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 nha
Trang 1BO 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 D A N XUAT EUGENOL CO TAC DUNG KHANG NAM C ALBICANS
LUAN AN TIEN St KHOA HOC HOA HOC
Trang 2MUC 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
Trang 3h- 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
Trang 43-2 Ban tong hop cac dan xuat eugenol 55
3-2-1 Nhu*ng phan trng ca ban lam thay doi nhom chuc alyl
3-2-1-5 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
Trang 5a- 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 d i n 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 I l l
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
Trang 6121
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
Trang 7Chuang 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
Trang 8Phan 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 h p c ' 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
Trang 9su* 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
Trang 10lugng 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
Trang 11PHAN TONG QUAN
0-1 Cac dan xuat eugenol duo'c biet den nay
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
Trang 12khi 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
Trang 13<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]
Trang 14B 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
- 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:
Trang 154- 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 d o
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
Trang 16dugc 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
Trang 17d- 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
Trang 18Cephalosporine 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:
Trang 19nghien 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
Trang 20dung 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
Trang 21cd 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 = J S / ' I trong d d i = l,2,3, ,n ( i )
2- Ton tai mdi quan he giua cau true hpp chat va tac dung sinh hpc ciia
Trang 22no, 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 p h a t 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 b i t
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
Trang 23[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 h i n h toan hoc n g h i e n 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
Trang 24tidn hanh phan tich, ma trong nhOng hdp chit dd cd ehiia nhung eiu triic con (T), tiicla: ''- '
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]
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
Trang 25tiep dd gia thiet rang, pi bien ddi mpt each kha ddi xiing ddi vdi thdng sd T, tiic la ddi vdi tinh t h i m lipid do su xuyen qua ciia vat chit qua mang sinh hpc ; cdn p2 bien doi mpt each kha ddi xiing vdi su h i p 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 t i c 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 t i t 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
b i t 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:
Trang 26[A](i,k) = 2 D(i,j) H(j,k) (6)
Trong dd [A](i,k) la tac dung sinh hpc thii k do dupe ciia vat c h i t i;
