beta lactam

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KHANG SINH -LACTAMIN (-LACTAM)

Azetidin = -lactamin

CAC THUOC CHNHPenicillin: (PENAM) penicillin G; penicillin V methicillin; oxacillin ampicillin; amoxicillin; carbenicillin; ticarcillin

S N O

Cht c ch -lactamase: (OXAPENAM) sulbactam; acid clavulanic

O N

OCARBAPENEM: imipenem

N O

CAC THUOC CHNHCephalosporin (CEPHEM)

S N

O Th h I :cephalexin; cephalothin Th h II: cefoxitin; cefaclor Th h III: cefotaxime; cefoperazone; ceftriaxone Th h IV: cefepimeMONOBACTAM: aztreonam

NH O

C CHE KHANG KHUAN

C CHE E KHANGVi khuan e khang lactamin theo cac c che sau: e khang enzym: VK sn xut -lactamase e khang khong enzym:

- thay oi tnh tham thau cua mang te bao - bien mat hoac bien oi cac PBP (Penicillin Binding Proteins) - Efflux pumps Vd: multidrug resistance (MDR) pumps

HOAT TNH KHANG KHUANQuan he cau truc tac ongR HN O 6 7 O N H

R1H O 5 3 COOH H 2 4

NH O 7 O

H 6 N

H S

5 4 3 R2

1

1COOH

Penicillin

R NH O N Omonobactam

cephalosporin

H

R1 R2 SO3H

NHOM PENICILLIN

Benzyl penicillin = Penicillin G

R HN O H H S

4

H2N

H

H S

4

6 7O N

63

5O

5N

7

3COOH H 2

1

1

COOH H 2

PenicillinDanh phap IUPAC

6-aminopenicillinic acid

Amid- 6 cua acid (2S, 5R, 6R-amino-6-dimethyl-3,3-oxo-7-thia-4-aza1-bicyclo [3.2.0]-heptan carboxylic). Danh phap thong dung Penicillin nh la nhng amid cua acid 6-amino penicillanic (6- APA).

IEU CHEH H CH2 CO HN N O H S CH3 CH3 COO R'

H2 O O C C NH H H N O H

S COO

R

Phng phap sinh hoc T nam Penicillium notatum.Penicillin G (them vao moi trng acid phenylacetic ) Penicillin V (them vao moi trng acid phenoxyacetic )

60mg/L

20 g/L

IEU CHE

Ban tong hpR HN O H H S

4A- condition

H2 N

H

H S

4

6 7O N

5 3COOH H 2

6 7O N

5 3COOH H 2

B-condition

1

1

PenicillinA-condition = Aclylase B-condition = 1. Me2SiCl22. n-Bu-OH, -40oC 3. H2O, 0oCR1 H2N H H S

6-aminopenicillinic acid

4R'COCl, Et3NO

HN

H

H S

4

6 7O N

5 31

6 7O N

5 3COOH H 2

COOH H 2

1

6-aminopenicillinic acid

Penicillin

BAN TONG HP AMOXICILLINO N H 2N COOH CH3 S CH3 6-APA + CH 3 Cl Si CH 3 CH 3 trimethyl clorosilon O N H 2N O H 3C CH3 O Si CH3 CH3

S CH3

6-aminopenicillanic acid trimethylsilyl ester (I) O H3C CH3 O Si CH3 CH3

HO (I) +

O Cl NH2

.HCl N,N-dimethylanilin HO O

O N HN NH 2

S CH3

D-(-)2-(4-hydroxyphenyl)-glycyl clorid. hydroclorid

amoxiillin trimethylsilyl ester (II)

O (II) H2 O, pH 1,3-1,5 HO O HN NH 2 N

COOH CH3 S CH3

Amoxcicillin

R HN H H S

4

Tnh chat vat ly

O

6 7O N

5 3COOH H 2

1

Penicillin

Cac penicillin di dang muoi hoac dang acid la nhng bot trang khong mui khi tinh khiet. Pho UV Pho IR: vung 1600-1800 cm-1 1760 va 1730 cm-1 1700 va 1650 cm-1 1600 cm-1

