Organic Chemistry

1218 CHAPTER 30 The Organic Chemistry of Drugs

Chemists have developed drugs that inhibit penicillinase. If such a drug is given to

a patient along with penicillin, the antibiotic is not destroyed. This is an example of a

drug that has no therapeutic effect itself, but acts by protecting a therapeutic drug.

One penicillinase inhibitor is a sulfone, which is easily prepared from penicillin by

oxidizing the sulfur atom with a peroxyacid (Section 20.4).

Because the sulfone looks like the original antibiotic, penicillinase accepts it as a

substrate, forming an ester, as it does with penicillin. If the ester were then hydrolyzed,

penicillinase would be liberated and, therefore, would be free to react with penicillin.

However, the electron-withdrawing sulfone provides an alternative pathway to hydroly-

sis that forms a stable imine. Because imines are susceptible to nucleophilic attack, an

amino group at the active site of penicillinase reacts with the imine, forming a second

covalent bond between the enzyme and the inhibitor. The covalently attacked group

inactivates penicillinase, thereby wiping out the resistance to penicillin. The sulfone is

another example of a mechanism-based suicide inhibitor(Section 25.8).

What makes the sulfone such an effective inhibitor is that the reactive imine group

does not appear until after the sulfone has been bound to the enzyme that is to be inac-

tivated. In other words, the inhibitor has a specific target. In contrast, if an imine were

RCOOH

C

RCNH HC

O

O

a sulfone

C

RCNH HC

O

O

penicillin

COO−

S

N

CH 3

CH 3

COO−

S

CH 3

CH 3

N

O O O

S

COO−

N

CH 3

CH 3

O

CH 2 O

NH 2

HC

C

+

CH 2 OH

O

RCNH

CH 2 O

ester hydrolysis

imine formation

CH 2 OH

HC

C NH

CH 3

CH 3

C

−SO 2

CH 3

CH 3

C

−SO 2

COO−

CH

H 2 N

O

O

O

N

RCNH

O

O

O

NH

NH CH

COO−

RCNH

O

O

RCNH

O

RCNHCH

O C

COO−

−SO 2

CH 3

CH 3

CH

+NH CH

C

penicillinase

an ester

an imine

penicillinase

inactive

penicillinase penicillinase

COO−

S

CH 3

CH 3

O O O O

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