D(i, j) la tinh chit j (hda hoac hda ly) ciia hdp chit i; H(i,j) la thdng s6 j (sinh ly)
eua tac dung sinh hpc k; Tong dupe liy theo mpi thdng sd dpc lap j Nhiing thdng
sd nay la can thiet de tinh toan cac ket qua thi nghiem
Sd hang [A](i,j) ed the dude do dem bang thue nghiem nhu la mpt tac
dung sinh hpc xuit hien d trudng hdp thii k nao dd, cdn sd hang H(j,k) thi lai hen
he 1 thdng sd sinh ly b i t ky nao dd cua vat chit va vdi dai lupng [A], nen phudng
phap phan tich nhan td cd the dupe sir dung de du bao tinh ddn tri eua vat chit
dupe thir nghiem hoac chi ra tap hpp cae tinh chit quyet dinh tac dung cd ich eao
nhit vdi eac hieu ifng phu bit Ipi nhd nhit
d) Cdc phwang phap nura thurc nghiem de nghien curu ca che cdc phan
lirng ctia cdc chat co tac dung sinh hoc [25]
Ngoai viec lua chpn ra eac hpp chit tdt nhit, trong k6t qua cua su phan
tich mdi lien quan eiu triie tac dung, ngudi ta cdn mong mudn thu dupe su hieu
biet ve cd che tac dung sinh hpc eiia chiing
Tren cd sd eiia thdng tin thu dupe bang con dudng thue nghiem^cd the de
xuit mpt md hinh gan diing cua tac dung sinh hpc eua eac chit, md hinh nay can
dupe kiem nghiem va chinh xac them bang nhOng thi nghiem bd sung Vi rang su
thiet lap thue nghiem kieu quan he :"Vat chit - bp nhan" la khd khan cho mdi
lien he dd, da cd kien nghi su dung bie'n ddi toan phan ciia nang lupng ( A E ) xay
ra khi tao cac phuc chit "vat chit - bd nhan"
trong dd AG = AE + const
Dai lupng AE la tong sd eiia eac phan ddng gdp dpc lap ciia dien til (AE*^),
eua su solvat hoa (AE ), cua lap the (AE'^) va eiia eiu hinh (AE*^) la cac thanh
Trang 27phan eiia su bien đi nang lupng Gia thiet nay dap ling quan he tuyen tinh ciia cac nang lupng tu dọ Bai toan tiep theola bieu thi cac phan đng gdp khac nhau AÉ qua cae dai ludng thue nghiem hoac tinh toan Vi du de tinh toan AÊ, diing
ly thuyet nhi^u ta dupe:
AE =S ^ E r s = S 2 i^-p^ +11-T^ ^ ^ ; - (8)
Trong đ Ers: nang lupng dien tii ciia tudng tac cae nguyen tii r va s
Qr va Qs la tong dien tich ciia nguyen til r va s tudng ung Drs - hang sd
dien mdi ciia mdi trudng Em - En la hieu sd nang lupng giifa qui dao phan til miic eao nhit (HOMO) eiia bd nhan'vdi mue tu do t h i p nhit (LUMO) cua chat, ^ la
tich phan trao đi xet tdi tudng tac giiia (MO); Cmr va Cns la he sd qui dao nguyen til (AO) khi đ, mdi mpt cap nguyen til tudng tac nhau til mpt phan tii eua hpp chit (s) va bp nhan (r) dupe xem nhu cd cae phan đng gdp dpc lap nhau va AỆ
De xac dinh tac dung sinh hpc, ed lien quan den "bp nhan" la nhiing kha nang rd rang bi han che bdi tinh phuc tap cua no, cho nen cd the thiy rang eac nguyen ly dat nen mdng cho phudng phap nay cd the chi ed hieu qua Idn rieng de giai thich cd ché cua su tao thanh cac phiic chit "vat chit - bp nhan" [25]
e) Phurang phap hoi qui nhieu thong sd
Cac mdi lien he dinh tinh dupe xac lap giira tac dung sinh hoc va cac tinh chit hda ly eiia vat chit da kich thich viec thiet lap eac cdng trinh de hieu rd ban chit eua cac mdi lien he đ Thii nghiem dau tien ciia loai phuong phap hoi qui
nhieu thdng sd la mo Iiinh phan hd cdn bdng [141] Md hinh nay dua tren gia thiét
