Page 114 - Medicinal Chemistry Self Assessment

5. Shown below is the structure of clonidine, an D adrenergic agonist that can be used to treat hypertension.
Clonidine contains a guanidine functional group (highlighted in bold) that has a pKa of 8.3. Other guanidine
functional groups, such as that seen with arginine are much more basic with a pKa of 12.5. Provide a chemical
explanation for this difference.

pK a = 12.5
pK a = 8.3
Clonidine
Arginine

Answer:
Unlike the side chain of the amino acid arginine, the guanidine group of clonidine is directly attached to an
aromatic ring. As such, the nitrogen atom directly attached to the aromatic ring (highlighted below) can donate
electrons into the aromatic ring, thus making it less available for resonance stabilization of a positive charge. In
addition, the aromatic ring of clonidine is attached to two ortho chloro groups. Each of these halogens is electron
withdrawing and further decreases the basicity of the guanidine group. The combination of these two effects
2.2 Identifying Acidic and Basic Functional Groups 103
decreases the basicity of the guanidine group by greater than four orders of magnitude.

Involved in resonance
Cl with aromatic ring
H H
N N
N
Cl
6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug molecule,
Clonidine
an amphoteric drug molecule, or a nonelectrolyte.

6. For each of the drug molecules shown below, determine if it is an acidic drug molecule, a basic drug
Answer:
molecule, an amphoteric drug molecule, or a nonelectrolyte.

Answer
Basic Acidic
O NH O COOH
CF 3
N
H Basic H 2 N N N
H
N O S NH CH 3
Acidic O H Basic
N
N
Lomitapide H O
CF 3
CH 3
Argatroban Page 4 of 5
Acidic
H O
COOH OCH 3
OH
O
H O NH
H 3 C O Cl N N NH S
CH 3 H CH 3 H 2 O CH 3
H 2 N N NH 2 Basic N
O O
H O
3 2
2
Pravastatin Amiloride CH N(CH ) Basic
Diltiazem

Drug Molecule Acid/Base Character of Drug Molecule
Lomitapide Basic: Contains only a basic tertiary amine
Argatroban Amphoteric: Contains two acidic functional groups (a carboxylic acid and a sulfonamide) and two basic func-
tional groups (a guanidine group and an aromatic amine)

Pravastatin Acidic: Contains only an acidic carboxylic acid
Amiloride Basic: Contains a basic guanidine group as well as a basic aromatic heterocyclic ring (pyrazine)
Diltiazem Basic: Contains only a basic tertiary amine

Go to Section 1.3 [Link to section 1.3 title]
Note: References to chapters are to Chapter 3 in Harrold MW and Zavod RM, Basic Concepts in Medicinal
Chemistry, American Society of Health-System Pharmacists, ©2013.

Page 5 of 5