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44 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
D. Amino acid #2 is a derivative of an amino acid. Identify the amino acid.
3. For each of the amino acids and derivative(s) identified in the previous questions, complete
the grid below:
Amino Acid Side
Chain Evaluation:
Name of Amino
Acid or Amino Acid
Derivative
1
2
3
4
Hydrophobic,
Hydrophilic, or
Both
Amino Acid Side
Chain Evaluation:
Acidic, Basic,
Neutral
Amino Acid Side
Chain Evaluation:
Nucleophilic,
Electrophilic, NA
REVIEW QUESTIONS
1. For the structure of darunavir, name all of the boxed functional groups in the grid below.
CH 2 - FUNCTIONAL GROUP CHARACTERISTICS AND ROLES 45
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Box Functional Group Name
A
B
C
D
E
F
G
2. For the structure of rocuronium bromide, name all of the boxed functional groups in the
grid below.
Box Functional Group Name
A
B
C
D
E
F
G
3. The structural features found within H2 receptor antagonists include a basic functional group
that is protonated at physiologic pH (A), an aromatic ring (B), and a terminal nonbasic polar
functional group (C) that is separated from the aromatic ring by the equivalent of a fourcarbon chain. The terminal nonbasic polar functional group participates in a key ion–dipole
interaction with an ionized carboxylic acid found in the binding region within the H2 receptor.
46 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
A. Identify all of the functional groups that are present in the structure of cimetidine.
B. Guanidines and amidines that are substituted with electron withdrawing groups have
significantly decreased basicity compared with unsubstituted guanidines (pKa ∼12.5)
and amidines (pKa ∼9) and are unprotonated (unionized) at physiologic pH. Name the
electron withdrawing functional group found within cimetidine.
C. The boxed functional group (show below) participates in a key ion–dipole interaction
with an ionized carboxylic acid group found in the H2 receptor binding region. Provide a
brief rationale why this functional group is not protonated (ionized) at physiologic pH.
4. A 20-year-old male has been rushed to the hospital following a severe head injury that
occurred while playing a college football game. Tests have confirmed the presence of cerebral edema. The decision is made to treat the edema with mannitol.
A. Consider the structure of mannitol drawn above when completing the grid below.
Name Two Oxygen
Containing
Functional Groups
Hydrophilic and/or
Hydrophobic
Contribution to Water
Solubility and/or Lipid
Solubility
Hydrogen Bond
Acceptor, Donor,
Both, or Neither
B. Mannitol is supplied as an aqueous solution for IV injection and is administered as a
bolus of 0.25 to 1 g/kg every 4 to 6 hours as needed. Based on your functional group
evaluation, provide a structural rationale for why mannitol can be formulated as an
aqueous solution.
C. Mannitol is classified as an osmotic diuretic and in this case is used to pull fluid across
the blood brain barrier to reduce the swelling in the brain. Similarly, at high oral doses
it can also be used as an osmotic laxative with which fluid is drawn into the intestine.
Based on your functional group evaluation, provide a structural rationale for why mannitol is able to draw water out of the brain to reduce swelling.
CH 2 - FUNCTIONAL GROUP CHARACTERISTICS AND ROLES 47
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D. Using the structure below, show (and label) examples of the following interactions:
a. Drug–water interaction: drug = hydrogen bond acceptor; water = hydrogen bond
donor
b. Drug–water interaction: drug = hydrogen bond donor; water = hydrogen bond
acceptor
c. Drug–water interactions: dipole–dipole interaction
5. A 19-year-old male comes into the pharmacy complaining about a skin rash that is berry
red and very itchy. He states that he just got back from a camping trip and believes he came
into contact with poison ivy. He asks for a recommendation for a cream that will help with
the itching. Your recommendation for this patient is Benadryl®, a topical antihistamine
cream that is sold over-the-counter.
A. Identify all of the structural features present in diphenhydramine and complete the
grid below.
Name of Functional
Group
Hydrophilic and/or
Hydrophobic
Contribution to Water Solubility
and/or Lipid Solubility
B. Using the information that you provided in the grid in the previous question, provide
a structural rationale for why diphenhydramine is an agent that can be applied topically. (Hint: Agents that are administered topically must absorb into the hydrophobic
components of the skin to be effective.)
6. Binding interactions with a biological target can be significantly impacted by the presence
or absence of functional groups that dictate a molecule’s shape. In each of these molecules,
functional groups in the ortho position of the aromatic rings force the two ring systems to
be perpendicular to one another. Circle the functional groups that influence the shape of
each of these molecules.
48 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
7. Specificity for a biological target can be significantly impacted by the presence or absence
of functional groups that alter the size of a molecule.