rang sau khi dua vat chit vao mpt he sinh hpc, thi giua ndng dp eiia chit tai ndi dupe dua vao va ndng dp d gan ndi phan irng dupe thiet lap mot can bang hda hpc Can bang nay dup c xac dinh bdi ding thire eiia cac the nang hda hpc ( / / ) ciia vat chit d cae pha khac nhaụ O cae ndng dp thap:
Trang 28A =/io + R T l n C (9)
Tu dd khi so sanh i-i eiia pha lipid va pha nude va khi gia thiet
Clip = const, ta cd the thu dupe lien he giQa ig ( ^) va he sd phan bd vat chat
trong he sinh hpc {?d) Cd the thay ?d bang P eiia 1 he md hinh (vi du dau olive
-nude; oetanol - nude)
/^ ( - ^ ) = a l g P + b (10)
Trong phuong trinh tren thay eho IgP ed the diing cac thdng sd hda ly
khcic ciia vat chat nhu parachor (Pr), the tich phan til (Vm), tinh hda tan (IgCs)
Tinh han che ciia md hinh phan bd can bang nay la hien nhien bdi vi
trong md hinh nay khdng dupe xet tdi ca ddng hpc ciia su thiet lap trang thai can
bang troing he, lan ca co che ciia nhung phan ung hda hpc xay ra trong he
Trong nhieu cdng trinh khac nhau ngudi ta dua them vao rat nhieu cac
thdng sd hda ly khac nhau nhu hang sd Hammet 6, hang sd lap the Taft, ban kinh
Van der Waals, eac hang sd dien til, hang so chuyen dien tich C j , mdmen ludng
c u e / ^ cac sd lieu pho ky cac thdng sd hda lupng til v.v t i t ca deu nham mue
dich giai quyet van de eau true - tac dung, mdi phuong phap deu ed uu diem
song van cdn nhung nhupc diem rieng eiia nd
Khi theo rdi nhieu cdng trinh ve vin de nay, thiy rang nhieu tac gia da sii
dung nhieu dac trung hda ly khac nhau de nghien ciiu mdi lien quan vdi eac tac
dung sinh hpc Mpt sd vi du dupe din ra d bang 1:
Trang 29// =/io + RTlnC (9)
Tii dd khi so sanh fi eiia pha lipid va pha n u d e va khi gia thiet
Clip = const, ta cd the thu dupe lien he giaa Ig (—r-) va he sd phan bd vat chit
trong he sinh hpc (P<3) Cd the thay ?d bang P ciia 1 he md hinh (vi du dau olive
-nude; oetanol - nude)
Ig ( - ^ ) = a l g P + b (10)
Trong phudng trinh tren thay cho IgP cd the diing cac thdng sd hda ly
khac eiia vat chat nhu parachor (Pr), the tich phan til (Vm), tinh hda tan (IgCs)
Tinh han che ciia md hinh phan bd can bang nay la hien nhien bdi vi
trong md hinh nay khdng dupe xet tdi ca ddng hpc eiia su thiet lap trang thai can
bang trojig he, lin ca ed che eiia nhiing phan ung hda hpc xay ra trong he
Trong nhieu cdng trinh khac nhau ngudi ta dua them vao rat nhieu cac
thdng sd hda ly khac nhau nhu hang sd Hammet t5, hang sd lap the Taft, ban kinh
Van der Waals, eac hang sd dien tii, hang sd chuyen dien tich C T , mdmen ludng
cuc/^, cac sd lieu pho ky eac thdng sd hda lupng tii v.v, t i t ca deu nham muc
dich giai quyet vin de eau true - tac dung, mdi phuong phap deu ed uu diem
song van cdn nhOng nhupc diem rieng eiia nd
Khi theo rdi nhieu cdng trinh ve van de nay, thay rang nhieu tac gia da sii
dung nhieu dac trung hda ly khac nhau de nghien ciiu mdi lien quan vdi eac tac
dung sinh hpc Mot sd vi du dupe dan ra d bang 1:
Trang 30Bdng LL: 22 dac trirng hoa ly ciia phan tir thudc
CO tac dung khdng khudn vd khdng nam
Tham sd ua nude "^ •
Tham sd SKLM, Rf
Parachor, Pr (g^'^^cm^/s^^^mol)
The tich moi VM(cm~Vmol )
Dp lien ket phan tii XM
Logarit dp hda tan trong nude
LgCs (mol/l)
Hang sd Hammet
Hang sd cam ung Taft
Hang sd the gdco^ E R
Su bien ddi hang sd ion hda 4)ka
