOC TONG HOP HA NOI
PGS PTS
PHAM TRUONG
THI THO
NGHIEN
CLTU
BAN TONG
HCfP
DjNH HU-QNG
CAC
DAN
XUAT
EUGENOL CO TAC DUNG
KHANG NAM C. ALBICANS
LUAN
AN TIEN
St
KHOA HOC HOA HOC
HA NOI
1994
MUC LUC
Phan mot
Trang
Chirang
ma dau 1
-
Gidi
thieu

luan
an 1
- Muc dich nghien cau cua luan an 2
- Tom tat cac luan diem co ban
ciia
luan an va nhung
^
dong gop mdi cua tac gia
Cinrang
tong quan 4
0-1 Cac dan xuiit eugenol
dupe
biet den nay 4
0-2 Van de nam benh;
NhOng
nhom khang sinh chinh;
NhOng
6
ch^t CO
tac dung khang
nim
C albicans
0-3
V^n
de tong hop noi chung va tong
hdp
cd dinh
hudng
12
0-4

Mdi
hen quan dinh
luong
"Cau
true
hoa hoc va 14
tac dung sinh hgc" (QSAR)
'
.
0-5 Nhung md hinh toan hpc nghien cuu
vtin
de QSAR 16
a-
Phuong
phap nhan dang, phuong phap phan tich cau
true
con 16
b-
Giai phap ve cac Juong
til thdng
ke 17
c-
L/ng
dung phan tich nhan td de tim hieu quan he
c^u
true
- tac dung
18
d-
Cac phuong phap ban

thue
nghiem de nghien cuu co che
cac phan ung cua cac chat cd tac dung sinh hoc
19
e-
Phuong phap hoi qui nhieu thdng
sd
20
g- Phan tich
cQu true
-
lac
dung theo phuong phap Hansch 23
h-
Md hlnh toan cdng tinh Free - Wilson 26
i- Nhung nghien cuu ly thuyet ve mdi lien quan cau
true
hoa hpc - tac dung sinh hpc. 29
Chu'wng
I:
Doi
tin/ng
nghien
cii'u,
muc dich cua cong
trlnli,
va cac
piiu'irng plidp ngiiien
cii'u.
1-1 Ddi tuong nghien cuu 33

1-2 Muc dich cua cdng trinh 34
1-3 Cac phuong phap nghien cuu 34
Phan hai
NHUNG KET QUA NGHIEN CUU
Cliitrang
2: Mot so
ichdo
sat ma dau
2-1 Nghien cuu thanh phan hda hpc tinh dau huong nhu
38
trang
(Ocimum gratissimum
L., Labiatae) Viet Nam 40
2-2 Khao sat dinh tinh tac dung khang khuan, khang
nSm
40
cua tinh dau huong nhu va eugenol.
2-3 Nghien cuu quy trinh tdi uu tach eugenol tu tinh dau huong nhu.
42
2-4 Nhung nghien cuu md dau chuan bi cho viec ban tong hop
45
cac din xuat eugenol.
2-5 Nghien cuu su phan bd dien tich cua nguyen tu trong phan 49
tu
eugenol,
isoeugenol
vave gidn
do phan
tir
cua chung

theo chuong trinh Alchemy II va phuong phap CNDO/2.
Cliwang
3 : Ban tong hap cac dan xuat eugenol tiieo quy
lioach,
52
3-1 Ban tong hop cac dan xuat eugenol theo quy hoach. 52
3-1-1 Lua chpn cac nhdm
the'va
vi tri thay the trong phan tu eugenol 52
3-1-2 Sd luong cac dan xuat can tong hpp theo md hinh
Free
-
Wilson. 53
3-2 Ban tong hop cac dan xuat eugenol 55
3-2-1
Nhu*ng
phan trng ca ban
lam
thay doi nhom chuc
alyl
3-2-1-1
Dbng
phan hoa
^5
3-2-1-2 Hydro hoa 56
3-2-1-3 Oxy hoa
'
57
3-2-1-4 Halogen hoa 58
* Xac dinh cau

true VH (1-hydroxy
- 2-metoxy -
4<2',
3'
dibrompiropyl)
-6-brom-benzen) 59
3-2-1-5 Cong hop hydrohalogenua 59
* Xac dinh cau
true
VIII (Bis (1-hydroxy - 2-metoxy - 62
4-propenyl-benzen)
3-2-2 Nhirng phan
irng
iam thay doi nhom - OH 64
3-2-2-1 Tao este voi axil ciorua
'
a- Este hoa eugenol vo'i benzoyl ciorua trong moi tnrang kiem
^
b-
Este hoa isoeugenol
vd*i
benzoyl ciorua 65
c-Este hoa eugenol
vol
p-clobenzoyl
ciorua 65
3-2-2-2 Tao este
vdi
p-toluyl
sunfoclorua

a- Este hoa eugenol vo'i p-toluyl sunfoclorua 66
* Xac dinh cau tnic XII
(1-tosyloxy
- 2-metoxy -
4-alyl-benzen)
67
b-
Este hoa dlisoeugenol
vd-i
p-toluyl sunfoclorua 71
* Xac dinh cau
true
XIII Bis (1-tosyloxy - 2-metoxy - 72
4-propenyl-benzen)
c- Este hoa isoeugenol vo'i axit 3-brom-2-metyl-propionoyl ciorua 74
* Xac dinh cau
triic
XIV (l-(2-metyl-propenoyl-oxy) - 2-metoxy - 75
4-propenyl-benzen)
3-2-3 Ban tong hop cac dan xuat eugenol thong qua
sir
the & nhan tham 78
a- Nitro hda eugenol 78
b-
Nitro hoa vanilin 78
c- Brom hda vanilin "79
3-2-4 Tao cac mudi kim loai cua eugenol 80
3-2-5 Tao este cua nitro eugenol vdi p-clobenzoyl ciorua
*
Xac dinh

c£u true
XX
81
(1-p-ciobenzoyl
oxy - 2-metoxy -
4-alyl
-
6-aitro-benzen)
•t
3-3 Tinh mat dp dien
tCt
hda tri tren cac nguyen tu C va O 88
theo
phuung
phap
CNDO/2'va
ve gian do phan tu cac
din xu^t
eugenol (theo chuong trinh Alchemy)
3-4 Ket qua va thao luan
96
Chirang 4: Xac dinh
dinii licang
tac dung
Iciidng
nam C.albicans cua
18 dan xuat eugenol theo mo
iiinh
toan
iioc

