Organic Chemistry

1220 CHAPTER 30 The Organic Chemistry of Drugs

The approval of by the FDA in April 2000 was met with great relief by the

medical community. is the first in a new family of antibiotics: the oxazolidi-

nones. In clinical trials, was found to cure 75% of the patients infected with

bacteria that had become resistant to all other antibiotics.

is a synthetic compound designed by scientists to inhibit bacterial growth at

a point different from that at which any other antibiotic exerts its effect. inhibits

the initiation of protein synthesis by preventing the formation of the complex between

the first amino-acid-bearing tRNA, mRNA, and the 30S ribosome (Section 27.13).

Because of the drug’s new mode of activity, resistance is expected to be rare at first and,

hopefully, slow to emerge.

30.8 Designing a Suicide Substrate

It is important for a drug to have a minimum of undesirable side effects. A drug must

be administered in sufficient quantity to achieve a therapeutic effect; however, too

much of a drug can be lethal. The therapeutic index of a drug is the ratio of the lethal

dose to the therapeutic dose. The higher the therapeutic index, the greater is the mar-

gin of safety of the drug.

Penicillin is an effective antibiotic that has a high therapeutic index because it in-

terferes with cell wall synthesis—and bacterial cells have walls, but human cells do

not. What else is characteristic about cell walls that could lead to the design of an an-

tibiotic? We know that enzymes and other proteins are polymers of L-amino acids. Cell

walls, however, contain both L-amino acids and D-amino acids. Therefore, if the

racemization of naturally occurring L-amino acids to mixtures of L- and D-amino acids

could be prevented,D-amino acids would not be available for incorporation into cell

walls, and bacterial cell wall synthesis could be stopped.

We have seen that amino acid racemization is catalyzed by an enzyme that requires

pyridoxal phosphate as a coenzyme (Section 25.6). What we need, then, is a com-

pound that will inhibit this enzyme. Because the natural substrate for the enzyme is an

amino acid, an amino acid analog should be a good inhibitor.

The first step in racemization is removal of the -hydrogen of the amino acid. If the

inhibitor has a leaving group on the -carbon, the electrons left behind when the pro-

ton is removed can displace the leaving group instead of being delocalized into the

pyridine ring. (Compare the mechanism shown here with that shown for racemization

in Section 25.6.) Transimination with the enzyme forms an -unsaturated amino

acid that reacts irreversibly with the imine formed by the enzyme and the coenzyme.

Because the enzyme is now bound to the coenzyme in an amine linkage rather than in

an imine linkage, the enzyme can no longer undergo a transimination reaction with its

amino acid substrate. The enzyme has thus been irreversibly inactivated. This is an-

other example of an inhibitor that does not become chemically active until it is at the

active site of the targeted enzyme.

a,b

b

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F

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