Benzylpenicillin K (BP 2007)

Absorbance (2.2.25) Dissolve 94.0 mg in water R and dilute to 50.0 ml with the same solvent. Measure the absorbance of the solution at 325 nm, 280 nm and at the maximum at 264 nm, diluting the solution, if necessary, for the measurement at 264 nm. The absorbances at 325 nm and 280 nm do not exceed 0.10 and that at the maximum at 264 nm is 0.80 to 0.88, calculated on the basis of the undiluted (1.88 g/l) solution. Verify the resolution of the apparatus (2.2.25); the ratio of the absorbances is at least 1.7.

R HN H H S

4

Tnh chat vat ly Nng sut quay cc

O

6 7O N

5 3COOH H 2

1

Penicillin

Benzylpenicillin K (BP 2007)

Specific optical rotation (2.2.7) Dissolve 0.500 g in carbon dioxide-free water R and dilute to 25.0 ml with the same solvent. The specific optical rotation is + 270 to + 300, calculated with reference to the dried substance.

Tnh chat hoa hoc

R HN O H H S

4

6 7O N

5 3COOH H 2

Tnh acid Tao muoi natri va kali (bn) Tan trong nc, pha tiem

1

Penicillin

Natri amoxicillin K Benzylpenicillin

Tnh chat hoa hocTnh acid Tao muoi vi cac amin: Procain penicillin: tac ong keo dai 24-48 h,

R HN O H H S

4

6 7O N

5 3COOH H 2

1

Penicillin

Benethamin penicillin: tac ong keo dai 3-7 ngay, Benzathin penicillin: tac ong keo dai 2-4 tuan.

Procain benzylpenicillin

Benzathin benzylpenicillin

Tnh chat hoa hoc

R HN O H H S

4

6 7O N

5 3COOH H 2

1

Tnh acid

Penicillin

Tao thanh nhng este, tien chat cua PNC co kha nang phong thch tr lai cac khang sinh nay in vivo.

Bacampicillin HCl

Tnh khong ben cua vong beta lactam (OH- hay penicillinase)R penicillin OH O H H H N S O N CO2 H O H H S R HO C HN O COOH acid penicilloic

S S ROCHN N H acid penilloic CO2H ROCHN N H COOH - CO2 ROCHN O

S N OH COOH

H ROCHN O +

HS H2 N

- Chu y tng k vi nhng chat co tnh kiemCOOH

- Phn ng d ng

penilloaldehyd

D-penicillamin

S alcol phan va amino phan

R

C O

NH

H S N CH3 CH3 COOH R C O NH

H S CO N D CH3 CH3 COOH

O D

Tac nhan ai nhan alcol R'OH amin R'-NH-R'' hydroxylamin NH2OH R'O R'-N-R'' NH-OH

san pham ester penicilloic amid penicilloic d/c a. hydroxamic

S m vng -lactam c xc tc bi cc ion kim lai (Phc to thnh vi ion kim lai hat ha s tn cng i nhn)

2+

O N S

O Ac HN

M

O CH 3 CH 3 Ac

2+

O N

O HN

M

O X S

H H

H H

H R C N O O N

S

CH 3 CH 3

H R C N NH 2OH O O HN NH OH

S

CH 3 CH 3

COOH Cu2+

COOH

H R C N O O

S

CH 3

HN CH 3 NH CO O Cu O

(xanh ngoc)

Tnh khong ben cua vong beta lactam (acid mnh, nng hoc HgCl2)R O O H H NH H N CH2 O2 H R S O O H NH H HN CO2H S

R R O HO H H H N HN O CO2H O O O S R N

NH

HS N

O

CO2H

HS HN CO2H

acid penicilloic

S ROCHN N H acid penilloic CO2 H

H ROCHN O +

HS H 2N

COOH

penilloaldehyd

D-penicillamin

H H CH2 CO HN N O H S CH3 CH3 COO R'

