Medicinal Chemistry

cis/transisomerism without the presence of a double bond; the restriction on their rotation
is ensured by the ring system itself. Diastereomerism can also occur in these molecules.
In substituted cyclohexanes, or their heterocyclic analogs, 1,2–diaxial or the equivalent
diequatorial substituent pairs are considered to be trans, while the axial–equatorial pair
is regarded as cis. 1,3–diequatorial substituents are, however,cis.
The axial or equatorial nature of a substituent has a bearing on its reactivity, or abil-
ity to interact with its environment. Equatorial substituents are more stable and less
reactive than their axial counterparts. For example, equatorial carboxyl groups are
stronger acids than axial ones because of the higher stability of the carboxylate ion,
whereas equatorial esters are hydrolyzed more slowly than axial ones because they are
less accessible to protons or hydroxyl ions during acid- or base-catalyzed hydrolysis.
Even better than an acyclic saturated hydrocarbon such as cyclohexane is the use
of aromatic rings, especially polyaromatic systems. The unsaturated structure of the
aromatic ring imparts planarity and rigidity. Drugs in which the functional groups are
appended to an aromatic ring have marked conformational rigidity. In the realm of
neurologic drug design, the use of tricyclic structures containing aromatic rings is
extremely common in major antipsychotics (e.g., chlorpromazine (1.3)), antidepres-
sants (e.g., amitriptyline (1.4)), and anticonvulsants (e.g., carbamazepine (1.5)).
Although they are superb for achieving planarity and rigidity, polyaromatic systems
may come accompanied with the risk of a side-effect—carcinogenicity. Such rigid,

DRUG MOLECULES: STRUCTURE AND PROPERTIES 35

Figure 1.10 The six-membered cyclohexane ring can adopt a series of different conformations.
The chair conformation is more stable than the boat or twist because it permits a maximal number
of substituents to exist in a staggered conformation relative to their neighbors.

N

N

N

N

S

Cl

ONH 2

Chlorpromazine

(1.3)

Amitriptyline (1.4) Carbamazepine

(1.5)