Organic Chemistry

1212 CHAPTER 30 The Organic Chemistry of Drugs

Gram-negative bacteria have an outer

membrane that covers their cell walls;

gram-positive bacteria do not have an

outer membrane, but tend to have

thicker and more rigid cell walls. The

two can be distinguished by a stain,

invented by Hans Christian Gram, that

turns gram-negative bacteria pink and

gram-positive bacteria purple.

over 10,000 dyes were screened in vitro in antibacterial tests, but none showed any

antibiotic activity. Some scientists argued that the dyes should be screened in vivo

because what physicians really needed were antibacterial agents that would cure

infections in humans and animals, not in test tubes.

In vivo studies were done in mice that had been infected with a bacterial culture.

Now the luck of the investigators improved. Several dyes turned out to counteract

gram-positive infections. The least toxic of these, Prontosil (a bright red dye), became

the first drug to treat bacterial infections.

The fact that Prontosil was inactive in vitro but active in vivo should have suggested

that the dye was converted to an active compound by the mammalian organism, but this

did not occur to the bacteriologists, who were content to have found a useful antibiotic.

When scientists at the Pasteur Institute later investigated Prontosil, they noted that mice

given the drug did not excrete a red compound. Urine analysis showed that the mice

excreted para-acetamidobenzenesulfonamide, a colorless compound. Chemists knew

that anilines are acetylated in vivo, so they prepared the nonacetylated compound

(sulfanilamide). When sulfanilamide was tested in mice infected with streptococcus, all

the mice were cured, whereas untreated control mice died. Sulfanilamide was the first

of the sulfa drugs.

We have seen that sulfanilamide acts by inhibiting the bacterial enzyme that incor-

porates para-aminobenzoic acid into folic acid (Section 25.8). Thus, sulfanilamide is a

bacteriostaticdrug, not a bactericidaldrug. A bacteriostatic druginhibits the further

growth of bacteria, whereas a bactericidal drugkills the bacteria. Sulfanilamide in-

hibits the enzyme because the sulfonamide and carboxylic acid groups have similar

sizes. Many successful drugs have been designed by using similar isosteric (like-size)

replacements (Sections 25.8 and 25.9).

30.5 Serendipity in Drug Development

Many drugs have been discovered accidentally. Nitroglycerin, the drug used to relieve

the symptoms of angina pectoris (heart pain), was discovered when workers handling

nitroglycerin in the explosives industry experienced severe headaches. Investigation

revealed that the headaches were caused by nitroglycerin’s ability to produce a marked

dilation of blood vessels. The pain associated with an angina attack results from the in-

ability of the blood vessels to supply the heart adequately with blood. Nitroglycerin re-

lieves the pain by dilating cardiac blood vessels.

The tranquilizer is another drug that was discovered accidentally. Leo

Sternbach synthesized a series of quinazoline 3-oxides, but none of them showed

any pharmacological activity. One of the compounds was not submitted for testing

Librium®

CH 2 ONO 2

CH ONO 2

CH 2 ONO 2

nitroglycerin

NH SO 2 NH 2 H 2 N

para-aminobenzenesulfonamide

sulfanilamide

CH 3 CSO 2 NH 2

O

para-acetamidobenzenesulfonamide

NH 2

H 2 NNNSO 2 NH 2

Prontosil

Gerhard Domagk (1895–1964)

was a research scientist at I. G.

Farbenindustrie, a German

manufacturer of dyes and other

chemicals. He carried out studies

that showed Prontosil to be an

effective antibacterial agent. His

daughter, who was dying of a

streptococcal infection as a result of

cutting her finger, was the first

patient to receive the drug and be

cured by it (1935). Prontosil received

wider fame when it was used to save

the life of Franklin D. Roosevelt, Jr.,

son of the U.S. president. Domagk

received the Nobel Prize in

physiology or medicine in 1939, but

Hitler did not allow Germans to

accept Nobel Prizes because Carl

von Ossietsky, a German who was in

a concentration camp, had been

awarded the Nobel Prize for peace in

1935. Domagk was eventually able to
      accept the prize in 1947.

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