Free - Wilson
4-1 Gidi thieu them ve md hinh toan Free - Wilson 100
4-2 Thu tac dung khang nam
C-albicans
cua
18 din
xuat eugenol 102
4-3 Tinh toan theo phuong trinh han che' 102
4-4 Gia tri tinh toan phan dong gdp vao tac dung khang nam
C. albicans cua 16 nhdm
th6.
Ill
4-5 Gia tri
thue
nghiem va gia tri tinh toan tac dung khang nam cua
18
dSn xudt
eugenol
^ 12
4-6 Kiem tra thdng ke cac ket qua tinh toan
112
4-7 Xac dinh
dfin xuQt
cd tac dung khang
nfim
cao
nhSt
trong day
nghien cuu va du
doc^n

dan xuat cd tac dung cao hon.
115
Chirang
5:
Xac dinh dinh
lirang
moi lien quan cdu
true
- tac dung
cila
cdc dan xuat eugenol theo mo
liinli Corwin
Hansch
5-1 Gidi thieu them ve md hinh Hansch
117
121
122
5-2 Cac thdng sd hda ly
^ 19
5-2-1
Hang
sd cam ung nhdm
th6 a ^-^9
5-2-2 Hang sd hieu ung lap the Es
5-2-3
Hangsd the'ky nude (Ig
P)
5-2-4 Hang sd ky
nude
bp phan hay hang sd phan ra f 124

5-2-5 Hang sd
khuc
xa phan tu MR
125
5-3 Nghien cuu mdi lien quan
giija
CLSU
true
- tac dung cua cae
dan xuat eugenol theo phuong phap Hansch 126
5-4 Phan tich hoi quy
• *^ 133
5-5 Ket luan 135
Cinrang 6 :
Plidn
tich vd
Idem ciiirng
nhung ket qua nghien
citu
theo mo hinh Free - Wilson vd Hansch
$-1
So sanh each tiep can cua Hansch va each tiep can cua
136
Free - Wilson ve mdi tuong quan cau
true
- tac dung 137
6-2 Thao luan cac ket qua nghien cuu QSAR cua cae din
xuiit eugenol theo phuong phap Free - Wilson va phuong
phap Hansch
6-2-1 Ket qua nghien cuu theo md hinh Hansch 137

6-2-2 Ket qua nghien cuu theo md hinh Free - Wilson 138
6-2-3 Ban tong hpp
din
xuit brdm eugenol (m) va dan xuit
este eua toluyl
sulfoeiorua
vdi brdm isoeugenol (M) 139
6-2-4 Ket qua thu tac dung khang nam C.albicans eua hai din
xuat (m) va (M)
142
6-2-5 Thao luan cac
k6t
qua 142
6-3
Ket
luan 142
Chuang
7: Thao luan ve kha nang
mo*
rong hai mo
hinh
nghien
cii'u
cua
Free-Wilson va Hansch 146
7-1
Nhan xet ve hai mo hinh Free-Wilson va Hansch
^43
7-2
Gid-i

thieu torn tat ly thuyet quy hoach thi nghiem tim dieu kien toi
u-u
145
7-3 Quan he
giua
mo hinh Free-Wilson va Hansch
vo'i
ly thuyet quy hoach
thi
nghiem tim dieu kien toi
\x\x 147
7-3-1 Ma tran quy hoach thi nghiem va
du*
bao dieu kien toi uu cua
phu-ang
phap Free-Wilson va Hansch 148
7-3-2 Bien phap tranh cho ma tran quy hoach Free-Wilson va Hansch khoi
bi suy bien 151
7-3-3 Phan
tich
so sanh ban chat cac tham so vao va tham so ra
ciia
hai
phu'ang
phap Free-Wilson va Hansch 151
7-3-4 Phan
tich tinh
giai
du*ac ciia
md hinh Hansch va Free-Wilson 156

7-3-5 De xuat them ve kha nang md' rpng
phirang
phap Free-Wilson 156
7-4 Ket luan 159
Phan ket luan: Nhirng ket luan. Nhung dong gop cua luan an 160
Phan thurc nghiem 162
Phan cdc tdi lieu tham
klido
Phan phu luc
169
189
Phan mot
CHl/QNG MQOAU
1.
Gi6>i
thieu luan an
Ten de tai: "Nghien
cmi
ban tong
hgp
dlnh
hud'ng
cac dan xuat eugenol co tac
dung khang nam Candida
albicans".
Luan an gom 190 trang va 40 trang phu luc, dan 185 tai lieu tham khao va
du-gc
chia
lam
7 chirang,

Phan
Id-n
npi dung
ciia
cong trinh nay da
dugc
trinh bay tru'd'c Hoi dong khoa
hpc Khoa Tong hgp
htni
ca
Truang
dai hoc Hoa hpc Sophia, Bungaria, va da
durgc
danh gia tot (xem cac ban nhan xet danh gia cua Hoi dong khoa hpc Khoa va cac
nhan xet cua cac giao su),
du-gc
de nghi cho phep tiep tuc hoan
thlen
de chuan bi bao
v$
luan an tien
si
hoa hpc. Npi dung
ciia
cong trinh da
dugc
cong bo,
dugc
cap hai
ban quyen sa

hmi
tac gia
ciia
Uy ban Phat minh sang che Bungaria (No. 43770 va
No.
43771), va da bao eao tai mot so hoi thao quoc gia va quoc te
nhir:
Hoi nghi
quoc.
te ve tinh dau va chat tham cua Bungaria (Vacna, 17-19/10/1985), Hoi nghi Hoa
hpc'
quoc gia lan
thu*
nhat cua Bungaria (Sophia, 26-28/11/1985), Hpi
nghj
quoc te ve tinh
dau va chat tham lan
thu*
2
ciia
Malaixia Kuala lampur (3-5/12/1990), Hpi nghi quoc
te ve
hirang
lieu my pham Chau A lan
thu*
nhat (Singapore, 22-24/10/1991), Hpi nghi
quoc te ve tinh dau va chat tham lan thu 3 Malaixia (Langkawi Island kedah), Hpi
nght "Cay nhiet
ddi
va ung dung" do UNESCO to

