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114 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
The Influence on Drug Binding Interactions
Ionized functional groups are capable of forming ionic bonds with binding sites located within their
biological targets. As discussed in more detail in Chapter 6, an ionic bond is one of the strongest
and most important types of noncovalent binding interactions. An ionic bond can form over the
longest distance and is often the initial bonding interaction between a drug and its biological target.
As shown in Figure 4-6, salicylic acid is initially attracted to its binding site on cyclooxygenase via
an ionic interaction between its ionized carboxylic acid and a cationic site present within the active
site of cyclooxygenase. The cationic site is most likely an ionized lysine or arginine side chain. The
aromatic ring of salicylic acid also contributes to the overall binding; however, its interaction with
the hydrophobic site of cyclooxygenase can only occur after the ionic attraction has drawn the two
groups close to one another.
FIGURE 4-6.The initial ionic interaction between salicylic acid and its binding site on
cyclooxygenase.
In exploring the interaction of drugs with their biological targets, it is important to note that
the pH at the site of interaction almost always remains constant; therefore, ionic interactions are
primarily affected by structural changes and altered pKa values of acidic and basic functional groups.
The following two examples use drug molecules previously discussed in this chapter to illustrate
this concept.
Let us first look at methylsalicylate, an ester analog of salicylic acid (Figure 4-7). This drug
does not contain a carboxylic acid and is unable to interact with cyclooxygenase because the initial
interaction is no longer possible. The interaction between the aromatic rings also does not occur
because the groups never get close enough. As a result, methylsalicylate, unlike salicylic acid, does
not possess anti-inflammatory activity.
FIGURE 4-7.No initial interaction between methylsalicylate and the binding site on
cyclooxygenase due to the lack of an ionized functional group.
CH 4 - SOLVING pH AND pKa PROBLEMS 115
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As a second example, let us revisit sulfamethoxazole and the sulfonamide class of antibiotics (Figure 4-8). This class of drugs exerts its antibiotic activity by structurally mimicking
para-aminobenzoic acid (PABA). As a result, they act as antimetabolites and prevent the bacterial
synthesis of folic acid, an essential cofactor associated with amino acid and DNA biosynthesis. To
mimic PABA, the acidic sulfonamide group (highlighted with boxes in the structures of both sulfamethoxazole and sulfanilamide) must mimic the carboxylic acid of PABA. With a pKa of 10.4, the
acidic sulfonamide group of sulfanilamide is only approximately 0.1% ionized at a physiologic pH
of 7.4. Because the carboxylic acid of PABA has a pKa of 4.9, it is more than 99% ionized at a physiologic pH of 7.4. While sulfanilamide does interact with its target enzyme, its overall binding ability
is hindered by the low ionization of the sulfonamide group and thus the inability to truly mimic the
ionized form of PABA. In comparison, the sulfonamide group of sulfamethoxazole is adjacent to an
electron withdrawing heterocyclic ring, causing it to be much more acidic and primarily ionized at a
pH of 7.4. This allows it to be a much better mimic of PABA and have an increased ability to interact with the target enzyme. Thus, the pK
solubility, the prevention of adverse effects, and their overall antibacterial activity.
and ionization of sulfonamide antibiotics is important for
a
Rule of Nines Approximation for the Carboxylic Acid of PABA
The pKa of the carboxylic acid of PABA is 4.9, whereas physiological pH is 7.4. The absolute
value of the pH minus the pKa here is 2.5, and the carboxylic acid of PABA is in a basic environment. Thus, the ionization of this functional group lies between 99% (two log units) and
99.9% (three log units).
FIGURE 4-8.Sulfonamide antibiotics and
para
-aminobenzoic acid.
Ionization and Chemical Antagonism
Chemical antagonism occurs when a highly ionized acidic drug interacts with a highly ionized basic
drug and the activities of both drugs are terminated. This antagonism is distinct from the acid/
base incompatibilities that are discussed in Chapter 5. As defined here, chemical antagonism occurs
among acidic and basic drugs in vivo. The acid/base incompatibilities discussed in Chapter 5 occur in
prepared solutions and result in drug instability and precipitation. There are not many examples of
chemical antagonism; however, a very important one is seen in the antagonism of heparin by protamine (Figure 4-9). Heparin is an acidic polysaccharide and is used as a parenteral anticoagulant.
It is highly ionized due to the presence of multiple sulfate groups, each of which has a pKa of 1 to 2.
