Page 206 - Medicinal Chemistry Self Assessment

2.20 Montelukast and Zafirlukast 195

3. The sodium salt of montelukast is required for its oral administration, whereas zafirlukast can be
administered orally as its unionized free acid form. Conduct a structural analysis of these two drug
molecules and provide an explanation for this difference.
Answer
A sodium salt is an inorganic salt of the parent drug. The primary purpose of using an inorganic
salt is to enhance the water solubility of a drug molecule. This in turn enhances its solvation and
dissolution with the aqueous environment of the gastrointestinal (GI) tract. Since montelukast must
be administered as an inorganic salt, whereas zafirlukast does not have this requirement, this indi-
cates that zafirlukast has higher water solubility than montelukast. In evaluating their structures, it
is found montelukast and zafirlukast each contain three water soluble functional groups, and the
remainder of their structures is comprised of alkyl chains, aromatic rings, a thioether, and a halogen.
All of these latter functional groups bestow lipid solubility to their respective drug molecules. A
key difference between these two structures is the overall nature of their water soluble functional
groups. The sulfonamide of zafirlukast has a wider charge distribution (four atoms) than does the
carboxylic acid of montelukast (two atoms; Comparison A). Additionally, the carbamate group of
zafirlukast has the ability to form more hydrogen bonds with water than does the tertiary hydroxyl
group of montelukast (Comparison B). The ability to act as hydrogen bond acceptors would be

expected to be similar for the methoxy group of zafirlukast and the aromatic heterocyclic amine of
Answer:
montelukast (Comparison C). Please note that the nitrogen atom of the indole ring is an extremely
weak base (pK < 0.1) and cannot participate in hydrogen bonds. This is because the lone pair of elec-
A sodium salt is an ility o the indole ring.
a
trons on the nitrogen atom are required for the aromaticity of the indole ring.

A O O –

B
OH
S H 3 C CH 3

Cl N
C C A
H 3 CO O CH 3
Montelukast O
B
N – S
H
O N O

O
N Zafirlukast
CH 3

In addition, the overall lipid soluble character of montelukast is greater than that of zafirlukast.

The structure of montelukast contains 34 aromatic or aliphatic carbon atoms (as well as a halogen
atom), whereas the structure of zafirlukast contains only 28 atoms. The combination of a lower water
4. Montelukast and. Assume that all binding interactions occur at a physiological pH of 7.4.
soluble nature and a higher lipid soluble nature is responsible for the need to utilize a sodium salt for
Answer:
the oral administration of montelukast.
Let us four nd hydrophobic interactions.

The four boxed areas could interact with a Ionic bond
hydrophobic pocket within the leukotriene receptors.

Hydrogen bond
(as acceptor)

Hydrogen bond
(as acceptor) Montelukast