chiix
tai Indonesia (Bukittingki,
10/1992), Hpi nghi "Tin hpc trong Hoa hpc" lan thu nhat tai Ha Npi (7/1993), Hpi
nghi Hoa hpc toan quoc lan 2 (Ha Npi, 12/1993).
2.
Muc
dich
nghien
ciru
cua luan an
Cong trinh nay nham giai quyet van de nghien
cihi
ban tong hgp mpt each co
dinh
hurd-ng
cac dan xuat eugenol eo tac dung khang nam C albicans, thdng quan viec
1
su* dung cac md hinh toan hpc eua Free-Wilson va Hansch ve moi lien quan giua cau
true
hoa hpc va tac dung sinh hpc, dong thai de xuat va thao luan kha nang nang cao
hieu qua su dung cua hai md hinh toan noi tren trong viec dinh
hud'ng
tong hgp cac
chat,
dira
tren viec su dung ly thuyet toan quy hoach thi nghiem tim dieu kien toi uu.
Van de dat ra d' day la tu* eugenol - thanh phan chinh cua tinh dau-
hirang
nhu
- mpt nguon nguyen lieu san cd d'

nud-c
ta, bang con du'o'ng nao de cd the tong hgp
du-gc
cac dan xuat
ciia
eugenol c6 tac dung khang nam C. albicans (mpt loai nam dac
tru'ng cua benh ngoai da va benh phu
nu)
cd hieu qua
ca*
de cd the
su*
dujig
trong
nganh y
dugc
hoac trong nganh my pham. Ket qua thu dugc co the dong gdp vao viec
nang cao hieu qua
su
dung tinh dau
huang
nhu, mpt nguon tai nguyen con ehua dugc
tan dung.
Vdi
muc tieu do, chung tdi da tien hanh thay doi cau
triic
eugenol bang each thay
doi cac nhdm chuc, roi nhd cac md hinh toan hpc khao sat moi lien quan giua su thay
doi cau
true

va bien thien tac dung.
Nhd su dung cac md hinh toan hpc nghien cuu moi lien quan giua cau
true
- tac
dung
ciia
Free-Wilson da tim dugc nhung gia tri dong gdp vao tac dung
ciia
cac nhom
the,
tu do khong nhung cd the xac dinh dugc dan xuat cd tac dung cao nhat trong day
nghien cuu, ma con du doan dugc nhung dan xuat mdi
ciia
eugenol cd tac dung
khang nam tot han nua, ma nhung chat du doan nay ve sau da dugc tong hgp va thu
nghiem va cac ket qua chiing tdi nhan dugc da cho thay su dung dan
ciia
cac du doan
nay. Theo md hinh Hansch da tim ra dugc nhung phuang trinh hoi quy
giiip
eho
ngudi nghien cuu hieu dugc ca che tac dung
ciia
che pham thu nghiem, tu do cd
hudng de di tim nhung dan xuat eugenol
hu-u
hieu han, vdi dudng di ngan
ho-n.[
60 ]
Nhung dieu vua trinh bay the hien

tinh
mdi me
ciia
cdng trinh.
Tinh Icinh
te vd
klioa
hoc
ciia
cdng trinh the hien d cho vdi mpt so
lugng
ft nhat
cac dan xuat can tong hgp (theo mpt quy hoach da chpn va la dai dien cho mpt sd
lugng
Idn
gap nhieu lan cac dan xuat le ra can phai dieu che de thu nghiem theo cac
phuang phap truyen thong), va viec su dung cac phuang phap
tinh
toan lugng tu,
khong lugng tu, xu ly so lieu vdi phuang tien may tinh dien tu v.v., cuoi cung da tim
ra dugc dan xuat cd tac dung tot nhat theo yeu cau vdi con dudng ngan nhat.
Ngoai ra, ve mat ly thuyet luan an cung da de xuat va thao luan kha nang md
rpng viec su dung hai md hinh Free-Wilson va Hansch nham tim vai trd tugng tac
ciia
cac nhdm the trong phan tu, dieu nay chua dugc hai md hinh tren nhac den.
Chung tdi da lien he hai md hinh Free-Wilson va Hansch vdi ly thuyet quy noach
thi
nghiem, phan
tich
so sanh ban chat cac tham so vao va tham so ra, phan

tich tich
giai dugc
ciia
hai md hinh, de xuat cac ma tran quy hoach
thi
nghiem vdi so lugng cac
chat
thi
nghiem hgp ly, phan tich cac bien phap de cho ma tran quy hoach khong bi
suy bien, nham tim dugc vai trd giao thoa
ciia
nhdm the, dieu nay la can thiet va cd
mpt y
nghia
quan trpng trong viec dinh hudng tong hgp thuoc mdi vdi hieu luc cao
mong dgi.
Van de ban tong hgp dinh hudng thdng qua viec nghien cuu mdi lien quan giua
cau tnic hda hpc va tac dung sinh hpc la mpt mdn khoa hpc lien nganh, bao gom
nhieu
linh
vuc: hda huu ca, hda ly, hda phan
tich,
hda lugng
tii*,
sinh vat hpc, toan
hpc,
may
tinh,
Day la mpt mdn khoa hpc con mdi me, mdi xuat hien tren the gidi
khoang 30-40 nam trd lai day, doi vdi

nude
ta van de nay cung rat mdi.
Diem ca ban
ciia
luan an nay la su tim kiem nhung phuang phap mdi, khoa hpc
va kinh te, nham giai quyet van de ban tong hgp cac dan xuat cd tac dung sinh hpc tu
nguon goc thien nhien mpt
each
cd dinh hudng.
Chiing tdi muon coi do la diem ddng gdp mdi va ca ban
ciia
luan an. Can noi
them rang phuang phap ban tong hgp dinh hudng nay khdng phai chi dung lai d
nhung ket qua cu the
ciia
luan an, ma con cd the lam tien de cho nhung nghien
cii'u
tiep theo, rat phong
phii
va da dang.
PHAN TONG QUAN
0-1.
Cac dan xuat eugenol
duo'c
biet den nay
Eugenol, C10H12O2 .
Phan tli' lugng M
=
164.
Eugenol cd 3 nhdm chuc ta