A. Epinephrine is a nonselective agonist at α and β receptors. Determine which functional
group in albuterol causes it to have β receptor selectivity and identify if the functional
group represents a change in electronic or steric factors.
B. Estrogen is the natural agonist at the estrogen receptor. Determine which functional
group in fulvestrant causes it to bind to, but not activate (antagonist), the estrogen
receptor. Does this functional group represent a change in electronic or steric factors?
8. The addition or loss of one functional group can significantly alter the biological activity
that a molecule exhibits. In this case, the loss of a methyl group changes the pharmacological effect of the drug from being a serotonin reuptake inhibitor to a norepinephrine
reuptake inhibitor. Determine whether this change is a result of a steric or electronic effect
and provide a rationale for your answer.
CH 2 - FUNCTIONAL GROUP CHARACTERISTICS AND ROLES 49
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9. Lopinavir is an HIV protease inhibitor. Structurally, this drug is considered a peptidomimetic, in that it resembles (at least in part), the peptide substrate for the protease. In the
presence of this agent, HIV protease is unable to cleave the gag-pol polypeptide into its
functional proteins during viral assembly and budding.
A. Consider the portion of the molecule designated as C. (You will notice that the atoms
and bonds of this portion of the molecule have been bolded for you.) Which amino
acid is this? How do you anticipate that the side chain of this amino acid will contribute to solubility and absorption of this drug?
B. Consider the portions of the molecule designated as A and B: while the normal peptide
bond sequence has been slightly changed, the side chains are unaltered. Which amino
acid do these portions resemble? How do you anticipate that the side chain of this
amino acid interacts with the biological target?
Aliskiren is an inhibitor of renin, the enzyme that catalyzes the conversion of angiotensino-
10.
gen to angiotensin I in the renin-angiotensin-aldosterone system. Aliskiren is also a peptidomimetic, in that it mimics the natural peptide substrate (angiotensinogen) for renin.
In this peptidomimetic, the hydrolysable peptide (amide) bond has been replaced with a
hydroxyethylene functional group.
A. Peptidomimetics often follow the same structural sequence of functional groups as
found in a normal peptide—amine, side chain, carbonyl. Find the left most arrow (→)
pointing to an amine. If you follow the sequence to the right, you will find a boxed
atom followed by a circled atom. What portion of the sequence does the box represent? What portion of the sequence does the circle represent?
B. Look for the next sequence of →, , . What amino acid does this mimic?
C. Renin normally catalyzes the cleavage of the peptide bond between Leu and Val. What
interactions are possible between renin and the side chains of Leu and Val? If you look
50 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
at the structure of aliskiren, you see that two amino acid side chains are docked in
enzyme “pockets.” What kind of interactions do you expect these amino acid side
chains to have with renin?
D. Box the nonhydrolyzable functional group that is replacing the peptide bond that nor-
mally links Leu and Val.
11. Shown below is the structure of tramadol. Three of its functional groups have been highlighted. Based upon their electronic properties AND their relative positions in the molecule, identify if they are electron withdrawing or electron donating. Additionally, identify
if this effect is due to resonance or induction.
12. Shown below is the structure of a tetrapeptide that is part of a larger protein receptor. The
side chains of the four amino acids have been highlighted.
A. Identify the four amino acids that comprise this tetrapeptide sequence.
B. For each amino acid, identify the key chemical properties of their highlighted side
chains.
IDENTIFYING ACIDIC
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AND BASIC FUNCTIONAL
3
GROUPS
LEARNING OBJECTIVES
After completing this chapter, students will be able to
• Identify the following acidic functional groups: carboxylic acids, a-dicarbonyls, imides,
sulfonamides, sulfonylureas, tetrazoles, phenols, thiols, phosphates, phosphonates, and
sulfates.
• Identify the following basic functional groups: aliphatic amines, alicyclic amines (aka
saturated heterocycles), aromatic amines, imines, hydrazines, amidines, guanidines, and
nitrogen containing aromatic heterocycles.
• Classify a drug molecule as one of the following: acidic, basic, amphoteric; an electrolyte;
or a nonelectrolyte.
• Explain how the acid/base nature of a drug molecule can influence its chemical,
pharmaceutical, and therapeutic properties.
Functional groups that are either acidic or basic have the ability to become ionized and as a result
become negatively or positively charged, respectively, within the structure of a drug molecule. This
ability to ionize increases the overall water solubility of the drug molecule, allows for the formation
of specific types of interactions between the drug molecule and its biological target(s), and influences the transport, metabolism, and elimination of the drug molecule. In addition, acidic and basic
functional groups can be used to produce water- or lipid-soluble salts for the purpose of providing a
specific physicochemical or therapeutic advantage.
