13.makrolidi, linkozamidi, polipeptidi
DESCRIPTION
Farmaceutska hemijaTRANSCRIPT
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Makrolidi
• Makrociklični laktoni – 12,14,16 - člani
• Makrociklični lakton-O-amino šećeri
• Eritromicin A,B,C (Streptomices erythreus)
• Makrociklični lakton = eritonolid A
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H3C
OH
O
OH
CH3H3C
OHH3C CH3
OHO
N
H3C
CH3
CH5
9
O
6122'
ERITRONOLID A
DEZOZAMIN-3,4,6-trideoksi-3-dimetilamino-D-ksilo-
heksoza
KETON
O3
CH3
O
CH3
O
O OHCH3
OCH3
O CH3
CH32'
1 3
1'
1'
ERITROMICIN A - MAKROLIDI
KLADINOZA- 2,3,6-tri-deoksi-3-metoksi-3C-metil-L-ribo heksoza
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• Eritromicin B = 12 deoksieritromicin A• Eritromicin C (razlika u strukturi kladinoze – demetoksi šećer)• Eritromicin A• Gorak • Stabilan pri neutralnom pH• Eritromicin baza se koristi u formi masti• Antimikrobni spektar sličan penicilinima• Infekcije gornjeg respiratornog trakta i pneumonije• Mehanizam dejstva – vezuju se selektivno za 50S subjedinicu
ribozoma bakterija i sprečava sintezu proteina bakterijske ćelije
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Modifikacije prirodnog proizvoda
• Povećanje hipo/lipo rastvorljivosti• Povećanje stabilnosti u kiseloj sredini i
lipofilnosti > ⇑ resorpcija i bioraspoloživost lipofilnosti > ⇑ resorpcija i bioraspoloživost • Prevazliaženje gorčine• Pored hemije = razvoj doziranih oblika sa
postepenim oslobadjanjem
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N(CH3)2
HO
MODIFIKOVANI DERIVATI
1) SOLI - DEZOZAMIN R N
CH3
CH3
- GLUCEPTAT – GLUKOHEPTANOAT – rastvoran u vodi, parenteralna primena
COOH
H OH
OO CH3
HOH OH
H OH
HO H
H OH
H OH
CH2OH
ERITRONOLID A
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N(CH3)2
HO
MODIFIKOVANI DERIVATI
1) SOLI - DEZOZAMIN R N
CH3
CH3
- LAKTOBIONAT – rastvoran u vodi, parenteralna primena
C C C C
H
HO
H H OH
C
H
COOH123456
ααααββββγγγγδδδδ
OO CH3
HO
ERITRONOLID A
C C C C
H
HO
OH
O
H
C
OH
COOH
O
OH
HOH
H
HO
H
HOH2C
H
ααααββββγγγγδδδδ
4-(β-D-GALAKTOZIDO)-D-GLUKONSKA KISELINA
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2) ESTRI I SOLI
O
N(CH3)2
OC
O
CH3
O CH3
H
CH3(CH2)11OSO3H
C12H25OSO3-
-
III
DODECILSULFATIII
ERITRONOLID AIII
LAURILSULFAT
PROPIONAT + DODECILSULFAT = ESTOLAT
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2) ESTRI I SOLI
O
N(CH3)2
OC
O
O CH3
O
OH3C
OO
ERITRONOLID A
CH3
ERITROMICINETILSUKCINAT – nerastvoran u vodi, pro drug, suspenzija za parenteralnu primenu
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6
O
H3CHO
CH3
CH3
9
ORHO
HHO
H3C O
CH3
CH3
ORHO
H
H+ - H2O
CH3
89
STABILNOST U KISELOJ SREDINI
6
H3C O
CH3
ORHO
789
10
118,9-ANHIDRO-6,9-HEMIKETAL
INAKTIVAN – DEJSTVO NA GIT
MIKROBIOLOŠKI SPOREDNO
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Cilj polusinteze
• Manje/slabije izražene gastrične smetnje• Veća bioraspoloživost leka• Veća conc.leka u plazmi koja se održava• Manje doze i redji dozi režim• Manje doze i redji dozi režim• Promene na C-6 aglikona• Promene na C-9 aglikona• Širenje makrociklusa
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OH3C
OH
O
OH
CH3H3C
OHH3C CH3
OHO
N
H3C
CH3
CH3
5
9
O
6122'
OH
OCH3
CH3H3C
OHH3C CH3
9
O
612
N
OH
OH
H3C
H3C CH3
OH
CH3
H3C
KLARITROMICIN
Polusintetski derivati –- Stabilni u kiseloj sredini- Smanjena interakcija sa citohrom P450
CH3
O
CH3
O
O OHCH3
OCH3
CH32'
1 3
1'
1' OHH3C CH3
1'2'
NH
CH3
CH3O
OHCH3
HO
H3C
OH3CO
ERITROMICIN