-OH;
-OCH3
va
-CH2-CH
= CH2 .
OCH3
CH2 - CH
=
CH2
Tli'
lau
hda hpc eugenol da dugc
ehii
y.
Tii"
1904,
hai tac gia ngudi
Due
Thorns va Zernick [91] da md
ta dan xuat nita
ciia
eugenol, va tiep sau dd la hang
loat
dan xuat mdi ra ddi [16, 17, 31, 48, 92, 98].
Cdng
thue
phan tu
ciia
eugenol cho thay ngoai ba nhdm chuc d nhan tham con cd ba
vi tri

chua bi the (vj tri so 3, 5 va 6). Nhin chung cac dan xuat deu xuat phat tu su thay
doi cac nhdm d vi tri 1, vi
tri
2 va vi
tri
4 [65, 67, 68, 69, 146], hoac dinh cac nhdm the
vao
vi tri
5 va 6. Cho den nay chua ed mpt tai lieu nao noi den viec dua nhdm the vao
vi
tri
3, cd the do vi
tri
nay bi can trd khdng gian bdi cac nhdm the metoxy va
alyl."
D6i
vdi cac vi
tri
5 va 6 thi nam 1933 David E, Levin va Alexander Lowy da dua cac
nhdm nitrobenzylamin va
nitrophenylamin
vao vi
tri
6 d vong tham
ciia
phan tu
dihydro eugenol [21], nam 1915 Brady Dann [11] da dua nhdm nitro vao vi trf 5
ciia
vong tham d vanilin, nam 1925 Menke B. [64] va nam 1930 Torrey Clarke [94] da dua
dugc nhdm brdm vao vi tri 5

ciia
vong tham d vanilin.
Ngay nay nhu-ng
tinh
toan ve su phan bd mat dp dien tu trong phan tu cd the
giiip
giai thich cho viec dua eac nhdm the nitro va brdm
chii
yeu vao vi
tri
6
ciia
vong tham,
nghIa
la vao vi tri orthor so vdi nhdm -OH, cung cd
nghIa
la cac nhdm the electrophil
nay uu tien the vao vi trf cd su phan bd mat dp dien tich
Idn
han, hay ngugc lai vi
tri
ed
su phan bd mat dp dien tu nhd han [76, 77]. Cac nhdm the electrophil chi di vao vi trf 5
khi cd su tac dpng den eac nhdm -OH hoac nhdm
elyl,
lam cho mat dp dien
tii*
d vi trf 5
Idn
han vi tri 6. Van de nay se dugc de cap cu the d phan tong hgp cac dan xuat

eugenol. Tu nam 1904 den nam 1979 so cac dan xuat eugenol dugc biet da len den 80
(xem phan phu luc [165 - 183]). Nhung dan xuat dugc tao nen do cd su thay doi nhdm
chuc d vj
tri
1,
thi
du thdng qua cac phan ung este hda, thudng cd mui tham dac trung.
Mpt so chat da cd mat d thi trudng va dugc su dung vao nganh huang lieu my pham
nhu axetyleugenol, axetylisoeugenol cd miii tham hanh nhan [88], einamyl eugenol,
eugenol cinamate deu cd nhung
miii
tham dac trung rat ben. Viec chuyen nhdm alyl
d vi
tri
4 thanh nhdm -CHO da tao thanh
chSl vanihn
quen thuoc. Thdng qua su dong
phan hda eugenol da thanh isoeugenol, phan ung nay da cd nhieu tien bd ve mat ky
thuat. Trudc day su dong phan hda nay dugc thue hien trong mdi trudng kiem
d$c
cd
dung mdi, sau nay qua trinh dong phan hda vdi kiem nong chay da cho hieu suat cao
hem.
Nhd cac
Id
vi sdng Andre Loupy va Le Ngpc Thach da dong phan hda eugenol
thanh isoeugenol mpt each hieu qua va nhanh chdng [2].
M6t
so dan xuat eugenol cd tac dung sinh hpc nhung khdng dac hieu, nhu san
pham the nitro vao vi trf 5

ciia
dihydroeugenoi cd tac dung lam giam dau va khdng
gay kich ung da, lieu dpc LD50
=
3,95 g / kg [11].
Mudi natri
ciia
dihydroeugenoi lam giam huyet ap nhe [21]. Dan xuat
ciia
dihydroeugenoi vdi nhdm amin
dinh
vao vi trf 5 cd tac dung chua tho huyet nhung rat
tiec
la
kha dpc [21]. Dac biet cac este
ciia
eugenol vdi cac axit cacboxylic vong va di
vong cd tac dung giam dau rd ret. Bang phat minh sang che
ciia
Mathieu Andre va
Blum
Jean (Phap) [182] da chung minh dieu dd.
Trong tap
chi
"M. S. bio acti
rela"
6-12/1990 [61] cd gidi thieu them mpt tac dung
sinh nua
ciia
eugenol, dd la kha nang lam tan cue mau ddng. Dae biet gan day

Kaempgen
Dieter
ndi den kha nang chua benh AIDE
ciia
hon hgp eugenol va
isoeugenol [50]. Dd la nhung tich chat quy gia ma chiing ta cd the khai thac. Tuy nhien
<iho
den nay chua cd nhieu cac dan xuat dugc dieu che nham uc che cac nam benh.
Nhin chung, nhung dan xuat eugenol dugc ban tong hgp cho den nay vdi muc
dich
con
rdl
rac chua dinh hudng.
0-2, Van de nam benh
6-
cac
nu'd'c
co
khi
hau nong am va
6*
Viet Nam
A - Benh ngoai da {da lieu)
Phan Idn cac benh ngoai da gay ra bdi eac dang nam ky sinh
thue
vat, cac loai
nam nay thich nghi va phat trien tren cac cho san
ciia
da.
Cac benh ngoai da d rgc gay ra bdi cac loai vi trung va nam khac nhau dugc gpi

la cac benh da lieu [152, 159].
O
cac nude cd
khi
hau ndng am benh da
lieu
de cd
dieu kien phat trien.
6*
Viet nam bac si Nguyen Thi Dao [103] khi nghien cuu cac benh pham
ciia
1636
benh nhan da thong ke dugc cac dang nam nhu sau: Trichophytn rubrum 56,6%,
Trichophyton violaceum 5,5%, Trichophyton mentagrophytes
1,45%,
Trichophyton
interaigitale 3,3%, Epidermaphyton floscosum 3,2%, Microsporum feragineum 1,4%,
Candida albicans 24,0%, Sporotricum schenskii
1,15%,
Blastomyces dermatitis 0,06%.
Bac si Nguyen Xuan Hien [104] tu benh pham
ciia 512
quan nhan da cd cac sd
lieu thdng ke nhu sau: Trichophyton rubrum 54%, Trichophyton mentagrophytes
26%,
Candida albicans 9,4%.
Benh nam d cac
nude
Ddng Nam A cung dugc bac sT Do Thi Thuan
[131]

