Organic Chemistry

Section 30.7 Drugs as Enzyme Inhibitors 1219

administered directly to the patient, it would be nonspecific, reacting with whatever

nucleophile it first encountered.

When two drugs are given simultaneously to a patient, their combined effect can be

additive, antagonistic, or synergistic. That is, the effect of two drugs used in combina-

tion can be equal to, less than, or greater than the sum of the effects obtained when the

drugs are administered individually. Administering penicillin and the sulfone in com-

bination results in drug synergism: The sulfone inhibits the penicillinase, so peni-

cillin won’t be destroyed and will be able to inhibit the enzyme that synthesizes

bacterial cell walls.

Another reason to administer two drugs in combination is that if some bacteria are

resistant to one of them, the second drug will minimize the chance that the resistant

strain will proliferate. For example, two antimicrobial agents, isoniazid and rifampin,

are given in combination to treat tuberculosis.

Typically, it takes a bacterial strain 15 to 20 years to evolve resistance to antibi-

otics. The fluoroquinolones, the last class of antibiotics to be discovered until very

recently, were discovered more than 30 years ago, so drug resistancehas become an

increasingly important problem in medicinal chemistry. More and more bacteria have

become resistant to all antibiotics—even vancomycin, until recently the antibiotic of

last resort.

The antibiotic activity of the fluoroquinolones results from their ability to inhibit

DNA gyrase, an enzyme required for transcription (Section 27.10). Fortunately, the

bacterial and mammalian forms of the enzyme are sufficiently different that the

fluoroquinolones inhibit only the bacterial enzyme.

There are many different fluoroquinolones. All have fluorine substituents, which

increase the lipophilicity of the drug, enabling it to penetrate into tissues and cells. If

either the carboxyl group or the double bond in the 4-pyridinone ring is removed, all

activity is lost. By changing the substituents on the piperazine ring, excretion of the

drug can be shifted from the liver to the kidney, which is useful to patients with

impaired liver function. The substituents on the piperazine ring also affect the half-

life of the drug.

F

ciprofloxacin

Cipro

active against gram-negative bacteria

N N

HN

O

COOH

sparfloxacin

Zagam

active against gram-negative bacteria

and gram-positive bacteria

N N

HN

CH 3

NH 2

H 3 C

O

F

F

piperazine ring COOH

pyridinone ring

O NHNH 2

N CH 3

O

O OH

OH

O

OH

CH 3

CH 3

CH 3

HO

CH 3 COO

CH 3 O

OH

CH

NH

NN

CH 3

NCH 3

CH 3 CH 3

O

isoniazid

Nydrazid

rifampin

Rifadin

3-D Molecules:

Rifampin;

Isoniazid

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