-1 Phan cue dien moi PE(cm /moi)
The cue nua sdng ^ (v)
Tham sd lap the Taft Es
Ban kinh Van der Waals
Tan sd dao dpng v (s) chi sd
sdng W (cm' )
Dien tich tong electron cua
nguyen tu r, qr hay £(c)
Sd lupng cac cdng trinh ed tac dung dupe ly
5 [37,38,40,53] [40,66,33,22,93] [93,62.54,3} [54,3,62] [62,19] [51]
[62] [56,12,57,97] [57,97,81] [37,7] [26,63,59,28] [13,39] [53] [34,35] [15]
[82]
[40,14]
Trang 31Nang lupng quy dao phan tii muc
cao va mire thip EB30 va EHCO (eV)
Hang sd tich dien E va phdng
dien N
Chi sd hda tri tu do Fr
He sd quy dao nguyen tu r Cr
gl Phan tich cdu triic tac dung theo phurang phap Hansch [148, 141]
Trong vong 30 nam trd lai day, nhdm nghien cuu ciia Corwin Hansch da
sii dung cac hang sd nhdm the vdi viec su dung phan tich thdng ke tren may tinh
de thiet lap mpt danh sach eac hang sd thich hpp va mpt rod hinh toan cua quan
he eiu true - tac dung dinh lupng (QSAR),trong giai phap nay tien de cd sd cua
C.Hansch la quan he sau day:
Phan ung sinh hpc A= f (AEI + AE2 + AEn) (11) Theo phudng trinh nay thi su bi6n ddi eua tac dung sinh hpc khi ed su
thay ddi eiu true hda hpc eua chit ban dau dupe xem xet cd the dupe tinh ra til
su bien ddi cua mpt sd thdng sd hda ly nao dd Ei, E2, , En Ndi each khac khi
dua vao mpt nhdm the, thi chit ban dau dd se cd nhiing thay ddi ve su phan bd
dien tir, ve tinh ky nude va ve nhiing tinh chit lap the Til su phan tich nhiing
bien ddi eua tac dung sinh hpc cua mpt loat cac hdp chit ciing hp, se cd the tim
ra dupe nhOng tinh chit Ei, E2, En nao dd ddng vai trd quan trpng trong viec
lam xuit hien tac dung sinh hpc dude quan sat thiy dd
V i n de dat ra la tim ra nhOng gia tri tUdng ung ciia cac tinh chit Ei
E2,- En tii nhung sd lieu thu dupe tren cac he md hinh Cho den nay, nhuniz
Trang 32thdng sd hda ly da dupe nhdm C-Hansch nghien cuu chi tiet hdn ca la nhiing
thdng sd sau day: ' thdng so ki nu'd'c (:T:hoac Ig P), thdng so dien tir CT, thdng so lap
the Taft E s ; tiang so khiic xa phan tii- MR, hang sd hieu irng dp \&n nhdm the Rm,
moment lu'dug lire \L, hang so phan ra f, hang so nhdm the goc E R
-Phudng trinh sau day bieu thi tong quat nhit ciia mdi quan he nang lupng
tu do do Hansch dua ra ddi vdi tudng quan tac dung sinh hpc vdi eac thdng sd
hda ly
Ig — = - kiJT- + k2.jT+ kya 4- K^Es + K5 C^^)
d day Ig — la phan ung sinh hpc bieu thi b ng logarit cua nghich dao ndng dp
phan til eiia chit thudc dua vao trong co the, gay ra phan ung sinh hpc
p la hang sd the ky nude, xac dinh bdi ding thue
^ = IgPx- I g P (13) JgPx 1^ logarit hang sd phan tan dung mdi/nude cua mot hdp chit the,
cdn Ig P la cua hdp chit khdng the (hang so jrphan anh su tham gia cua nhdm
the vao su tao thanh lien k6t ky nude Pr.R
0 la hang sd the' Hammett va phan anh anh hudng eua cac hieu ung dien
til cam ung va lien hpp cua eac nhdm the tren hang sd toe dp kx cua phan ung xac
dinh tdc dp
Es la hang sd lap the Taft, phan anh su bien ddi eua cae hieu ung khdng
gian gay ra bdi nhdm the
Ki,2,.,5 la he sd eiia phuong trinh
Cae trudng hpp eu the ciia he thue Hansch thudng gap trong thue t6 la [185]:
Ig 1/C = k2^+ K5 (14)
Ig 1/C = K2^+ K3a+ Ks (15)
hoac ig 1/C = - KiTT- + K2;T-h Ks (16)
hoac Jg 1/C = K[n- KiJi" + K3(;+ K4Es + Ks (17)