nghien
cuu ky nam 1973 tai phong thi nghiem
thii
y Sai Gdn.
(y
cac nude Ddng Au nhu Bungaria nhieu loai nam benh ngoai da cung phat
trien [153, 154, 155]. Loai nam pho bien nhat d Bungaria la Epidermaphyton
floscosum
[152].
Nam 1970 bac si I. Gruzozov [156] da phan lap tu 100 benh nhan ed
cac loai nam nhu sau:
Trichophyto rubrum 57%, Candida albicans 32%, Trichophyton interdigitel 6%
va Trichophyton mentagrophytes 5% [159, 160].
B.
Nhitng
nhom chat khdng sinh chinh [183]
1.
De nghien cuu cau
true
va ca che tac dung
ciia
eac chat khang sinh, ngudi ta da
phai khao sat ti mi tu cau tnic
ciia
vach te bao vi khuan (vi khuan gam am, vi khuan
gam duang) den cau triic
ciia
vach
ciia
cac loai nam benh (thanh phan hda hpc va kha

nang pha vd cac vach ).
Ket qua dudi day cho ta thay mpt each tong quan ve cac thanh phan dac trung
cho cac khuan nam.
Khuan gam duang: - peptidoglycan (murein)
- axit teichoic (hoac teiehuronic)
-
oligo
hoac polysaccharld
Khuan gam am: - peptidoglycan (ty le nhd)
- protein
- lipid Lien ket bang lipoprotein
- poly saccharid hoac lipopoly saccharid
- peptidogylcan
-
glicolipid
polysaccharld chua arabinose va galactose
- peptidoglycan
- ddi khi cd ca protein
- carotenoid
Trung ran va trung vet xam:
- peptidogluean va cac thanh phan khac
Ve mat hda hpc, de nghien cuu ban chat khang sinh ngudi ta con dung su phan
loai theo thanh phan tao nen chiing nhu sau:
1-
Chat khang sinh cd the dong hda cac lipid
2-
Chat khang sinh ban chat ozidic, cd the ddng hda cac holosid va heterozid
3-
Chat khang sinh thuoc nhdm protid
Khuan nam:

Tao
xanh:
4-
Chat khang sinh ban chat nucleotidic hoac cd hp hang vdi cac baza puric, hoac
thupe loai nucleozid, hoac tao thanh bdi
sy
lien hgp
ciia
nucleozid vdi eac
chat khac
5-
Chat khang sinh vdi nhan tham ngung ket
6- Chat khang sinh vdi di vong nita
7-
Chat khang sinh chua cac dan xuat oxy hda
ciia
nita
8- Chat khang sinh chua cac dan xuat
ciia
glutarimid
9- Chat khang sinh vdi di vong oxi
10-
Chat khang sinh vdi phan tu lugng nhd, dan xuat tu cyclopentan hoac
cyclohexan
11-
Chat khang sinh chua do
12-
Chat khang sinh chua luu huynh
13-
Chat khang sinh chua brom

ho$c
photpho
14-
Chat khang sinh chua mpt kim loai
Trong tai lieu Antibiotiques [179] G. Hagemann da cho biet cac so lieu ve cac
chat khang sinh dugc phan lap trong nam 1962, phan loai theo ban chat cac nguyen td
cd mat trong chiing nhu sau:
CHO
(C5H4O2
tdi
C48H60O16)
CHON
(C3H4ON2
tdi
C74H106O14N4)
CHOCI (C7Hi207Ci2tdi C27H40C16CI)
CHONCl (CiiH703NCl2tdi C22H23O8N2CI)
CHONS
(C7H6O2N2S2
tdi
C6H107O18N17S)
CHONSFe
(C4oH6i02oNioSFe)
2.
Cac chat khang sinh cd ban chat tecpen
Mpt so khang sinh dugc
s^n
xuat bdi nam cd phan tu hoac mpt phan
ciia
phan tu

da mo ta
83
198
10
3
28
1
da sic dung
0
24
1
2
3
3
dugc tao ra bdi mpt ehuoi eac dan vi isopren nhu:
a- Moenocinol:
CH2OH
b- Fumagilline: cd cdng thue (b), dugc dung cho ngudi de chong lai amfp
rudt,
hai dpc (LD50 800 mg/kg - theo dudng dudi da chupt)
CH3
\CO-(CH=CH)^-COOH
(b)
c- Trichodermine (c): la mpt khang nam sinh chong nam va la dai dien dan gian
nhat cua ca nhdm khang sinh secquiterpen - trong so nay cd the ke tdi
crotocine
(d)
chiet suat tu caphalosporium crotocinigenum va rocridine A (e) chiet suat tu
myrothecium roridum.
CK-CHOH

CO-CH-CH-CH
d- Chat khang sinh tritecpen tetracyclic
Ba chat sau day co hoat tinh khang sinh chu yeu doi vai cac khuan gam duang
nhu Stap hy lococus aureus,
Corynebacterium
diptheriae,
Clostridium tetani:
1-
Axit helvolic (f)
dugc
chiet suat tu
Aspergillus
f umigatus var. helvola.
2-
Cephalosparine
Pi
(g) dugc chiet suat tu
Cephalosporium
synnamatum.
3-
Axit fusidic (h) dugc chiet suat tir Fusidium coccineum.
(f)
COOH
CH3
O -CO-CH3
HO
OH
HO
-
H

(h)
H
O
CH3O
COOH
CO-CH3 (g)
(i)
10
Cephalosporine manh han axit nelvonic 5 lan. Con axit fusidic lai manh han
cephalosporine
Pi
tdi 10 lan. Cae chat khang sinh nay cd tac dung tdi khuan gam
duang d nong dp tu
0,02//g/ml
-
0,2/^g/ml,
ddi vdi khuan
M.
tuberculosis thi ndng dp
1
/ig/ml
(chiing ft dpc LD50 200 mg/kg dudng ven chupt).
e- Viridine (i): Viridine la chat chong nam, chiet suat tu Gliodadium virens va
Trichoderma viride. Viridine cd tac dung chdng nam tot, song rat dpc ddi vdi ngudi
(LD50 < 5 mg/kg) nhung cd the diing cho cac benh thue vat.
Nhirng chat co
iac
dung khang nam C. albicans
Cac tac gia My Erie J. Lien va Corwin Hansch [24] khi nghien cuu
tinh

chat
khang nam
ciia
han 560 chat da nhan thay nhung kieu chat sau day cd tac dung doi
vdi nam
C
albicans
&
muc dd khac nhau:
HOC6H4COOOR
ArNCS;
RCOO";
PHCH2N(CH3)2Cl
XPhHN
N
NHPhX
Br
OH
R
OH
X-PhNHCH2-/^'
Van de ca che tac dung
ciia
chat khang nam sinh len nam da thu
hiit
su
ehii
y
ciia
rat nhieu nha nghien cuu. Hp da dua ra nhieu giai thich

