Betalactam II Dai Hoc 2012.SV

7/28/2019 Betalactam II Dai Hoc 2012.SV

1/57

CEPHALOSPORIN

N

NH

O

O

R1H H

1

3

4

5

67

Cephalosporin

S

2

COOH

R2


2/57

12

3

45678

N

S

H HN

COOH

O

H

C

OAcO

CH2CH2CH2CH

H2N

COOH

nhanh ben 7-aminoadipic

Cephalosporin C

7-aminocephalosporinic acid (7-AC

1945: Cephalosporium acremonium

Peni N, cephalosporin P1, cephalosporin C

Cepha C :

- hoat tnh KK khiem ton, nhng hoat tnh tren S. aureus.- ben vi penicillinase cua Bacillus subtills


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Cephalosporin C (thin nhin)

CEPHALOSPORIN BN TNG HP

- M rong pho KK sang gram am- Gia tang kha nang khang lai beta lactamase- Cai thien ve dc ong hoc


4/57

azetidine-2-on

NH +

OHN

S

dihydrothiazine

NO

S

cephem

Cephalosporin = Azetidin-2-on + dihydrothiazin(cephem)

N

NH

O

O

R1H H

1

3

4

5

67

S

COOH

R2

Cephalosporin


5/57

N

NH

O

O

R1OCH3

H

1

3

4

5

67

S

COOH

R2

Cephamycin

N

NH

O

O

R1H H

1

3

4567

H2C

COOH

R2

Carbacephem

N

NH

O

O

R1R3

H

1

3

4

5

67

O

COOH

R2

Oxacephem

DAN CHAT CEPHEM

Khung cephalosporin ni chung bn hn penicillin i vi acid v -lactamase

Loracarbefcefoxitin

latamoxefO

NH

O

NH2

H H

COOHCl


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Cephalosprin INHOM 1: cefalotin,NHOM 2: cefaloridin, cefazolin,NHOM 3: cefalexin, cefadroxil, cefaclor,

Cephalosprin the he IICefamandol, cefuroxim, cefoxitin

Cephalosporin the he th IIICefotaxim, ceftriaxon, cefixim, cefepim, moxalactam

Cephalosporin the he th IVCefpirom, cefipim

Cephalosporin the he th V


7/57

N

O

XHNR7

O

R

COOH

R31

37

H

DAN CHAT CEPHEMLien quan cau truc tac dung

12

3

45678

N

SH H

N

COOH

O

H

C

OAcO

CH2CH2CH2CHH

2N

COOH


Cephalosporin C



8/57

Ban tong hp t cephalosporin C

IEU CHE

12

3

45678

N

SH H

N

COOH

O

H

C

OAcO

CH2CH2CH2CH

H2N

COOH


Cephalosporin C



9/57

IEU CHES

O

HNR1

O

H H

OAc

CO2SiMe3

protecting group

34

7

PCl5R1

Cl

imino chloride

ROHR1

OR

imino ether

H2O

- R1CO2H

S

O

H2NH H

OAc

CO2H

34

7

7ACA

R2 Cl

O

Acid chloride

S

O

HN

H H

OAc

CO2H

34

7

O

R2

Range of cephalosporins

Tng hp 7ACA v cc cht tng ng cephalosporin

HNR1

7

..

O

H

PCl4

Cl

NR1

7

O

H

Cl3P

Cl

Cl

..

..: :

R1

ClO

H

Cl3P=O

C ch to imino chloride


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N

S

O

HNC

O

R

CO2Me

26Me

Me

H

H2O2

N

S

CO2Me

Me

Me

O

N

S

CO2Me

CH2

Me

OHH

N

S

CO2Me

CH3

OHH

N

S

CO2Me

CH3

OH

H

:.. - H

N

S

CO2Me

CH3

H

OH

H

H

N

S

CO2Me

H

CH3

Tng hp 3-methyl cephalosporin t mt penicillin

R


11/57

TNH CHAT VAT LY

- Bot tinh the trang hoac co mau nhe, khong mui.

Vai cephalosporin co mui lu huynh (cefalexin, cefradin).

- Co nang suat quay cc nhat nh

- Pho UV: cau truc cephem cho hai hap thu: 220nm va 260nm

- Pho IR: vung ac trng nhat: 1600-1800cm-1

N

NH

O

O

R1H H

1

3

4

5

67

S

COOH

R2


12/57

C=O ( lactam carbonyl) = 1770-1790 cm-1 / KBr


13/57


14/57

Cefaloridine

Ph UV:

- Hai hp thu ti a 240 nm (thienyl) v khang 255 nm (cephem)

- Vng b m (do kim hay -lactamase) hp thu 255nm - 260 nmbin mt , xut hin hp thu 230nm (bin mt sau vi gi do phn tb tip tc phn hy).


