Organic Chemistry

Section 30.7 Drugs as Enzyme Inhibitors 1217

Molecular modification of promethazine, an antihistamine, led to chlorpromazine,

a drug that, although lacking antihistamine activity, lowered the body temperature.

This drug found clinical use in chest surgery, where patients previously had to be

cooled down by wrapping them in cold, wet sheets. Because wrapping in cold, wet

sheets had been an old method of calming psychotic patients, a French psychiatrist

tried the drug on some of his patients. He found that chlorpromazine was able to sup-

press psychotic symptoms to the point that the patients assumed almost normal behav-

ioral characteristics. However, they soon developed uncoordinated involuntary

movements. After thousands of molecular modifications, thioridazine was found to

have the appropriate calming effect with less problematic side effects. It is now in clin-

ical use as an antipsychotic.

Sometimes a drug initially developed for one purpose is later found to have proper-

ties that make it a better drug for a different purpose. Beta-blockers were originally in-

tended to be used to alleviate the pain associated with angina by reducing the amount

of work done by the heart. Later, they were found to have antihypertensive properties,

so now they are used primarily to manage hypertension, a disease that is prevalent in

the Western world.

30.7 Drugs as Enzyme Inhibitors

In earlier chapters, we discussed several drugs that act by inhibiting enzymes

(Sections 25.8 and 25.9). Penicillin, for example, destroys bacteria by inhibiting the

enzyme that synthesizes bacterial cell walls (Section 17.15).

Bacteria develop resistance to penicillin by secreting penicillinase, an enzyme that

destroys penicillin by hydrolyzing its -lactam ring before the drug can interfere with

bacterial cell wall synthesis.

b

active

enzyme

inactive

enzyme

C

OH COO

−

RCNH HC

O

C

O

O

O C

RCNH HC

O

penicillin

S

N

H

CH 3

CH 3

COO−

S

N

CH 3

CH 3

S NCH 2 CH 2 CH 2 N(CH 3 ) 2

Cl SCH 3

CH 3

NCH 2 CH 2

N

S

chlorpromazine

Thorazine

thioridazine

Mellaril

CH 2 OH + C N +

HC CH

O O

CH 2 ONC

H

N

H

CH CH

H 2 O

O

CH 2 OH C

CH CH

O−

penicillinase penicillin penicillinase penicillinase penicilloic acid

active drug

inactive hydrolysis

product

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