H2 O O C C NH H H N O H

S COO

R

Peni G

Peni V

H H C NH2 O H CO NH N COO Na H S

H H HO C NH2 O CO NH N H COO Na H S

Amoxicillin

Ampicillin

Kiem nghiem

nh tnh:- Pho IR - Sac ky lp mong

H CH2 CO HN

H S N CH3 CH3 H COO R'

O

- Phan ng vi hydroxylamin, sau o vi CuSO4 - Phan ng mau vi acid H2SO4 - Phan ng mau vi dd formaldehyd trong H2SO4

Kiem nghiemKiem tinh khiet - pH- Nang suat quay cc - Cac tap chat thong thng: Th du kim loai nang - Cac tap chat lien quan: Th du N,N-dimethylanilin (trong ampicillin hoac amoxicillin) bang sac ky kh.H H C NH2 O H CO NH N COO Na H S

H H HO C NH2 O CO NH N H COO Na H S

Amoxicillin

Ampicillin

Kiem nghiemnh lng

1. PHNG PHAP OXY HOA KH

Penicilin

phan huy

D-penicillamin + acid penaldic

2. PHNG PHAP HPLC 3. PHNG PHAP VI SINH VAT (Xac nh hoat lc cua khang sinh)

OC TNH VA TAI BIEN Cac khang sinh nhom penicillin rat t oc, Tai bien chu yeu do d ng, D ng nhe gay nga, noi me ay D ng nang gay shock phan ve

PENICILLIN NHOM IPenicillin thien nhienH H CH2 CO HN N O H S CH3 CH3 COO R'

H2 O O C C NH H H N O H

S COO

R

Peni G

Peni V

Penicillin G (benzyl penicillin)Dang tac dung nhanh: Na/K benzyl penicillin Dang tac dung cham: procain PNC, benethamin PNC, benzathin PNC Penicillin V (phenoxy methyl penicillin)

PENICILLIN NHOM I

Penicillin ban tong hpX

Ben trong moi trng acid, hap thu tot hn, hoat chat trong huyet thanh cao hn, T1/2 dai hn.

H CH CO N Z X O

H H S N H CH 3 CH2 COO

Z = N3 - ; X = H : azidocillin Z = OCH3 - ; X = Cl : clometocillin

T PNC-G: azidocillin, clometocillin T PNC-V: pheneticillin, propicillin, phenbenicillin

H O CH CO N Z O

H H S N H CH 3 CH2 COO

Z = CH 3- : pheneticillin Z = C2 H5 - : propicillin Z = C6 H5 - : phenbennicillin

PENICILLIN NHOM IPho khang khuan Pho khang khuan hep, chu yeu tren gram (+): Cau khuan gram (+): tu cau khong tiet

penicillinase, lien cau, phe cau

Cau khuan gram (-): lau cau (khuynh hng tang

MIC va xuat hien nhng chung e khang). va Borelia burgdorferi.

Xoan khuan: xoan khuan giang mai, leptospira Trc khuan gram (+): trc khuan gay benh bach

hau, benh than, listeria(viem mang nao), erysipelothrix (viem quang).

KHONG TAC DUNG TREN TRC KHUAN GRAM (-)

Meticillin, oxacillin, cloxacillin, dicloxacillin, Pho hep gan giong penicillin nhom I, nhng co kha nang khang lai penicillinase do S. aureus tiet ra.

PENICILLIN NHOM II

O

CH3 H CO HN N O Meticillin H H S CH3 CH3 COO Na

O

CH3

PENICILLIN NHOM II Meticillin, oxacillin, cloxacillin, dicloxacillin,X H C N Y O O isoxazolylpenicillinX Y ------------------------------------------------------------Oxacillin (Bristopen) H H Cloxacillin (Orbenin) Cl H Dicloxacillin (Dicloxil) Cl Cl Fluocloxacillin (Floxapen) Cl F Chu y: s a thay the