This chapter reviews the acidic and basic functional groups that are present within the structures of drug molecules. The discussion of each acidic and basic functional group includes an
explanation as to why it is acidic or basic as well as examples of commercially available drugs
that contain the functional group within their structures. When applicable, the relative acid/base
strengths among the different functional groups are provided along with an explanation. The
chapter ends with a discussion regarding the therapeutic significance of the acid/base nature of
a drug molecule.
DOI 10.37573/9781585286959.003
51
52 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
ACIDIC FUNCTIONAL GROUPS
Acidic functional groups are those that can donate (or lose) a proton (H+). From a very simplistic
view, an acid can be represented as follows:
There are two key features of an acidic functional group: the presence of a hydrogen atom that
can dissociate from the group (H+), and the ability of the remaining atoms to delocalize the resulting
negative charge via resonance. As a reminder, resonance delocalization refers to the ability of the
functional group to spread the charge in a manner that allows it to be shared among two or more
atoms.
The pK
important fact here is that the lower the pKa value, the stronger the acid. As an example, an acidic
functional group with a pKa of 2.4 is more acidic than one with a pKa of 3.4. A more extensive discussion of pKa values and their determination can be found in Chapter 4. It is strongly suggested that
you focus more on learning the relative acidity and ranges of the groups listed above rather than
memorizing specific pKa values for specific drugs. A summary table of pKa values and ranges is provided later in this chapter.
Carboxylic Acids
A carboxylic acid is the most common acidic functional group found in drug molecules. The acidic
hydrogen atom has been highlighted with a box below.
values of these functional groups are used to compare their relative acidity. The most
a
The resulting anion (i.e., negatively charged species) is stabilized by resonance delocalization or
the sharing of the negative charge between the two oxygen atoms.
The ionized form of a carboxylic acid is known as a carboxylate. Four drugs that contain a carboxylic acid as part of their structure are shown in Figure 3-1.
Two key points need to be made regarding the drug molecules in Figure 3-1. First, the carboxylic acids present in these drug molecules have purposely been drawn differently to represent the
various ways that they are commonly depicted. Gabapentin, alprostadil, and carbidopa are drawn
in their unionized, carboxylic acid forms, while cetirizine is drawn in its ionized, carboxylate form. In
addition, carboxylic acids can be represented by drawing all of the bonds, as seen in alprostadil, or
by using the R-CO2H or R-COOH abbreviations, as seen in gabapentin and carbidopa, respectively.
Carboxylates can be drawn with all of the bonds, as seen in cetirizine, or by using the abbreviated
R-COO− or CO
−
designations.
2
The second key point is that carboxylic acids, as well as all other acidic and basic functional
groups, have a general (or normal) pKa range. The variation within this range is the result of the elec-
tron donating or withdrawing character of adjacent or surrounding groups.
CH 3 - IDENTIFYING ACIDIC AND BASIC FUNCTIONAL GROUPS 53
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FIGURE 3-1.Examples of drug molecules that contain a carboxylic acid. The various ways
this functional group is commonly drawn are represented.
While the normal pKa range for a carboxylic acid is between 2.5 and 5, there are situations in
which the pKa value of a functional group lies outside of its normal range. To illustrate this concept,
the variation in carboxylic acid pKa value among the four drugs in Figure 3-1 can be explained by their
adjacent functional groups. Let’s see if we can figure out why the carboxylic acids within the structures of carbidopa and cetirizine have lower pKa values and hence are more acidic than those within
the structures of gabapentin and alprostidil.
The structure of carbidopa has a basic hydrazine group (NHNH2) that is closely adjacent to its
carboxylic acid. This basic functional group acts as an electron withdrawing group and enhances the
acidity of the carboxylic acid. A similar situation is seen with cetirizine. The closely adjacent ether
oxygen atom is electronegative and withdraws electrons away from the carboxylic acid, thereby
decreasing its pKa value. In contrast, the carboxylic acids within the structures of gabapentin and
alprostadil are directly adjacent to alkyl chains. As discussed in Chapter 2, alkyl chains are electron
donating in character. The overall electron flow enhances the negative charges of these carboxylic
acids and decreases their acidity. It should be noted that the structure of gabapentin does contain
a basic amine; however, unlike the basic functional group in carbidopa, this amine is not adjacent to
the carboxylic acid and would have minimal effects on its acidity and pK
.
a
a-Dicarbonyl Groups
β-Dicarbonyl groups have the following general structure. The acidic hydrogen has been highlighted
with a box. The “X” atom can be either carbon or nitrogen. When the “X” atom is nitrogen, the functional group is also known as an imide.
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