Phudng phap Hansch dupe diing de bieu thi tac dung sinh hoc ciia dav
Trang 33cae hdp chit ciing hp dudi dang mpt ham sd ciia cae thdng sd hda ly dac trung cho eiu true ciia cac hdp chit dd Tinh quan trpng tuong ddi eua viec xet tdi eac thdng sd dd de mieu ta tac dung sinh hpc trudc dd ehua dude biet ddn, dieu dd budc ta phai thii nghiem mpt loat cae phuong trinh md hinh chira cac td hdp khac nhau cua cac thdng sd Cae phudng trinh dd thudude nhd su phan tich hoi qui sau dd tien hanh viec chpn ra mpt phu ong trinh md hinh tdt n h i t frong chung tren cd sd tinh cd nghia ciia eac he sd hoi qui Viec nay dupe kien nghi theo diing
1 sd qui tac sau day [95, 181]:
1 Can xem xet mpt sd lupng Id i cd the cac thdn^g sd dpc lap
2- Cac thdng sd dupe xem xet tren day, theo qui dinh la eac dai ludng tich phan (tuc dai ludng tong) dac trung mpt each toan the cho cac tinh chit phan til, vi the' giua chiing ton tai mpt lien he lin nhau xac
dinh (De dac trung eho su vang mat ciia mdi quan he giiia cac thdng
sd hda ly, ta dung cac he sd tudng quan ' ' r, dupe xac dinh nhu cac dai lupng khdng thu nguyen, bien ddi trong pham vi - 1 ^r ^1 -
r cang gan sd 0 thi eac thdng sd hda ly tudng ung cang khdng phu thudc gi vao nhau),
3- Sau khi nghien cuu sd bd cae phudng an ed the cua td hdp eac thdng
sd va tien hanh viec phan tich hoi qui cua day cac phuong trinh md hinh, can dung chuan thdng ke Student - t de xac dinh muc cd nghia ciia cae he sd rieng re cac thdng sd cd miic cd nghia t h i p thi khdng dupe xet tdi
4- De udc lupng thdng ke eac phudng trinh thu dupe ta dimg
-he sd tirrrng quan boi R, dp lech chuan S va diing chuan
F (Fischer) Binh phudng tudng quan boi (R^) chi ra phan bien ddi trong cac sd lieu thu dude til cac phudng trinh tuong ung R" cang xip xi 1, thi quan he ham thiic thu dupe cang gan vdi quan he ham
Trang 34thue can tim 6 eac tri gia R gan sat nhau, can thiet xet tdi dp lech chuan va sii dung cae phudng trinh cd dp lech chuan nhd nhit Chuan thdng ke F diing de udc lupng xac suit rang ph udng trinh chpn dd la ngiu nhien
5- De loai tru cac tudng quan ngiu nhien d mdi thdng sd hda ly thii nghiem kien nghi can ed 5 - 6 ket qua cua do sinh hpc
6- O ciing cae dieu kien khac nhu nhau, nen uu tien diing eac phudng trinh ddn gian hdn ca ^
7- Nham giam nhd va ddn gian tinh toan va d • tranh nhung sai sd nguyen tac can thie't xet tdi tinh hien thue eiia ed che' ciia hien tudng nghien cuu, bdi vi theo eac d i u hieu hinh thue ta ed the thu dupe cac phuong trinh vdi eac tri R r i t tdt va tinh cd nghia eao theo chuan F, nhung phuong trinh dd lai khdng phu hdp gi vdi hien thue ca Cho d6n nay mac du phuong phap Hansch ciing eon nhOng nhupc diem rieng, song tac gia Nga HHJKHHH C B
BnmTewH H.A [141] da viet: "Ngay nay khdng ton tai b i t eu mpt phuong phap thay th^ nao do phudng phap Hansch va nhiing dang cua nd trong viec thiet lap mdi quan he dinh lupng giua cau true hda hpc va tac dung sinh hpc D i e n nay lien quan ehii yeu den nen tang cua phudng phap Hansch ed nhung nguyen tac vat ly - hda hpc chung n h i t ; chac chan rang nd la nen mdng cho cd eiu tac dung sinh hpc eua nhiing lien ket hoat ddng [100, 101]
h) Mo hinh toan cong tinh Free - Wilson [141, 30]
