protivirusne učinkovine
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UČINKOVINE Z DELOVANJEM NA VIRUSE
a) lažni substrati-analogi gradnikov DNA nukleozidni inhibitorji encimov zaključevalci verig DNA
b) nenukleozidni inhibitorji encimov (reverzne transkriptaze, proteaze, sialidaze)
c) spojine, ki onemogočajo slačenje virusov
d) interferon in induktorji interferona- leti stimulirajo nastajanje ribonukleaze, ki razgrajuje informacijsko RNA (zavira sintezo virusnih proteinov)
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PROTIVIRUSNE UČINKOVINE Z VPLIVOM NA DNK VIRUSE
OB
OH
OP3
•inhibicija encimov, ki povzroče vgrajevanje gradnikov DNK v DNK•prekinjevaci verige
aciklovir, ganciklovir, penciklovir- derivati gvanozina (inhibicija virusne DNK polimeraze)vidarabin- adenozinski analog (prekinjevalec verige)idoksuridin- timidinski analog ribavirin- vpliva na sintezo mRNKfoskarnet- zavira DNK polimerazo
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SINTEZA ACIKLOVIRJA
N N
NHN
O
NH2
O
O
O
N NH
NHN
O
NH2
OO
Cl
O
N N
NHN
O
NH2
O
OH
NH3
CH3 OH
9-(2-hidroksietoksimetil)gvanin
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SINTEZA PENCIKLOVIRJA9-[4-hidroksi-3-(hidroksimetil)butil]gvanin
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SINTEZA IDOKSURIDINA2'-deoksi-5-jodouridin
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NUKLEOZIDNI INHIBITORJI REVERZNE TRANSKRIPTAZE
N
NH
O
N+N
-N
O
O
CH3
OH N
NH
O
O
O
CH3
OHN
N
O
O
NH2
OH
N
N
O
S
O
NH2
OH
N
N
O
N
N
OH
OH
LAMIVUDIN DIDANOZIN (citizinski analog) (inozinski analog)
ZIDOVUDIN STAVUDIN ZALCITABIN(timidinski analog) (timidinski analog) (citozinski analog)
zaviralec gos. DNA polimeraze
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SINTEZA ZIDOVUDINA3'-azido-3'-deoksitimidin
mezilklorid
5´-O-tritiltimidin
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SINTEZA DIDANOZINA
9-[2',3'-dideoksi-beta-D-ribofuranozil]-9H-purin-6-ol
glutaminska kislina
N
N
N
NH
NH2
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NENUKLEOZIDNI INHIBITORJI REVERZNE TRANSKRIPTAZE
•vezava na alosterično mesto encima v bližini substratnega vezavnega mesta
N
N
NNH
MeSO2NH O
NHCH(Me)2NH
OCl
CF3
O
EFAVIRENZ DELAVIRDIN
N N
NH
N
OCH3 Cl
Cl
NH
Me
COMe
CONH2
NEVIRAPIN LOVIRID
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SINTEZA NEVIRAPINA11-ciklopropil-4-metil-6,11-dihidro-5H-dipirido[3,2-b:2',3'-e][1,4]diazepin-6-on
2-amino-4-metil piridin
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SINTEZA DELAVIRDINA1-[3-(izopropilamino)-2-piridil]-4-[5-(metanesulfonamido)-1H-indol-2-ilkarbonil]piperazin
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PROTEAZNI INHIBITORJI•posnemanje aminokislinske sekvence Phe-Pro•so pravi peptidomimetiki•so mimetiki prehodnega stanja
N
O
NH
O
NH
OHCONH2
N
O
t-BuNH
SAKVINAVIR
OHN
NN
O NHt-Bu
OH
O
NH
INDINAVIR
O
NH
OH
NHOH
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SINTEZA SAKVINAVIRJAN1-[1(S)-Benzil-3-[4(S),8(S),3(S)-(tert-butilkarbamoil)dekahidroizokinolin-2-il]-2(S)-hidroksipropil]-N2-(kinolin-2-ilkarbonil)-L-asparaginamid
RNH COOH O
O
O
OEt
Mg RNHO O
OEtRNH
OH O
OEt
NaBH4
O
O
TsOH
RNO O
OEt
NaOH
RNO O
OH
(COCl)2
MPOCBrCl3
RNO
Br
AcOH
+
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HUNSDIECKERJEVA REAKCIJA (BROMO-DEKARBOKSILACIJA)
RCOOAg + Br2RBr + CO2 + AgBr
RCOOAg + X2 RCOOX + Agx
RCOOX RCOO + X
RCOO R + CO2
R RX + RCOO
.