The major adverse effect of heparin is hemorrhage or excessive bleeding. This adverse effect can be
116 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
FIGURE 4-9.Heparin and protamine.
quickly reversed by the administration of protamine sulfate, a highly basic polypeptide that is rich
in arginine units. The guanidine functional group present within arginine has a pKa of 11 to 12. Due
to their strong and opposing acid/base properties, these drug molecules have a strong ionic attraction for one another. Thus, protamine forms an acid–base complex with heparin that results in rapid
inactivation of heparin.
Drug Interactions Based on pH and/or pKa Changes
Alterations in the pH of an environment or the pKa of a functional group can directly or indirectly
cause or eliminate a drug interaction. In terms of physiologic environments, alterations in pH are
most likely to be seen in the urine and the stomach. Let us look at an example for each of these
environments.
Examples that illustrate how changes in urinary pH can affect the solubility and duration of
action of drug molecules have already been discussed; however, it is important to note that these
previous examples focused on the intentional alkalization of the urine to achieve a specific therapeutic benefit. Changes in the solubility and duration of action of a drug molecule can also occur when
another concurrently used drug alters the urinary pH as part of its mechanism of action. The thiazide
diuretics, a class of drugs commonly used to treat hypertension and other cardiovascular disorders,
provide a good example of this. The diuretic action of this class of drugs is due to the ability to
inhibit the Na+/Cl− symporter in first portion of the distal tubule; however, the thiazides can cause
drug interactions based on their ability to also inhibit the enzyme carbonic anhydrase. Carbonic
anhydrase catalyzes the reversible hydration of carbon dioxide (Figure 4-10). The primary functions
of carbonic anhydrase in the kidney are to acidify the urine and to aid in the reabsorption of sodium
bicarbonate. By inhibiting carbonic anhydrase, thiazides increase the normal urinary pH range. In
general, this causes an increase in the ionization and water solubility of acidic drugs and decreases
their ability to be passively reabsorbed. The opposite is true for basic drugs. The actual magnitude
of this pH change on the solubility, reabsorption, and duration of a specific drug molecule depends
on the pKa values of its functional groups. The key point here is that thiazide diuretics can cause drug
interactions due to their ability to alter urine pH.
FIGURE 4-10.Hydrochlorothiazide and its inhibition of carbonic anhydrase.
CH 4 - SOLVING pH AND pKa PROBLEMS 117
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Additionally, thiazide diuretics can decrease the activity of drugs requiring an acidic urine as
part of their activation or mechanism of action. One example of this is observed with the antibacterial agent methenamine. Methenamine is a prodrug of formaldehyde and is used to treat urinary
tract infections. The conversion of methenamine to formaldehyde requires that the urine pH be
≤ 5.5. Thus, if a patient taking a thiazide diuretic to treat hypertension develops a urinary tract infection, methenamine would be ineffective due to the elevated urine pH.
Similar to urinary pH, alterations in gastric pH can affect the dissolution of some drug molecules.
Specifically, the use of antacids, his tamine H2 receptor antagonists, or proton pump inhibitors increases
the gastric pH from its normal value of 1 to 2 up to 3.5 to 4, and decreases the oral bioavailability of
drugs that require an acidic pH to dissolve. An example of this is seen with the antifungal agent ketoconazole shown below. Ketoconazole is highly lipid soluble and depends greatly on the ionization of
the highlighted imidazole ring. Increases in gastric pH decrease the ionization of this basic functional
group as well as its water solubility, dissolution, and absorption. As a result, patients requiring ketoconazole therapy should not concurrently use H2 antagonists (e.g., cimetidine, ranitidine) or proton pump
inhibitors (e.g., omeprazole, lansoprazole). Antacids can be used; however, doses must be appropriately spaced to ensure the gastric pH is in the normal range when the ketoconazole is administered.
The alteration of the molecular structure of a drug molecule can affect the pKa values, and hence
the ionization, of its acidic and/or basic functional groups. This particular topic is most likely to arise
when discussing the struct ure activity relationships (SARs) of a specific drug class. Wh ile SARs are not
a main focus of this chapter, a brief overview is provided in Chapter 9. Within the context of the
concepts discussed in this chapter, you should be aware that structural alterations that affect the pKa
of functional groups can cause or eliminate a specific drug interaction though the following processes:
y Changes in the structure of a drug molecule may alter the acidity or basicity of a given func-
tional group, which results in a lower or higher pKa value for the affected functional group.
y Alterations in the pKa value of a functional group may result in significant changes in its
ionization, which may affect the overall water solubility of the drug molecule.
y Changes in ionization and solubility may affect the plasma protein binding of the drug mol-
ecule and may cause some drugs to be more or less susceptible to plasma protein displacement interactions than others.
y Changes in ionization and solubility may also affect the route of metabolism. Changes that
increase ionization and water solubility may cause a drug molecule to rely more on renal elimination versus hepatic metabolism. Decreased hepatic metabolism may cause a drug molecule
to be less susceptible to a drug interaction with cytochrome P450 (CYP450) metabolizing
enzymes. Changes that decrease ionization and water solubility have just the opposite effect
and may cause a drug molecule to be more prone to CYP450 related drug interactions.