Md hinh toan cdng tinh (MAD) ciia Free - Wilson dua tren gia thuyet la tac dung sinh hpc ciia mpt phan tu [A] la tong ddng gdp tac dung ciia cae nhdm the trong phan til va ciia khung [}hfin tu
Trang 35d day aij la ddng gdp tac dung nhdm the thir i d vi tri j
IX la ddng gdp trung binh hang dinh ciia khung phan tu len tac dung sinh hpc
xij la nhdm i\\t i d vi tri j
xij cd gia tri 0 hay 1 tiiy thudc vao dieu la nhdm the dd cd mat hay khdng
cd mat trong phan til
Theo md hinh MAD, thi sd lupng eiu true eac din xuit can thiet dua vao
md hinh toan la
m
P ^ 2(n\)¥\ (19)
d day P la sd cac din xuit can nghien cuu
m la sd vi tri thay th6 trong phan til
n la sd cac nhdm th6
Trong dieu kien dd ed the viet mpt he thdng m phudng trinh vdi n -m an
sd dpc lap, vdi dieu kien la p ^n - m
Giai he thdng phudng trinh ta se tim dude cac gia tri aij tuc la tim dupe
gia tri ddng gdp tac dung eua eac n -m nhdm the va tiep tuc tinh gia tri // va gia
tri ddng gdp eac nhdm ke' eon lai khac nhd-cae phudng trinh han che
Nhd cae gia tri ddng gdp dd ma ta cd the xac dinh va tien doan gia tri tac
dung eua mpt c h i t du rang ehit dd cdn chua dupe tong hpp va thii nghiem
0 day can ndi them de thiy rd tinh chit uu viet cua md hinh MAD nay la:
Neu nj (sd cac nhdm the la a, b, c d 3 vi tri, vi du a = 6; b = 7; e = 3) thi
sd cac din suit can nghien cuu theo phuong an ly thuyet bang p ^ a x b x c ^ 6 x
7 x 3 = 126 chit trong khi dd sd cac dan xuit can nghien ciiu theo md hinh Free
-Wilson la p ^a + b + c + 1 =6 + 7 + 3 + I = 17
nhu vay rd rang sd thi nghiem giam di rd ret Phuong phap Free - Wilson se la
mot cdng cu manh me trong cac tinh hudng phuc tap hdn, khi sd vi tri cd the dat
Trang 36nhdm the' ciia phan tii cang Idn Vi du phan til P dudi day ed 6 vi tri khac nhau ciia vdng phenantren, dupe the vdi 3 3, 6, 3, 6 va 3 nhdm the tudng ung
B = 3 nhom the Ra = 6 nhom the
Ri = 3 nhom the Re = 6 nhom the
R2 = 3 nhom the R7-= 3 nhom the
Neu tong h d p t h e o t o a n bd n h a n td thi p h a i t o n g h p p
3 x3 x3 x6 x3 x3 = 2916 ehit de thi nghiem Trong khi dd sd d i n xuit theo phuong phap Free - Wilson can phai tong hpp chi bang 3 + 3 + 3 + 6 + 3 + 3 = 21
d i n xuit
Nhieu tac gia da ap dung phudng phap Free - Wilson vdi nhieu ket qua tdt dep Vi du Purcel va cdng su da nghien citu Quinolin chdng Plasmodium 'gallinaceum Da liy lieu dieu tri hieu qua tdi thieu lam phan ung sinh vat Vdi mpt he thdng gom 14 phuong trinh tuyen tinh, cd 10 an sd da tim ra dupe d i n xuit cd tac dung tdt nhit Cac tac gia loan Simiti va loan Schwartz da giai 1 he thdng 20 phudng trinh tuyen tinh vdi 14 i n theo ngdn ngO FORTRAN tren may tinh Felix C 256 Da tinh dude gia tri ddng gdp cua cac nhdm the va da tim ra chit cd uc che phan bao cue dai
Nhupc diem ciia phudng phap nay la ehua xet tdi anh hudng eiia su phan bd tudng hd eiia cac nhdm the ddi vdi nhau tdi tac dung sinh hoe Dieu nay lai r i t quan trpng trong viec tim kiem thudc mdi, bdi le vi tri cac nhdm the cd the lam tang hoac lam giam tac dung sinh hoe ciia chat thudc dd Ve vin de nay chiing tdi da phat hien thiy qua qua trinh nghien ciiu, va da cd
Trang 37ddng gdp cai tien nhd su dung ly thuyet qui hoach thi nghien cuu tim dieu kien tdi uu Npi dung v i n t^ nay dupe the hien d ehudng cudi va cung da dupe trinh bay d hpi nghi tin hpc lan thu I d Viet Nam 7 - 1993 tai Ha Npi