15/57

M vong azetidin-2-on d/c acid cephalosporic

Tac nhan ai nhan m vong:

NaOH, KOH: tao muoi cua acid cephalosporic

Cac alcol: tao cac este cua acid cephalosporanic.

N

HHN

R

O

O

HS

R3COOH

N

HHN

R

O

O

HS

R3

COOHH

N

HHN

R

O HS

R3

COOH

-O

A N

Nu- Nu

H+

Nu

HOA TNHTnh khong ben cua vong beta lactam


16/57

cac amin tao amid

N

HHN

R

O

O

HS

R3

COOH

NH2OHN

HHN

R

O

O

HS

R3

COOHNHOH

H

acid hydroxamic

Cephalosporin ben hn trong moi trng acid (so vipenicillin).

HOA TNHTnh khong ben cua vong beta lactam


17/57

Nhom COOH C2, cac cephalosporin the hien nhcac acid , bat bao hoa kha manh:

Tao muoi: muoi Na, dang thuoc tiem

Tao cac este c xem la tien chat (cefuroximacetyl va cefpodoxim procetyl).

N

O

XHN

R7

O

R

COOH

R31

37

H

HOA TNHTnh acid


18/57

Cefuroxime


19/57

Nhom ben: CH3, NH2-COOCH2-(carbamoyloxymethyl), Cl

Nhom d phan ng: CH3-COCH2- (acetoxymethyl)

HOA TNHPhan ng nhom the R3 N

O

XHN

R7

O

R

COOH

R31

37

H

N

S

O

ROCHN

H H

O

OCO2H

esteraseN

S

O

ROCHNH H

OH

CO2H

lacton hoa

N

S

O

ROCHN

H H

OO

Giam hoat tnh khong hoat tnh


20/57

12

3

45678

N

S

H H

N

COOH

O

H

C

OAcO

CH2CH2CH2CH

H2N

COOH


Cephalosporin C


S

O CH3

OCO2HO

ROCHN H H

OH

S

CH2

CO2H

ROCHN H H

OHO

+CH3HO

O


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Nhom acylamino 7- tnh ben cephalosporin.

S can tr khong gian gan vong -lactam ngan can tac dungcua -lactamase do vay co t/d bao ve.

ac biet ung trong trng hp cac dan chat -alcoxyimin.

N

O

XHN

R7

O

R

COOH

R31

37

H

HOA TNHNhm acylamino

Cefuroxime natri


22/57

KIEM NGHIEM

(tng t nhom Penicillin)- nh tnh

Pho UV, IR

Sac ky lp mong

Phan ng vi H2SO4, vi formaldehyd/H2SO4

- Kim TK

Ph UV ( hp thu)

Nng sut quay cc

pH

-

- nh lng

Phng phap HPLC


23/57

Cephalosprin INHOM 1: cefalotin, cefapirin, cefacetril

B thuy giai bi cephalosporinase, dung tiemCefalothin, BTH au tien s dung vao 1963.

N

SHN

H H

COOH

O

R

O

R-------------------------------------------------------

Cephalotin

NCH2OAc

S

S Cephapirin

N Cephacetril



24/57

Nhom nay c s dung bang ng tiem.

Cephalosprin INHOM 2: cefaloridin, cefazolin

N

SHN

H H

COOH

O

R

O

R-----------------------------------------------------------------------------

R3

S

R3

N Cephaloridin

N

NN

NN N

SSCephazolin

CH3

12

3

45678

N

SH H

N

COOH

O

H

C

OAcO

CH2CH2CH2CH

H2N

COOH


Cephalosporin C

p p (


25/57

Cephalosprin INhm3: cefalexin, cefadroxil, cefradin

Cau truc - amino phan t themmot C*, cau dang R co hoat tnh.

Dung ng uong

N

S

COOH

CH3O

R

cefalexin

HO cefadroxil

cefradin

N

H

O

R

NH2


26/57

cau khuan gram (+), gram (-) va vai trc khuan gram (-).

Tu cau khuan noi chung nhay cam (mot so tu cau e khangvi peni G va ampi nhay cam vi cefazolin).