118 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Key Summary Points Involving the Importance of pH and pKa
in Drug Therapy
• The urinary and gastric pH values can be altered; however, the pH of the blood and
other tissues is relatively constant and cannot be significantly altered.
• Drug molecules can be altered to increase or decrease the pKa of their functional
groups.
• Alterations of the pH of the environment or the pKa of acidic and/or basic functional
groups can affect.
the water solubility of a drug molecule.
the dissolution of a drug molecule.
the bioavailability of a drug molecule.
the prevalence of specific adverse drug reactions.
complications arising from specific disease states.
the duration of action of a drug molecule.
the ability of a drug molecule to bind to its biological target(s).
the therapeutic activity of a specific drug molecule.
the prevalence of specific types of drug interactions.
STRUCTURAL ANALYSIS CHECKPOINT
Checkpoint Drug 1: Venetoclax
1. In Chapter 3, you were asked to identify all acidic and basic functional groups present
within the structure of venetoclax. You should have identified a total of five functional
groups, one that is acidic and four that are basic. Two of the basic functional groups have
predicted pKa values less than 1.
A. Identify these very weakly basic functional groups and provide an explanation as to
why they will not be appreciably ionized within the human body.
B. The remaining three acidic and basic functional groups have predicted pKa values of 3.5,
4.3, and 8.0. Match these pKa values to the appropriate functional groups. If you need a
hint, consult the Structural Analysis Checkpoint questions for Chapter 3.
CH 4 - SOLVING pH AND pKa PROBLEMS 119
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2. Using your answers from Question 1B, individually identify if the functional groups will be
primarily (> 50%) ionized or primarily (> 50%) unionized at the following pH levels:
A. Stomach pH of 1.8
B. Urinary pH of 5.3
C. Cellular pH of 7.2
3. In looking at Question 2, there are nine scenarios.
A. Which of these scenarios allows you to calculate the percent ionized using the Rule of
Nines?
B. Using the stomach pH of 1.8 and the pKa values of the tertiary amine and the sul-
fonamide, explain how the Rule of Nines could be used to approximate the percent to
which these two functional groups would be ionized.
Using the Henderson-Hasselbalch equation, calculate the following:
4.
A. The percent that the functional group with the pK
of 4.3 is ionized at a gastric pH
a
of 3.1.
B. The percent that the functional group with the pKa of 8.0 is ionized at a plasma pH
of 7.3.
C. The pH that is required for the functional group with the pKa of 3.5 to be 30% ionized.
Checkpoint Drug 2: Elamipretide
In Chapter 3, you identified that the functional groups in boxes A, B, and C are either acidic or basic
in character as well as the associated pKa value/range. Identification of this information represents
critical steps in solving pH/pKa problems.
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
Character:
Acidic, Basic, Neutral pK
Basic ∼12.5
Basic ∼10.5
Acidic ∼10.5
a
Value or Range
120 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
1. Evaluate the entire structure of elamipretide and determine if there are any additional
acidic or basic functional groups.
A. If the answer is “yes,” then name the functional group(s), identify a pKa value or range
for each group, and add this information to the table above.
B. If the answer is “no,” then determine if either or both of the amino or carboxy termini
of this tetrapeptide have been modified and provide a rationale for this modification.
(HINT: consider normal degradation catalyzed by a variety of peptidases.)
2. In light of the fact that functional groups B and C have nearly the exact same pKa value,
provide a brief rationale for why it is important to identify the acid/base character of each
functional group irrespective of the pKa value and BEFORE trying to determine the percent
ionized in a given physiologic environment.
3. Using a qualitative process, determine if each of the functional groups will be primarily
(> 50%) ionized or primarily (> 50%) unionized in each of the physiologic environments
listed below. Fill in the tables with the relevant information.