i) Nhirng nghien ciiru ly thuyet ve mdi lien quan cdu true hoa hoc - tdc dung sinh hoc
NhOng tien bp dat dupe trong linh vuc hda hiiu cd ly thuye't lam eho khai niem eiu triic hda hpc va mdi lien quan giiia eiu true hda hpc va hda ly tinh dupe
md rpng va soi sang tren co sd eua Hoa luong tu [107] Khai niem ed ban eua Hda
lupng til coi dien til viia cd tinh chit hat viia cd tinh chit Sdng Do dd khdng the ndi rang dien til chi phu thupe ve mpt nguyen til nay hay mpt nguyen tii khac, ma tit ca thudc ve toan bp phan til ndi chung Do tinh chit sdng ciia dien til, tudng tac ciia chiing khdng phai la tudng tac cua nhiing dien tich diem ma la tudng tac eua cac dien tich phan bd dudi dang dam may nao dd Mat dp cua dam may dien til ed the Idn hdn hay nhd hdn, xung quanh nhan nguyen tii, dieu dd dupe ngdn
ngii Hda lupng tii gpi la Mat do dien tii Cd hpc ludng tu da chung minh dupe
rang su giam nang lupng xay ra khi cd su tang mat dp dien til trong khoang khdng gian giifa eac hat nhan; su tang mat dp dien tii nay lai xay ra do mpt hien tupng gpi la tuong tac trao ddi cua cac dien til Khi nang lupng toan phan cua he giam, thi lien k6t hda hoc se hinh thanh Khi su trao ddi din den su mam mat dd dien
til d giua hai nguyen til nang lupng toan phan eua he tang, cae nguyen tii seday nhau va khdng tao thanh lien k6t [106]
Bai toan lien k6t hda hpc dat ra eho cd hpc lupng tii la: Xac dinh su phan
bd mat dp dien til giOa cae nguyen tu trong phan tu, hay ndi theo ngdn ngii eiia
cd hpc lupng til la: Xac dinh su phan bd xac suit ton tai eiia dien tii Idp ngoai trong khoang giua cac nguyen til ciia phan til - Chinh su phan bd xac xuat nay se quyet dinh khoang each giifa cae nguyen til va HINH HOC ciia eac phan til, xac dinh mpt sd dac tinh ke ca kha nang phan ifng ciia phan til
Trang 38Cho den ngay nay, da ed rit nhieu phudng phap nghien eifu vin de nay nhu phudng phap Del - Re tinh dien tong cdng [185] phudng phap HUckel md
rpng [89] dt tinh mat dp dien tu, eiu dang phan til tii dd cd the du doan
kha nang phan ung va du doan mpt vai tinh chit khac nua ciia phan til nhu moment ludng cue, chuyen dich sdng v.v chuyen dich hda hpc trong quang phd CHT^H[110, 8, 45, 99, 25]
Nhd tin hpc phat trien, nhieu chudng trinh may tinh nhu ALCHEMY, PCMODEL, CNDO/2 va HONDO da giai quyet vin de nay mot each nhanh chdng vf tien Ipi [7, 102]
Ngay nay, trong sinh vat hpc ngudi ta da nghien eifu cac qua trinh sdng thdng qua viec nghien eifu eiu triic phan tu eiia cac ehit sdng, nghia la nghien eifu qua trinh sdng d mifc vi md
Cd hpc lupng til dupe van dung vao sinh vat hpc nham xem xet vin de tren ed sd dien til, ching han, biet eiu triic dien tu ciia cac phan tii axit nucleic, ngudi ta hieu su bi6n ddi tautdme cua eac badd nitd, hien tupng nay lai lien quan den vin de bien di Hoac la biet eiu triic dien tii eua cac men, ed the giai thich dupe tac dung cua men, tudng tac giiia men va cac chit bi men xuc tac
Tuy vay neu xem xet vin de lien ket chit thudc - chit thu cam tren cd sd
d'ien tu thi gap phai mpt sd khd khan chinh, dd la khdng de bidt dupe eiu tao dien til ciia chit thu cam sinh vat Do dd ngudi ta diing phuong phap gpi la