Cong hieu tren E.coli, Klebsiella pneumoniae, Salmonella

Khong co hoat tnh tren trc khuan gram am san xuatcephalosporinase: Enterobacter, Serratia, Providencia,Pseudomonas.

PHO KHANG KHUANCephalosprin I

C h l i th h II


27/57

Nhng phan t co cau truc thay oi,Co ac tnh khang lai beta lactamase.

- Hypothrombinemie

-

Antabuse

S este hoa khac phuc tnh khong ben cuacefamandol khi c bao quan dang kho

Cefamandol nafat (hat tnh tt trn enterobacter v H. influenzae)

Cephalosprin the he IIcefamandol, cefuroxim, cefoxitin, cefotetan, cefaclor, loracarbef

C h l i th h II


28/57

Cefuroxime natri

Cefuroxime acetyl


(hat tnh tt trn H.influenzae)


29/57

N

Ar

OR

O

(7-ACA/ADCA)

Syn

( Stabilizing againstmany beta-lactamse )

N

Ar

O

(7-ACA/ADCA)

RO

Anti

( Not stabilizing againstmany beta-lactamse )

C h l i th h II


30/57


Sodium (6R,7S)-3-[(carbamoyloxy)methyl]-7-methoxy-8-

oxo-7-[[(thiophen-2-yl)acetyl]amino]-5-thia-1-

azabicyclo[4.2.0]oct-2-ene-2-carboxylate.

(Cefoxitin natri)

Cephalosprin the he II


31/57

(7S)-7-[(4-Carbamoylcarboxymethylene-1,3-dithietan-2-

yl)carboxamido]-7-methoxy-3-[(1-methyl-1H-tetrazol-5-

yl)thiomethyl]-3-cephem-4-carboxylic acid

(Cefotetan)

Ph khng khun tng t cefoxitin




32/57

Cefaclor

Escherichia coli,

Klebsiella pneumoniae,Neisseria gonorrhoeae

Proteus mirabilis

* Haemophilus influenzae.

loracarbef


O

NH

O

NH2

H H

COOH

Cl


33/57

Tren cau khuan gram (+) khong bang cephalosporin I.

Tren cau khuan gram (-) cephalosporin II manh hncephalosporin I, ac biet tren cau khuan khang

penicillin. hoat tnh tot oi vi vi khuan gram am (ng ruot e

khang vi cephalosporin I) mac phai tai benh vien:

cefamandol hoat tnh hn tren Enterobacter cefuroxim , cefamandol, cefaclor ac biet co

hoat tnh tren Hemophilus influenzae.


Pho khang khuan


34/57

Cephalosporin the he th III

Xuat hien t 1980, nhieu tien bo so vi cac the he trc:

Manh hn oi vi vi khuan gram am, MIC thap.

Phan phoi tot nhng vung cephalosporin I va II

khong en c. Nhom nay gom nhng khang sinh s dung chu yeu

bang ng tiem nhng cung co vai phan t hoat tnhkhi dung uong.



35/57

Cephalosporin the he th III-Sulfocephalosporin

(rat ben oi vi - lactamase)

SO

O

O

N

O CO2H

R3

cefsulodin

Sodium 3-(4-carbamoylpyridiniomethyl)-7-

[(2R)-2-phenyl-2-sulphoacetamido]-3-

cephem-4-carboxylate

S

H

N

O

SO3H

OC

N

C O

NH2

OO

cefsulodin



36/57

Cephalosporin the he th IIIUreido cephalosporin

cefoperazon

(7R)-7-[(R)-2-(4-ethyl-2,3-dioxopiperazin-1-ylcarboxamido)-2-(4-

hydroxyphenyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-

cephem-4-carboxylic acide


37/57


38/57

Cefotiam hexetil



39/57

Methoxyimino cephalosporin: hoat tnh khang khuan manh; gom:cefotaxim, cefmenoxim, ceftriaxon, ceftizoxim, ceftazidim, cefixim,cefpodoxim proxetil, va cefetamet pivoxyl.


N

SHNN

SH2N

N

O

OCH3

O

H

COOH

R3

H

Methoxyimino-cephalosporin

R3

----------------------------------------------------------

O

CH3

O Cefotaxim

NN

N N

CH3

S Cefmenoxim

N

N

N

O

OH

S

H3C

Ceftriaxon

H Ceftizoxim

CH3 Cefetamet



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Ceftazidim

Cephalosporin the he th IIIMethoxyiminocephalosporin

cefpodoxim proxetil



41/57

Cephalosporin the he th IIIMethoxyiminocephalosporin

(6R,7R)-7-[[(Z)-2-(2-aminothiazol-4-yl)-2-[

(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trihydrate.