thii
vi song thue ra cho den
nay van de nay van cdn chua giai quyet tudng tan, vi vay trong
luan
an nay tac gia
khdng cd tham vpng di sau vao ca che tac dung
ciia
che pham thuoc len nam ma chi
11
nghien
cii'u
vai trd cac nhdm chuc va vi trf cac nhdm the trong phan tu eugenol len
tac dung khang nam C.albicans, nham tim ra mot che pham ed hieu qua tac dung cao
cd the su dung vao lam sang,
0.3 . Van de tong
ho-p
noi chung va
su*
tong
ho'p
co dinh
hirdng
Vao nhung nam cuoi
ciia
the ky 19, ly thuyet cau tao hda hpc sang lap bdi A. M.
Butlerov
nam 1861 la mpt cudc
each
mang trong hda hpc,
ciing

vdi true giac la lung
ciia
Van T. Hoff va
Lebel
(1874) ve hudng hda tri
ciia
cacbon theo hinh tu dien da lam
sang chdi mpt giai doan
ci
a tong hgp hu-u cu*. Vdi nhung thanh cdng
ciia
C. Graebe va
C. Liebermann da tong hgp dugc alizarin nam 1869. A. Baeyer tong hgp dugc indigo
nam 1883. E. Fisher tong hgp dugc Cafein nam 1883 va A. Pictet da tong hgp thanh
cdng nicotine nam 1904. Dac biet vdi su tong hgp thanh cdng cac dudng, peptidva
tanin
ciia
F. Fisher, da ket
thiic
giai doan rue ra nay, de chuyen sang mpt thdi ky tien
bp
Idn,
do la thdi ky phat trien tong hgp
hiru
ca va tong hgp cac hgp chat tu nhien lien
quan den khai niem sinh tong hgp. Nam 1917 R. Robinson thue hien thanh cdng tong
hgp tropinon tu andehit
suxcinic,
metylamin va axit axetodicacbonic. Su tong hgp nay
trong mpt thdi gian dai da la mau muc cho mpi ngudi.

Dii
vay, cho den thdi ky nay cd
the ndi rang, dudng hudng tong hgp van mang nhieu
tinh
chat ngau nhien, may
riii
va
'
rdi rac.
Nhung nam 40
ciia
the ky 20 da md ra nhung
bude
tien mdi trong hda hpc huu
ca, bat dau bang nhung thanh tuu ve hda huu ca ly thuyet va hda ly thuyet, nhu ve ca
che phan ung, ve cac tieu phan trung gian khdng ben vung (Caebocation, Cacbanion,
cac goc, eac arin ), ve phan tfch cau hinh, ve hda lugng tu thi viec tong hgp huu
ca da ed nhieu thanh cdng mdi.
Den nam 1956 nha khoa hpc dugc giai thudng Noben R. B. Woodward da nhan
manh den vai trd
eiia
quy hoach cd y thue trong
linh
vuc tong hgp hu-u ca bdi le
thuoc thdng thudng can tong hgp khoang 5000 - 7000 chat mdi, mdi cd dugc mpt chat
12
dung
dupfc
vao dieu tri, do do con ngudi
ludn

mong mudn
tim
ra con dudng ngdn han
nhat de di den dich. Tuf dd hudng quy hoach trong
thi
nghiem duac nhac tdi nhieu.
Dac biet van de da
duoc dt
cap den trong quyen
"
Quy hoach hprp ly trong tong hop
him ca
phu:c
tap
" ciia
O.S. Chizov va A.O Chizov
[149].
Trong tai
lieu
nay cac tac
gia da de cap den tong
hpfp ly
tudng. Trong
tdng
hop
ly
tudng cd the cd hai trudng
hop : Tong hpfp hap ly va tong hop phi ly. Tong hop
hofp
ly cd the coi

la
nhiing tong
hap da trd thanh khudn
mSu,
cdn tong
hgrp
"phi
ly"
dupfc hinh thanh nhd cd su sang
tao trong suy
nghi
cua nha
thi
nghiem va quy tac chung de quy hoach tong hpfp
la
bat dau tuf phan
tich
cau tao phan tuf
cha't
c^n
tong hpfp, cd
nghia la
chpn phan tu can
tong hpfp, rdi xem xet cac con dudng hoac each thiic de tong hpfp dupfc chat dd. Tu dd
din den viec thanh
Iap(md
hinh) bieu dd tong hpfp .( Md
hinh
) bieu dd tong hpfp nay
cd cac nhanh - van de

la
bat dau tuf nhanh nao, hay ndi
each
khac la nen
lua
chpn quy
hoach tong hpfp nao cd trien vpng nhat, bat dau ttf
nhOtig
tieu
chudn
chung nhat. Viec
danh gia hieu qua cung duac dat ra va mot nha nghien
cihi
ngudi My la
S.Bers
da su
dung dinh
ly
bieu dd di danh gia hieu qua - nhung chinh tac gia
ciing
chua viifa
ij
vdi
each
danh gia nay .
Cd the ndi rang cho den giiia
th6'
ky nay viec quy hoach tong hpfp tim
kiem
nhutig

che
phim
mdi vSn cdn nhieu han che. Mai den sau nam 1960 khi ma cac
nganh khoa hpc phat trien mpt budc dai, dac biet
la
cac nganh dien tu, tin hpc,va su
su£t
hien nhung mdn khoa hpc
lien
nganh mdi nhu khoa hpc ve" mdi
lien
quan
gifia
cau tnic hoa hpc va tac dung sinh vat hpc" [30,32] thi viec tong hpfp hoa hoc da mang
mpt mau sac mdi. Dd la viec tong hpfp hoa hpc cd dinh hudng. Su tong hpfp cd dinh
hudng
la sa
tong hop chat mdi theo mpt chien
luac
tim
ki6m,
theo mpt muc tieu de ra
trudc,
tac dung da dinh sin, ke hoach cu the de tien hanh. Ngudi nghien cuu biet
rd can phai thay ddi cau tnic nhu the nao, thay doi nhdm the nao, d vi tri
nao va can tong hpfp bao nhieu din chat mdi de cd the tim ra duac mot
chat mdi cd tac dung cao hon ca theo tac dung da dinh trudc,
ching
nhirn*^
xac dinh duac chat cd tac dung tot nhat ma cdn cd the du doan duac chat