phuOng phap nhieu loan te bao, khi dd eho rang chit thu cam lam nhi^u loan cdu tQO\dien tu cua ehit thudc [185]
Tren cd sd ly thuydt cua Dewar la chit thu cam lam nhi^u dien tii ciia chit thudc, da xuit hien mot vai phudng phap quan trpng khac nua de nghien cuu hda ludng tii ciia tac dung chit thudc - Dd la phudng phap ciia Inonye va Klopmann [185]
Ngay nay, chiing ta deu thua nhan rang eo hpc lupng til da tao ra bp mat
Trang 39mdi cho hda hpc Hda hpc lupng tii dii rang eon ehua dem lai cho khai niem lien ket hda hpc mpt dinh nghia toan hpc chat che, nhung lien ket hda hpc vin la mpt khai niem trung tam cd ban Lien k6t hda hpc la mpt trong nhung bi an ma vat ly
va hda hpc c6 tim khdng kham pha ra dupe Khdng nam dudc ban ehit mdi tudng
tac giiia cac nguyen tii trong phan til thi khdng the hieu dudc su da dang ciia eac hdp ehit hda hpc, nguyen nhan hinh thanh eac hdp chit dd va kha nang ciia eac phan ifng til ban ehit lien ket hda hpc giup ta hieu dupe va giai thich dupe nhieu khai niem quan trpng khac trong hda hpc
Hien nay, mot sd nha hda hpc di theo hudng dimg nhiing ham sd sdng ddn gian ket hpp vdi thue nghiem va diing phudng phap gan diing de dua ra nhOng tien doan dinh tinh va ban dinh ludng Hudng nay td ra cd hieu qua Nd din den viec tong hpp nhifng hdp chit mdi vdi nhiing lien ket thii vi Vin de hda lupng tu trong viec nghien eifu mdi lien quan giifa eiu tnic hda hpc va tac dung sinh hpc mpt each ban dinh lupng hoac dinh lupng la mpt hudng cd r i t nhieu trien vpng, va vin cdn la mpt chan trdi rpng rai bao la eho cac nha nghien eifu
Trong cdng trinh nay, chiing tdi khdng di sau vao vin dt nghien ciiu theo
hudng hda lupng til, ma chi sii dung mpt sd ket qua tinh toan theo phuong phap CNDO/2 nham phuc vu cho muc dich nghien eifu
Cai chinh la giai quyet vin de nghien eifu ban tong hdp eac hpp chit tu nhien cd tac dung sinh hpc, mpt each cd dinh hudng cao, theo phudng hudng nghien cuu mdi, theo phudng phap va cdng vu mdi Dd la viec su dung cae md hinh toan hpc nghien eiiu mdi lien quan dinh lupng giua eiu triic hda hpc va tac dung sinh hpc (QSAR) ciia Free - Wilson va Hansch C [ 5, 63 ,163 ]
Nhung trudc khi budc vao giai doan nghien cuu ban tong hdp eac din xuit theo mot qui hoach (Chudng 3); de rdi tinh toan theo md hinh Free -Wilson (Chudng 4), theo md hinh Hansch (Chudng 5) va kiem chiing danh t^ia ket qua theo hai md hinh Free - Wilson va Hansch the hien d Chuong 6 - chiinu
Trang 40tdi khdng the bd qua nhOng nghien eifu ban dau ve eugenol - la mpt ddi tupng
lan dau tien dupe dua vao nghien cuu vin de QSAR - nhu viec nghien eifu dinh
tinh khang nim benh ciia eugenol va tinh dau huong nhu, nghien eifu vai trd
khang n i m cua cac nhdm chifc trong phan tii, su phan bd mat dp dien tii ciia
nguyen tu trong phan til eugenol, thanh phan hda hpc va qui trinh tdi uu chiet
eugenol ra khdi tinh dau hudng nhu dupe the hien d Chudng 2 • Chirang 7 la
chu-cng cuoi ciia luan an thao luan ve kha nang m a rpng hai md hinh nghien
ciru ve moi lien quan giira cau triic va tac dungi sinh hpc ciia Free-Wilson
va Hansch - ,"
Tren day la nhiing net chinh eiia luan an, va ciing la vai Idi gidi thieu
trudc khi di vao cac chudng eu the