(Cefixim)

cefdinir



42/57

Cau truc 1-oxacephem khang manh tren gram (-) hieu kh

Cephalosporin the he th IIIOxacephamycin

(tc dng tng t cefotaxim)

LatamoxefO

CO2NaO

O H

CH3

NN

N

N

OH

HN

O

SF

F

Flomoxef natri


43/57

Hoat tnh manh tren vi khuan gram (-)

Tren chung gram (+) va hieu kh t co thay oi.

Hoat tnh chu yeu tren Enterobacterie a e khang:

cefotaxim, cefmenoxim, ceftriaxon, moxalactam Cefotaxim co MIC rat thap vi Enterobacterie a e

khang, Haemophilus influenzaeva Neisseria(meningitidis va gonorrhoeae).

Cefotaxim tac ong tren nhng vi khuan gram am(tr Pseudomonas aeruginosae) tot hn t 10 en 100lan so vi cac cephalosporin co ien.

Pho khang khuanCephalosporin III


44/57


45/57

Cephalosporin the he th IV

Cefpirom (1994)

C3: cyclopentenopyridintang hoat tnh khang caukhuan gram (+) vaenterobacterie, VK tietcephalosporinase.

Cefepim (1994)

C3: 3-(N-methylpyrrolidin).

N

SHN

H H

COOHO

R1-----------------------------------------------------------------------------

R2

O

NOR1

R2

N

SH2N

CH3 N

CH3 NH

3C

Cefpirom

Cefepim



46/57


N

S

ON

HN

N

O

H H

O

O

NN

O

CH3

NS

N

H2N

(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)- 2-methoxyiminoacetyl]amino]-3-(imidazo[2,3-f]pyridazin- 4-ium-1-ylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylate

Cefozopran



47/57


N

S

O

HN

N

O

H H

O

O

O

CH3

S

N

H2N N

1-[[(6R,7R)-7-[[(2Z)-(2-Amino-4-thiazolyl)-(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0-oct-2-en-3-yl]methyl]-

5,6,7,8-tetrahydroquinolinium inner salt

Cefquinome


48/57

Cephalosporin the he 1 va 2:

- d phong phau thuat nhat la nhng trng hp conguy c nhiem Staphylococcus sau mo.

- dung trong nhng trng hp nhiem trung ngoaibenh vien

Cephalosporin the he 3 va 4:

- ieu tr nhiem trung Pseudomonas

- ieu tr nhng nhiem trung cha xac nh nhng acbiet nang: nhiem trung nao, ng tieu tren, san phukhoa, ho hap, tieu hoa hoac vung bung, nhiem trungmau mac phai tai benh vien

CH NH CHUNG


49/57

D ng: t hn Penicillin

oc tnh vi than: ac biet oi vi cefaloridin,khi phoi hp vi cac khang sinh khac co oc

tnh than Roi loan ve mau va tac ong antabuse, tranh

dung chung vi ru.

OC TNH

Cac cepha co cha nhom the tetrazolthiomethyl


50/57

M-14659



51/57


-Ceftobiprole inhibits the 2a penicillin-binding protein (PBP 2a) ofMethic i l l in-

resistant Staph yloco ccu s aureusand the PBP 2ofStreptococcus

pneumoniaeas well as the classic PBP2 of MSSA.

- Ceftobiprole is resistant to staphylococcal -lactamase

N

S

O

HN

N

O

H H

O

O

OH

NS

N

H2NN

O

NH

Ceftobiprole

(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-ylidene)- 2-nitroso-1-oxoethyl]amino]-8-oxo-3-[(E)-[2-oxo-1-[(3R)- 3-pyrrolidinyl]-3-pyrrolidinylidene]methyl]-

5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
http://en.wikipedia.org/wiki/Penicillin-binding_proteinhttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Streptococcus_pneumoniaehttp://en.wikipedia.org/wiki/Streptococcus_pneumoniaehttp://en.wikipedia.org/wiki/Beta-lactamasehttp://en.wikipedia.org/wiki/Beta-lactamasehttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Streptococcus_pneumoniaehttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Beta-lactamasehttp://en.wikipedia.org/wiki/Beta-lactamasehttp://en.wikipedia.org/wiki/Beta-lactamasehttp://en.wikipedia.org/wiki/Streptococcus_pneumoniaehttp://en.wikipedia.org/wiki/Streptococcus_pneumoniaehttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Penicillin-binding_proteinhttp://en.wikipedia.org/wiki/Penicillin-binding_proteinhttp://en.wikipedia.org/wiki/Penicillin-binding_protein


