The Chemistry in Drugs

for Medicine
Chirality in Drug Molecules
Chemistry Assignment 2017

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 Why most chiral drugs extracted from natural sources
often contain only a single optical isomer?
WHAT IS CHIRALITY ?
Chirality is derived from the Greek word that stands for "hand". An object is said to be chiral if the
object and its mirror image are non-superimposable, just like our right and leY hand. Now you
must be wondering what we mean by non-superimposable. When the mirror image of the object
is placed over the original object and they do not overlap, as shown in the gure below, then the
object and its image are said to be non-superimposable.

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 SINGLE OPTICAL ISOMER

The importance of chiral drugs in the drug development space cannot be understated. In
pharmaceu]cal industries, 56% of the drugs currently in use are chiral molecules.
Although the enan]omers of chiral drugs have the same chemical connec]vity of atoms;
they exhibit marked dierences in their pharmacology, toxicology, pharmacokine]cs and
metabolism. Therefore, when chiral drugs are synthesised, as much eort goes towards the
rigorous separa]on of the two enan]omers. This ensures that only one biologically ac4ve
enan4omer is present in the nal drug prepara]on.
The enan]omers of a chiral drug dier in their interac]ons with enzymes, proteins,
receptors and other chiral molecules too including chiral catalysts. These dierences in
interac]ons, in turn, lead to dierences in the biological ac]vi]es of the two enan]omers, such as
their pharmacology, pharmacokine]cs, metabolism, toxicity, immune response etc.
Biological systems can recognise the two enan]omers as two very dierent substances.

BUT WHY, DO ENANTIOMERS HAVE DIFFERENT BIOLOGICAL ACTIVITIES ?

Recogni]on of chiral drugs by specic drug receptors is explained by a three-point

interac]on of the drug with the receptor site, as proposed by Easson and Stedman. The dierence
between the interac]on of the two enan]omers of a chiral drug with its receptor is illustrated
below.

Easson-Stedmans illustra]on of hypothe]cal interac]on between the two enan]omers of a

racemic drug with a receptor at the drug binding sites: The three subs]tuents A, B, C of the ac]ve
enan]omer (leY) can interact with three binding sites a, b, c of a receptor by forming three

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contacts Aa, Bb and Cc, whereas the inac]ve enan]omer (right) cannot because the contact is
insucient.

THESE OTHER ENANTIOMERS CAN ALSO HAVE POTENTIAL SIDE EFFECTS TO THE BODY or will be
inac]ve

1. Thalidomide: One enan]omer is eec]ve against morning sickness, whereas the other may
cause birth defects. In this case, administering just one of the enan]omers to a pregnant
pa]ent does not help, as the two enan]omers are readily interconverted in vivo. Thus, if a
person is given either enan]omer, both the R and S isomers will eventually be present in the
pa]ent's serum.

2. Ethambutol: Whereas one enan]omer is used to treat tuberculosis, the other causes
blindness.

3. Naproxen: One enan]omer is used to treat arthri]s pain, but the other causes liver poisoning
with no analgesic eect.

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4. Penicillins ac]vity is stereo dependent. The an]bio]c must mimic the D-alanine chains that
occur in the cell walls of bacteria in order to react with and subsequently inhibit bacterial
transpep]dase enzyme.

5. Only S-propranolol is a powerful adrenoceptor antagonist, whereas R-propranolol is not.

However, both have local anaesthe]c eect. The -blocking ac]vity of (-)-(S)-Prop is about 100
]mes higher than the ac]vity observed for (+)-(R)-Prop.

6. The L-isomer of Methorphan, levomethorphan is a potent opioid analgesic, while the D-

isomer, dextromethorphan is a dissocia]ve cough suppressant.

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7. S(-) isomer of carvedilol, a drug that interacts with adrenoceptors, is 100 ]mes more potent as
beta receptor blocker than R(+) isomer. However, both the isomers are approximately
equipotent as alpha receptor blockers.

8. The D-isomers of amphetamine and methamphetamine are strong CNS s]mulants, while the L-
isomers of both drugs lack appreciable CNS(central nervous system) s]mulant eects, but
instead s]mulate the peripheral nervous system.

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 REASONS WHY THE SYNTHETIC PREPARATION OF
DRUG MOLECULES OFTEN REQUIRES THE
PRODUCTION OF A SINGLE OPTICAL ISOMER

The most drama]c case of enan]omers that have dierent eects in

the body is that of thalidomide. "Right-handed" thalidomide stops
nausea and vomi]ng, while "leY-handed" thalidomide causes severe
birth defects. Thousands of babies were born in the late 1950s and
early 1960s, mostly in Europe, with birth defects caused by the
thalidomide their mothers were given for morning sickness. (Even if
pregnant women had access to the "safe" enan]omer, the body
changes it back and forth into both enan]omers, so it would s]ll
cause birth defects.)

REASONS

Armodanil (Nuvigil) is a newly-approved drug

that is the R-enan]omer of modanil (Provigil).
This enan]omer stays in the body longer than
the S-enan]omer, so theore]cally, it may work
be;er or longer than racemic modanil.

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