13
cd tac dung tot hon nua, du rang chat dd cdn chua
dupe
tong hpp. Tat ca nhung
dieu dd lam cho viec nghien cuu khoa hpc kinh te hon, tiet kiem dupe dung mdi
hda chat, thdi gian va cdng
sue
nhieu hon. Tat ca
nhQng
dieu ndi tren
thue
hien
dupe nhd su dung cac
md
hinh toan nghien
ciiu
mdi lien quan dinh
ludng
giua
eau
true
hda hpc va tac dung sinh vat hpc (QSAR)- [72, 78, 100, 101, 103, 148]
:
Cdng trinh nghien cuu
ciia
chiing tdi nam trong hudng phat trien nay
0.4 Van
de
moi lien quan giua cau triic hoa hpc va tac dung sinh hpc
Thue ra kha

nfmg
thiet lap mdi lien quan giua ca
' true
hoa hpc va tac
dung sinh hoc da
dupe
de cap gan 100 nam trudc, khi ma ngudi ta phat hien
ra rang luc tac dung gay me
eiia
eac chat thuoc giam cung vdi su tang len dp
hoa tan
eiia
chung d trong
nude.
It
ifiu
sau, mdi lien quan
giOa
kha nang gay
me va su phan bo eac chat trong he thdng nude
-
lipid.cung
dupe
phat hien.
Tiep sau dd, toan bd day cae thdng sd hda ly cua cac chat cd lien quan den tac
dung gay me va dpc tinh tang len cung da dupe thiet lap va dupe mo ta bdi
H.B.
JIasapeB
[137].
Mac du cdn han che va cdn mang tinh chat djnh tinh, da so nhung phat

hien tren, trong
niia
dau the ky 20 ed the coi !a nhung tong ket ngan gpn lam nen
tang eho viec nghien
ciiu
van de cau true - tac dung.
Trong khoang 30 nam trd lai day, van de cau true - tac dung da phat trien
theo chieu hudng hien dai tren co sd cua nhung nguyen ly.
ciia
hda huu eo ly
thuyet, hda ly ly thuyet va toan hpe[l,-36,
79,
96]. [44]
Nhung tien de chung
nhfit
cua chieu hudng nay cd the
dupe
ke ra sau
day
[141]:
1-
Criu
true
S cua hpp chat hda hoc Y, ky hieu la Sy ed the
dupe
bieu thi
qua 1 bp (tap) cac thdng sd cau
true
nao dd:
Sy

= JS/'I trong ddi=
l,2,3, ,n.
(i)
2-
Ton tai mdi quan he giua cau
true
hpp chat va tac dung sinh hpc
ciia
14
no,
tiic la
ton tai mpt ham Fy(AySy) nao dd lien quan tac dung A
ciia
chit Y vdi eiu
triie
Sy, hoac la vdi dac trung rieng re
ciia
cau true dd -
Fy(S/,Ay).
3-
Neu dang cua ham so F(S,A) dupe thiet lap thi ham nay cd the dupe
ngoai suy ra eho diy hpp chat
Yi,
Y2,Y3,
cd eiu
triie
gidng nhau chi
khac nhau bdi cac nhdm the'
Xi,
X2, X3 hoac la bdi vi tri eac nhdm

the trong phan
tii.
4-
Tu su phan tich tap cac ham
Fyj
(Sy^
Ay^),
Fy^(Sy2,Ay2)
(2)
.
edthe phat hien
thii
tu tac dung manh yeu
ciia
cac hpp chat. Vi du
Ax,i
>
Ax.2
>•"
cua mpt day cac hdp chat nao dd de ed
dupe
mpt md
hinh lam viec, tu dd de cd
dupe
mpt ham
F(S,A).
O day can
thi6t
phai
thu dupe A d dang dinh

lupng
[A]. Dai
lupng
[A] thudng
dupe
xac
dinh bdi cac thi nghiem sinh hpc.
N6u
cac dac trung hoa ly
ciia
cae
chit phan anh su bien ddi eiu triic eua chiing qua day cac thdng sd
ciia
chiing dupe
thue
hien thi quan he Fy (Sy,Ay) dupe thiet lap. Rd
rang rang nhiem vu
phiic
tap nhit de
thi6t
lap quan he ndi tren la
viec tham sd hoa [A].
[A]
la
sd do
Jinh
lupng eua tac dung sinh hpc. bieu thi bang ndng dp, va
[BR] la sd do dinh lupng hieu
ling
sinh hpc bieu thi bdi cae

ddn
vi (thi nghiem bit
ky nao).
Tii
nam 1965 - 1967 bat dau ndi
len
ten tudi eua ba nha khoa hoc My la
Free - Wilson [30] va Corwin Hansch va trudng phai
ciia
cac ong ve vin de
nghien
ciiu
QSAR [32] md hinh nghien
ciiu ciia
cac ong la nen tang eho mpi
nghien
ciiu
tiep theo. Mai den nam 1970 d Nhat mdi xuit hien ten tudi
eiia
A.Canmarate
[M],
Fugita
-
Ban [27]
,M.
Yoshinolo [102] - Nam
1974
nhdm
R.Franke [29] d Due va nhdm
I.Simiti,

LSchwratz [185]
va
J.Kopecky
[184] d
Rumani, Nam
1978
d Nga xuit hien nhdm
ciia
HHJKHHH
CB,
anmTewH
H.A.
15
[141]
va nhdm
eiia roneH6ep
B.E va
PoaeHd/iMT
A.B.
[135].
Ndi chung, van de nay cdn
rai
mdi ddi vdi eac nude Ddng Nam A va
vdi
nude
ta thi cang mdi me.
Ngay nay,
vice
nghien
ciiu ''Mui

lien quan
giCia cdu true lioa
hoc vd tac
dung
sinh
hoc''
da di vao djnh lupng cao nhd cae md hinh toan hpc va phuong
tien
may tinh dien tu, va mdn khoa hpc lien nganh nay da phat trien den muc hpi hda
hpc My
UPAC
eu 2 nam mot fan to
chiic
semina hoac
hpi
nghi khoa hpc ve
QSAR. Nam
1992
to chuc lan thu 11 tai Phap. Nam 1994 se td
chiic
tai Tay Ban
Nha.
De danh gia vin
de
nghien
ciiu
QSAR - Corwin Hansch ndi: "Trong viec
tim kiem che' tao ra mpt loai thudc mdi, Viec "may
riii"
ludn ddng mpt vai trd