AZITROMICIN
DIRITROMICIN“PRO-DRUG” ERITROMICIKLAMIN
1'2'
NH
CH3
CH3O
OHCH3
HO
H3C
OH3CO
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KLARITROMICIN
6-METILETAR ERITROMICINA
↑ STABILNOST U H+
OH
OCH3
CH3H3C
OHH3C CH3
9
O
612
↑ BIORASPOLOŽIVOST (ORALNA)
↓ GIT – SPOREDNI EFEKTI
METABOLIT – 14-OH DERIVAT ZADRŽAVA ANTIMIKROBNU AKTIVNOST
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6
NOO
H3COH
CH3
CH3
9
10
OCH3
ROKSITROMICIN
9-[O-[(2-METOKSIETOKSI)-METIL]OKSIM]-ERITROMICIN
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AZITROMICIN
Eritromicin A OKSIM (C9) → BECKMANOVO PREMEŠTANJE do iminoetra >>>>redukcija do 9-deoksi-9a-AZA-9A-homoeritromicin A→ redukcija i N-metilovanje do
AZITROMICINAŠIRI SE ZA 1C ATOM
15-CIKLIČNI MAKROLID
N
OH
OH
H3C
H3C CH3
OH
CH3
H3C
AZALID
ELIMINACIJA C=O (9)
3º-AMIN (SLABA BAZA)
LIPOFILNOST
STABILNOST U H+ SREDINI
OHH3C CH3
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DIRITROMICIN
DERIVAT 9S-ERITROMICIKLAMINA
+
2-(2-DIMETOKSIETOKSI)-ACETALDEHIDA
9N, 11O-OKSAZIN
1'2'
NH
CH3
CH3O
OHCH3
HO
H3C
OH3CO
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DIRITROMICIN
-PRO DRUG – ENTEROSOLVENTNE TABLETE
NESTABILAN U H+ i OH- SREDINI
ERITROMICIKLAMINA
ANTIBAKTERIJSKE OSOBINE
HIDROLIZA
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REZISTENCIJA !!!!!
• Modifikacija makrolida – ribozom –metilovanje aktivnog mesta ribozoma -erm-coded
• Povećanje efluksa makrolida – mef coded• Povećanje efluksa makrolida – mef coded▼
Nova grupa KETOLIDI
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3-KETO-KLARITROMICIN
TELITROMICIN
3-KETO DERIVATI ERITROMICINA3-KETO DERIVATI ERITROMICINA
KETOLIDI
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O
H3C
OCH3 CH3H C
CH3
N
N
N N
O
Stabilnost (H+)
Aktivnost
Karbamat –povećana
Telitromicin - 2001
O
H3C
H3C
CH3
O O
OCH3
CH3
O
N
CH3H3C
CH3
N
O
O
HOH3C
ermR
povećana aktivnost
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MIDEKAMICIN – 16-OLID
SPIRAMICIN – 16-OLID
JOSAMICIN -16-OLID
▼
Manji stepen interakcije sa Cyt P450
Smanjena modifikacija - ERMSmanjena modifikacija - ERM
Nisu supstrati za mefE
Stabilniji u kiseloj sredini
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N
CH3
C3H7
H
COOH
12
34
5
LINKOZAMIDI
H
N-METIL-n-PROPIL-TRANS-HIGRINSKA KISELINA
AMIDI – TIOMETILAMINOOKTOZIDA I N-METIL-n-PROPILHIGRINSKE KISELINE
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5
CH3
HO H
H NH
O
OH
C
O
N
CH3
CH3
6
7
8
CH3
H Cl
H NH
O
OH
C
O
N
CH3
CH3
SOCl2
12
3
45 O
HO
OHSCH3
H
O
HO
ORSCH3
H
LINKOMICINKLINDAMICIN R = H
KLINDAMICIN FOSFAT R = PO3H
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O
OHOH
OH
O
O
O O
HOH
O
ClHO
H
O
Cl
O
CH3
H3C
HO
NH2
O
PEPTIDI
NH
O
O
HN
NH
HN
OHOH
H HN
O
NH
O
HN
Cl
O
OH
HOOC
HO
HH
O NH2
CH3HHH
CH3
H3C
VANKOMICIN
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L-His
D-Asp L-Asn
L-Lys L-Ile D-Glu L-Leu
D-OrnL-Ile
D-Pheαααα
εεεε O
NCH3
HH3C
L-Cistein
S
H NH2
L-Izoleucin
BACITRACIN A
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L-Dab
L-Dab L-Thr
L-Dab
L-Dab
L-Dab L-DabL-Thr
L-Leu X
O
CHPolimiksin B, X = D-Phe
CH3
CH3Polimiksin B, X = D-Phe
Kolistin A, X = D-Leu
NH2
CH
NH2
C
O
DAB =
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HNO
HN
NH
NH
HN
HN NH2
O
H2N
OOH
O
NH
NH2
O NH2
OO
NH
NH
NH
H
KAPREOMICIN 1A
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OH
HN
O
OH
CH3
CH3
O
CH
H3CO
OHO
O
H2N
CH3
12
345
6
78
R
4, 3
O
CH3
OO CH3CH3
O1
28
R’
R
NOVOBIOCIN