CEPHALOSPORIN STRUCTURE-ACTIVITY RELATIONSHIP [PDF]

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, spectrum of activity, PBP affinity, beta-lactamase resistance, oral activity, stbaility, metabolism, plasma protein binding, adverse reactions, etc. H

X

H

N

R7

O

S

N R3

O COOH

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

CEPHALOSPORIN STRUCTURE-ACTIVITY RELATIONSHIPS: THE 3-POSITION H R

H

H

N

R = H, C H3 , C l, CH 2O CH 3, CH= CH R'

S

3

N

O

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

O

R CO O H

H R

H

H

O

N

O

R

H

H

O

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

S

N N

O

O

H

H

H

O

H

H

H

N O

3-Thiothiadiazole: Acid unstable but metabolically stable: - Minimal effective on spectrum of activity - Not orally active: H+ instability - Metabolically stabilized

S

N CH 2S

O

CO O H

R

N

N

H

O

N-Methylthiotetrazole (NMTT):

N CH 2S

N N

CO OH

N

CH 3

S

N

N CH 2S

N N

CO OH

H

S

N

N CH 2 S

Longer t1/2

- Increased ppb (vs compds above)

S

N

H

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

S

N O

NH 2

O CO O H

R

CH 3

O CO O H

H

Cephalosporanic Acids: Acid unstable and metabolically unstable 3-substituent: - Minimal effective on spectrum of activity - Not orally active: H+ and metabolism - Metabolically unstable and low ppb: Short t1/2

S

N

N

CH 2SO 3 H

CH 2C OO H

N-Methylthiotetrazole-1-acetic acid:

N N

CO OH

N

N-Methylthiotetrazole-1-methansulfonic acid:

- NMTT group has minimal effect on spectrum of activity - All are metabolically stable - All are acid unstable : Not orally active - %ppb and half-life increases with NMTT side chain acidity - Disulfiram and hematologic adverse reactions? S

CH 3 N

N

N

H OH

CH2 S CO OH

N O

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

H

S + N

N CO O

S +

N

N

-

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

CO O

-

CH 3

3-Pyrrolidinium Group - Antipeusodmonal activity - Low ppb

CEPHALOSPORIN STRUCTURE-ACTIVITY RELATIONSHIPS: THE 7-POSITION Z

H

H

H

Ar

Z = NH2 or OH, OCHO: (1st and 2nd generation) - Minimal resistance to beta-lactamases - More acid stable than Z = H - G (+) activity; Minimal to Low G(-) Activity

S

N N

O

O

R CO OH

OCH 3 H R

H

N O

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

S

N O

R CO OH

N

OCH 3 H

H

H

N

Ar

N S Ar

O

N O

O

R

H

O(C H)n COO H H H H S N

C Ar

N O

O

R

CO OH

(CH )n COOH H H H S N N O

Methoxyimine

Alkene-acid

N-alkoxyacid-imine

- Stereochemistry: syn for activity - Acid stability/oral activity dependent on imine/alkene structure - Good beta-lactamase stability - Induce beta-lactamases - Incr G(-) activity - Decr G(+) activity

S

H2 N

H N

C

H

S

CO NH N

N

R

O

O R'

R CO OH

CO OH

CO OH

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