. .
.
. .
Predviden je potek po naslednjem radikalnskem mehanizmu:
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RCH2COOH+ (COCl)2RCOCl
N
SH
O
N
S
RCOOCBrCl3
RCH2Br
Podobno poteka bromo dekarboksilacija preko tio-hidroksamskih estrov:
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RNHOH
Br
KOH
RNHO
RNHOH
N
ONH
NH
ONH
NH2OH
N
ONHNHZ
O
O
NH2
OH
TFA ali katalitskohidrogeniranje
Z-asparagin
DCC
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NHZ
O
O
NH2
NH OH
N
ONH
H2,Pd/C
O
O
NH2
NH OH
N
ONH
NH2
N COOH
DCC
O
O
NH2
NH OH
N
ONH
NH
ON
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OSTALE PROTIVIRUSNE UČINKOVINE
NH2
NH2 CH3
AMANTADIN RIMANTADIN
O
O
CH3
NH2
NH O
CH3
O
CH3
CH3
OZELTAMIVIR(INHIBITOR NEURAMINIDAZE)
O
O
OH
NH
NH
OH
OH
NH2
NH
OH
OCH3
ZANAMIVIR
(INHIBITOR NEURAMINIDAZE)
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RIMANTADIN
Drug Name: Rimantadine hydrochloride; EXP-126; Oclovir; Roflual; Flumadine
Chemical Name: alpha-Methyl-1-adamantanemethylamine hydrochloride; alpha-Methyltricyclo[3.3.1.1(3,7)]decane-1-methanamine hydrochloride. CAS(R) Reg. No.: 1501-84-4; 13392-28-4 (free base) Phase: Launched-1987. Source: DuPont Pharmaceuticals; Roche; Forest. Activity / Mechanism: Anti-Influenza A Virus Drugs.
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SINTEZA RIMANTADINA -metil-1-adamantanmetilamin
BrCH2
Br
OH K
CH
h idra tacija
CH3O
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SESTAVA VIRUSOV•PROTEINSKI PLAŠČ (KAPSIDA)•LIPOPROTEINSKA OVOJNICA (PRI NEKATERIH)• ENCIMI •GENETSKI MATERIAL (DNA, RNA )
DNA virusipoksvirusi, herpesvirusi
RNA virusirinovirusi, virus influence
retrovirusiHIV-virus
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REPLIKACIJSKI CIKEL DNA VIRUSOV
1. pritrjevanje,
2. endocitoza,
3. slačenje proteinske kapside
4. transport virusne DNK v jedro gostujoče celice,
5. gostiteljeva mRNK polimeraza tvori mRNK virusa (tvorba proteinov)
6. virusna DNA polimeraza tvori virusno DNK
7. proteini virusa in DNK se strukturirajo in zreli transportirajo iz celice gostitelja
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REPLIKACIJSKI CIKEL RNA VIRUSOV1. pritrjevanje,
2. endocitoza,
3. slačenje proteinske kapside
4. transport virusne RNK v jedro gostujoče celice, kjer je RNA sama mRNK ali pa celična mRNK polimeraza na osnovi RNK sintetizira mRNK
5. sinteza virusnih proteinov
6. tvorba virusa in prenos iz celice gostitelja
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REPLIKACIJSKI CIKEL RETROVIRUSOV (HIV-virusa)
1. vezava na specifičen receptor (CD4)2. fuzija membrane gostitelja in virusne ovojnice 3. vstop nukleokapside v citoplazmo gostujoče celice4. izstop virusne RNK5. virusna reverzna transkriptaza prepiše RNK v provirusno DNK6. pod vplivom integraze se DNK vključi v gostiteljevo DNK7. nastanek mRNK8. produkcija virusne RNK9. pakiranje in transport do celične membrane10. izstop virusa, ki ga virusna proteaza pretvori v zrelo obliko