nhit dinh". Tuy vay, viec
ling
dung quan he eiu triie - tac dung dinh lupng dang
sap xep lai chinh ndi dung eua nganh hda y.
0.5.
Nhiing md hinh toan hoc nghien cuu
vSn
de QSAR
Dudi day tdi xin gidi thieu nhiing net cd ban eua mpt sd cac md hinh toan
hoac phuong phap toan thudng dupe dung de nghien
eiiu
vin d6 mdi lien quan
giOa
"eiu triic - tac dung", va se gidi thieu ky hdn ve hai md hinh eua
Free-Willson
va
ciia
Corwin Hansch la hai md hinh
dupe sii
dung trong ban luan
an nay.
a)-Phurang
phap nhan dang
-pharang
phap phan tich cdu
triic
con
Ca hai giai phap nay dua tren gia
thi6t
rang tac dung sinh hpc cua vat

chit phu thupe vao su ed mat
nhOng
yeu to eiu true xac dinh
(eiu
triic con) trong
phan
til ciia
no.
Tan suit tac dung
ciia
mpt eiu true eon L dupe dac trung bdi su ddng gdp
eiu triic con nay vao xac xuit
ciia
su kien la hpp chit cd tac dung sinh hoc [20]
Ve tri sd tan xuit dd dUde bieu thi bang ty sd sd lupng cae chit cd tac
duns
sinh
hpc
chiia
mpt don vi cau triic xac dinh B. tren tong sd lupng cac hdp chit
dupe
16
tidn
hanh phan tich, ma trong
nhOng
hdp chit dd cd
ehiia
nhung
eiu
triic con

(T),
tiicla:
''- '
-f
(3)
Khi
sii
dung he mieu ta
ciia
su ma hda
tiing
manh [58] la he ed kha nang
phan biet 1.200 manh khac nhau eua eiu triie la cac nhdm chiic, eac chuoi chiic,
eac vong chuc v.v va 110 dang ket hdp khac nhau
ciia
chiing da de xuit dude
viec hinh
thiie
hda va mpt chudng trinh may tinh cho phep xac dinh L cho cac
hdp chat khac nhau kha
Idn
ve eiu tao hda ho
•
vdi mpt loai tac dung sinh hpc da
bi6t ed so sanh vdi cac hpp chit dupe dem ra phan tich.
b)-Gidi phap ve cdc lirang
tur
thong ke [55, 141].
De cd dude mpt md hinh tinh toan ngudi ta da dua nhiing gia thiet sau day:
1-

Trong mpt qua trinh nhieu giai doan,
tii liic
dua vat chit vao mpt he
sinh hpc tdi
liic
phan
ling
vdi bp nhan dan tdi mpt tac dung sinh hpc
thi sac xuit thue hien
ciia
mdi mpt giai doan khdng phu thuoc vao cac
giai doan khac.
2-
Cac chit dat tdi ndi nhan nhd mpt chuyen dpng tudng tu nhu chuyen
ddng Brown.
3-
Cac vi tri
ciia
phan
ling
la eac nguyen
tii
rieng re da
dupe
dinh vi.
4-
Su lien ket
ciia
chit cd tac dung sinh hpc d mpt bp nhan hoac mpt
nhdm bd nhan khdng phu thupe vao su lien ket

ciia
chit dd d nhung
noi cdn lai.
Theo nhung gia thiet
dd,phuong
trinh xuit phat ed the bieu thi d dang:
d[BR]
dt
= kCopip2
(4)
Trong dd:
k
la
he sd ti le
Co
la ndng dp ban dau cua chit
pi
sac xuit hoan thanh giai doan dua chit tdi bp nhan
p2
sac xuit lien ket
ciia
chit
vdi
bp nhan
17
-cjiOii
T
1
:
*.

J^'*
tiep dd gia thiet rang,
pi
bien ddi mpt
each
kha ddi
xiing
ddi vdi thdng sd
.T,
tiic
la
ddi vdi tinh thim lipid do su xuyen qua
ciia
vat chit qua mang sinh hpc ; cdn
p2
bien doi mpt each kha ddi
xiing
vdi su hip phu
ciia
vat chit ndi nhan hoac d
nhOng
ndi khac trong cd the. Neu gia
thi6t
la su lien
k6t ciia
vat chit vdi bd phan
xay ra tai cac vi tri khac nhau trong cd the theo quan diem nang lupng, thi sac
xuit
P2
can phai phu thupe hoan toan vao trang thai dien tu eua cae nguyen

tii di the eua vat chit
dupe
hip phu. Ddi vdi giai phap nay cdn ehua cd nhieu sd
Heu
de tin cay. Ngay nay mdi chi cd the udc lupng dupe tinh uu viet ve nguyen tic
ciia
phuong
phaj
ma thdi, dd la
n.iCfng
thdng sd can thiet nhu tinh thim lipid , sd
sdng
ciia
cac nhdm phan
ling
dupe
de
xuit nghien
ciiu,
ed the la kha
d^
dang xac
dinh dude bang thue nghiem,
c)
Ifng
dung phan tich nhan td de tim hieu quan he cdu
true ~tdc
dung
De cd the giai bai toan ve mdi lien quan giiia eiu triic - tac dung mpt
each chat che thi can thiet phai xet tdi tit ca mpi qua trinh sinh ly cd the cd va

gan cac qua trinh nay vdi mpi td hpp eac thdng sd hda
ly
dac trung hoac xac dinh
tiing
giai doan
eiia
su tuong tac cua vat chit.
Ve mat hinh
thiic,
su phan tich nhan td toan hpc ed the
dupe
ap dung vao
bit ky mpt bai toan
phiic
tap nhieu chieu nao, neu nhu bai toan dd cd the bieu
thi dudi dang tong
ciia
cac ham sd lien he tuong hd
ciia
mpt sd bien sd nao dd,
nghia la d dang:
m
P (i,k)
= 2 U(i,j) V(j,k)
(5)
trong dd
P(i,k)
la tinh chit dupe do eua he d trudng hdp
thii
i khi bien

ddi k ;
U(i,j)
la nhan td j eua trudng hdp i ; V(j,k) la nhan td bien thien j
ciia
b\6n
sd da cho k. Tong dupe
liy
theo mpi nhan td j la
nhOng
nhan td
dupe
xem la quan
trpng. Trudng hpp rieng cua mdi lien quan eiu triic - tac dung ma ta quan tam la:
18