cephrev

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CEPHALOSPORIN STRUCTURE-ACTIVITY RELATIONSHIP SUMMARY

The following pages contain a summary of the more general structure-activity

relationships observed for the cephalosporins. These three pages do not contain all of the

information you are required to know, but should focus your thinking on the general

relationships between structure and properties involving reactivity, formulation, spectrumof activity, PBP affinity, beta-lactamase resistance, oral activity, stbaility, metabolism,

plasma protein binding, adverse reactions, etc.

Beta-Lactam Ring:

• Required for PBP reactivity and antibacterial activity

• Reactivity reduced compared to the penicillins (2 reasons)

• Compare mechanism of action, resistance, pharmacodynamics, etc to penicillins

2-Carboxyl Group:

• Acidic: Salt formation, product formulation

• Prodrug formation

• Elimination profile: Renal

X-Substituent:

• Cephalosporins and cephamycins

• Determines, in part, resistance to beta-lactamase inactivation

3- Substituent (R3): SEE PAGE 2 FOR SAR SUMMARY

• Chemical/acid stability/instability

• Metabolic stability/instability

• Minimal impact on antibacterial activity

• Protein binding and half-life: Heterocycles

• Adverse Reaction and Drug Interaction

• Some role in cephalosporin classification (generation)

7-Substituent (R7): SEE PAGE 3 FOR SAR SUMMARY

• Incorporated by semisynthesis: Variable structures

• Impact on spectrum of activity (beta-lactamases, PBP affinity, etc.)

• Significant role in activity and classification by generation

N

S

COOH

O

HX

R3

N

H

O

R7



N

S

COOH

O

HH

N

H

O

R

O

O

CH3

N

S

COOH

O

HH

R

N

H

O

R

R = H, C H3, C l, CH2O CH3, C H=CHR'

N

S

COOH

O

HH

CH2S

N

H

O

R

N N

S

N

S

CO OH

O

HH

CH2S

N

H

O

R

N N

N

N

CH3

N

S

COOH

H

CH2S

N N

N

N

CH2COOH

N

S

C O O H

H

CH 2S

N N

N

N

CH 2SO 3 H

N

S

COOH

O

HH

N

H

O

R

O

O

NH2

N

S

COOH

H

CH2S

N

NN

CH3

OH

O

H

N

COO-

S

N + +

H

COO-

S

N N

CH3

CEPHALOSPORIN STRUCTURE-ACTIVITY RELATIONSHIPS: THE 3-POSITION

Cephalosporins/cephamycins with acid stable

and metabolically stable 3-substituents:

- Minimal effective on spectrum of activity- May impart oral activity

- Metabolically stable and low ppb: Short t1/2

- Metabolically unstable and low ppb: Short t1/2

- Not orally active: H+ and metabolism- Minimal effective on spectrum of activity

metabolically unstable 3-substituent:Cephalosporanic Acids: Acid unstable and

3

3-Carbamoylcephalosporins: Acid unstable butsomewhat metabolically stable (>cephalosporanic acids):

- Minimal effective on spectrum of activity- Not orally active: H+ instability- Metabolically stabilized, but low ppb: Short t1/2

- Metabolically stabilized

- Not orally active: H+ instability

- Minimal effective on spectrum of activity

metabolically stable:3-Thiothiadiazole: Acid unstable but

- Increased ppb (vs compds above) Longer t1/2

N-Methylthiotetrazole (NMTT):

- All are metabolically stable

N-Methylthiotetrazole-1-acetic acid: N-Methylthiotetrazole-1-methansulfonic ac

- All are acid unstable : Not orally active

- NMTT group has minimal effect on spectrum of activity

- %ppb and half-life increases with NMTT side chain acidity- Disulfiram and hematologic adverse reactions?

3-Thiotriazine ring system:

- Metabolically stable but acid unstable- High ppb: Longer t1/2- Shift toward hepatic clearance- Pseudocholelithiasis

3-Pyridinium group

-Acid and some metab. stable- Permanent ion: Decr absorption

- Antipeusodmonal activity- Low ppb

3-Pyrrolidinium G



N

S

COOH

O

H

R

N

H

O

R

OCH3

N

S

COOH

O

HH

R

N

H

O

Ar

Z

N

S

COOH

O

HH

R

N

H

O

Ar

N

OCH3

N

S

COOH

O

HH

R

N

H

O

Ar

N

O(C H)nCOOH

N

S

COOH

O

HH

R

N

H

O

Ar

C

(CH)nCOOHH

N

S

N

C

H

CONH

H

RO

COOH

S

N

H2N

O

R'

CEPHALOSPORIN STRUCTURE-ACTIVITY RELATIONSHIPS: THE 7-POSITION

Z = NH2 or OH, OCHO: (1st and 2nd generation)

- More acid stable than Z = H- G (+) activity; Minimal to Low G(-) Activity

- Minimal resistance to beta-lactamases

Cephamycins:- Stability to some beta-lactamases- May induce beta-lactamase- Incr G(-) nd decr G(+) activity

Aminothiadiazole alkoximines:

- Good beta-lactamase stability- Good PBP binding except G(+)- Generally more CDAD

MethoxyimineN-alkoxyacid-imine Alkene-acid

- Good beta-lactamase stability- Induce beta-lactamases

- Stereochemistry: syn for activity

- Incr G(-) activity

- Decr G(+) activity

- Acid stability/oral activity dependent on imine/alkene structure

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