52/57

Ceftobiprole medocaril. Ceftobiprole medocaril (BAL-5788), a water-soluble cephalosporin

prodrug, belongs to a new class of cephem antibiotics with activity against a wide range of

gram-positive organisms, including MRSA and penicillin-resistant Streptococcus

pneumon iae (PRSP), and g ram-negativepathogenic bacteria .

O

CH3


53/57

- Ceftaroline fosamil (10/2010) is a fifth-generation cephalosporin antibiotic. It is

active against methicillin-resistant Staphylococcus aureus (MRSA) and Gram

positive bacteria.

- It retains the activity of later generation cephalosporins having broad

spectrum activity against Gram negative bacteria.

- It is currently being investigated forcommunity-acquired pneumonia and

complicated skin and skin structure infection

N

S

O S

HN

N

O

H H

O

O

O

N

S

N CH3

NS

N

NHPO

HO OH

Ceftaroline f osamil

(6R,7R)-7-[(2Z)-2-ethoxyimino-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-3-[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl]

-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

MONOBACTAM
http://en.wikipedia.org/wiki/Cephalosporinhttp://en.wikipedia.org/wiki/Antibiotichttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Gram_positivehttp://en.wikipedia.org/wiki/Gram_positivehttp://en.wikipedia.org/wiki/Gram_negativehttp://en.wikipedia.org/wiki/Community-acquired_pneumoniahttp://en.wikipedia.org/wiki/Complicated_skin_and_skin_structure_infectionhttp://en.wikipedia.org/wiki/Complicated_skin_and_skin_structure_infectionhttp://en.wikipedia.org/wiki/Complicated_skin_and_skin_structure_infectionhttp://en.wikipedia.org/wiki/Complicated_skin_and_skin_structure_infectionhttp://en.wikipedia.org/wiki/Community-acquired_pneumoniahttp://en.wikipedia.org/wiki/Community-acquired_pneumoniahttp://en.wikipedia.org/wiki/Community-acquired_pneumoniahttp://en.wikipedia.org/wiki/Gram_negativehttp://en.wikipedia.org/wiki/Gram_positivehttp://en.wikipedia.org/wiki/Gram_positivehttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureushttp://en.wikipedia.org/wiki/Antibiotichttp://en.wikipedia.org/wiki/Cephalosporin


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MONOBACTAM

NO

HNR

O

OH

HOOC

HOOC O

NOH

NH2

_______________________________________________R

Nocardicin A

AZTREONAM

MONOBACTAM


55/57

AZTREONAM

Acid (Z)-2[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1sulfo-3-azetidinyl]

carbamoyl]methylen]amino]oxy]-2-methyl propionic

HOH

O

H2NH OHCH3

H(S)

(R)(S)N

O

H2N H OHCH3H(R)(S)

OR NO

H2NH

CH3(S)

H

H

(S)

NO

H2NH

CH3(S)

SO3H

H

(S)

NO

NH

CH3(S)

SO3H

HHN

S O

N

H2N

O

COOHH3CH3C

Aztreonam

MONOBACTAM


56/57

Pho khang khuan

Aztreonam khong co hoat tnh tren vi khuan gram (+).

Hoat tnh tren vi khuan gram am tng ng vicephalosporin III: Enterobacterie, H. influenzae,Pseudomonas, Neisseria menigitidis

AZTREONAM

Acid (Z)-2[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1sulfo-3-azetidinyl]

carbamoyl]methylen]amino]oxy]-2-methyl propionic

COOH


57/57

Cai thien tac ong trenEnterobacteriaceae

manh tren gram am ;

ben vi -lactamase;

hp thu tt qua ng ung

(2-carbamoyloxymethyl) 2,2-dimethyl

N

HN

S

N

H2N

N

O

O

O SO3H

Aztreonam

N

HN

S

N

H2N

N

O

O

COOH

O SO3H

OCONH2

Carumonam

N

HN

S

N

H2N

N

O

O

COOH

O SO3H

Tigemonam

Betalactam II Dai Hoc 2012.SV

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Transcript of Betalactam II Dai Hoc 2012.SV