A. Stomach pH of 2
B. Urinary pH of 5
C. Plasma pH of 7.4
Primarily Ionized
(> 50%)
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
Character:
Acidic, Basic,
Neutral
Basic ∼12.5
Basic ∼10.5
Acidic ∼10.5
pKa Value or
Range
Primarily
Unionized (< 50%)
pH = 2
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
Character:
Acidic, Basic,
Neutral
Basic ∼12.5
Basic ∼10.5
Acidic ∼10.5
pKa Value or
Range
Primarily Ionized
(> 50%)
Primarily
Unionized (< 50%)
pH = 5
CH 4 - SOLVING pH AND pKa PROBLEMS 121
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Primarily Ionized
(> 50%)
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
Character:
Acidic, Basic,
Neutral
Basic ∼12.5
Basic ∼10.5
Acidic ∼10.5
pKa Value or
Range
Primarily
Unionized (< 50%)
pH = 7.4
4. Using a quantitative process, determine the extent to which each of these functional groups
will be ionized in each of the physiologic environments listed below. Fill in the tables with
the relevant information.
A. Duodenum pH of 5.4
B. Large intestine pH of 8.5
Character:
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
Acidic, Basic,
Neutral
Basic ∼12.5
Basic ∼10.5
Acidic ∼10.5
pKa Value or
Range
Percent Ionized
pH = 5.4
Name of Functional
Group
A Guanidine (arginine side
chain)
B Primary amine (lysine
side chain)
C Phenol (modified
tyrosine side chain)
Character:
Acidic, Basic,
Neutral
Basic ∼12.5
Basic ∼10.5
Acidic ∼10.5
pKa Value or
Range
Percent Ionized
pH = 8.5
122 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
REVIEW QUESTIONS
1. Each of the drug structures below contains at least one functional group that is either acidic or
basic in character. Determine which functional group is associated with each pKa value listed
in the grid and whether the functional group (in its unionized or parent form) is acidic or basic.
Drug (pKa Value) Name of Functional Group Acidic/Basic
Carvedilol (7.8)
Ketoprofen (5.94)
Dasolampanel (3.93)
Dasolampanel (6.73)
Haloperidol (8.6)
2. Each of these agents can be administered via an oral route and experiences several physiologic
environments in its journey from administration to its target for biological action. Evaluate
each physiologic environment to determine if the environment is acidic, basic, or neutral.
Saliva
(pH = 6.4)
Stomach
(pH = 2)
Duodenum
(pH = 5.4)
Plasma
(pH = 7.4)
Urine
(pH = 5.7)
3. Evaluate each physiologic environment to determine if the functional group is predominantly (> 50%) ionized, unionized, or will be 50% ionized/50% unionized.
Drug (pKa Value)
Carvedilol (7.8)
Ketoprofen (5.94)
Dasolampanel
(3.93)
Dasolampanel
(6.73)
Haloperidol (8.6)
Saliva
(pH = 6.4)
Stomach
(pH = 2)
Duodenum
(pH = 5.4)
Plasma
(pH = 7.4)
CH 4 - SOLVING pH AND pKa PROBLEMS 123
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4. The structure of tolbutamide contains an acidic sulfonylurea group with a pKa = 5.4. Using
the Rule of Nines and the pH values provided in Question 3, determine the percentage
ionization of this sulfonylurea in the duodenum, saliva, and plasma.
5. For the acidic and basic functional groups found in dasolampanel, use the HendersonHasselbalch equation or a qualitative approach to determine the following:
A. Is the functional group predominantly ionized or unionized in the plasma?
B. What is the percentage of ionized and unionized drug in the plasma?
6. Consider the answers provided in the Question 3 grid and determine which drug (based on
ionization state only) is the least soluble in the duodenum. Which drug is the most soluble
in the duodenum (based on ionization state only)?
7. In the active site of cyclooxygenase-1 (COX-1) there is an ionized arginine residue
(pH = 7.4; pK
∼12.5) that interacts via a critical ionic interaction with the nonsteroidal anti-
a
inflammatory agents. Evaluate the structures of ketoprofen and haloperidol and determine
which drug(s) can participate in this type of interaction with the COX-1 arginine residue.
8. Evaluate the structure of batefenterol and identify all acidic and basic functional groups
and complete the table. Using the completed table, determine if there is a physiologic
environment in which this drug is found predominantly in its unionized form.
A. If the answer is “yes,” then is this the most likely site for absorption?
B. If the answer is “no,” then provide a rationale for how this drug is absorbed.
Functional
Group Name
Acidic or
Basic
Saliva
(pH = 6.4)
Stomach
(pH = 2)
Duodenum
(pH = 5.4)
Plasma
(pH = 7.4)
Urine
(pH = 5.7)
9. Moxifloxacin is an antibacterial agent that is formulated as a solution for topical use in the
treatment of bacterial conjunctivitis. Moxifloxacin has two pKa values (6.3 and 9.3).
A. Consider all of the acidic and basic functional groups found within the structure of
moxifloxacin and match each pKa to the correct group. Identify each functional group
as either acidic or basic.
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