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304 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
2. Consider the structure below and do the following:
A. Box the ether that can participate in oxidative O-dealkylation.
B. Cross out the ether that cannot participate in oxidative O-dealkylation. Provide a brief
explanation why this transformation isn’t possible.
C. Provide a brief explanation as to why the boxed halogenated aromatic hydrocarbon
cannot undergo para aromatic hydroxylation.
D. Circle the functional group(s) that can undergo hydrolysis.
3. Cefprozil is a second-generation cephalosporin used in the treatment of bronchitis
and infections of the throat, ears, and sinuses. List all of the possible Phase I metabolic
transformation(s) in the space below. Directly modify the structure below to show the
product of one of the transformations listed.
4. Consider the structures of treprostinil and atecegatran drawn below. Can these drug molecules undergo benzylic oxidation? (Circle one) YES NO
A. If you answered YES, then modify the structures below to reflect the product of this
Phase I metabolic transformation.
B. If you answered NO, then briefly explain the structural reason for this.
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5. For each of the drugs below, list all of the Phase I and any Phase II metabolic transformation(s)
possible.
6. For each of the drug molecules drawn below, circle which of the following is TRUE:
A. The molecule can undergo a Phase II metabolic transformation without having to
undergo a Phase I metabolic transformation first.
B.
The molecule can only undergo a Phase II metabolic transformation after undergoing
a Phase I metabolic transformation.
306 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
7. Clofibrate, fenofibrate, and gemfibrozil are fibric acid derivatives used in the management
of hypertriglyceridemia and dyslipidemia.
A. Using the chart provided, determine which phase I metabolic transformations are pos-
sible for each drug. Answer YES or NO for each metabolic transformation.
B. One of the outcomes from Phase I metabolic transformation is drug activation. Given
that the fibric acid derivatives participate in a key ionic interaction with their biological
target, identify the agent that is drawn in its active form.
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Clofibrate
Fenofibrate
Gemfibrozil
Oxidative
O
-dealkylation
Benzylic
Oxidation
Ester
Hydrolysis
para
Aromatic
Hydroxylation
ortho
Aromatic
Hydroxylation
8. Consider each of the four drug molecules and determine if allylic oxidation is possible. For
each drug molecule, circle all of the carbon atoms for which allylic oxidation can occur. If
allylic oxidation is not possible, then provide a brief structural rationale for why this is the
case.
308 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
9. For each of the drugs shown below, evaluate their structures and determine which
Phase II metabolic transformations can occur without the need for any Phase I metabolic
transformations.
10. The structure of rociletinib and three of its inactive metabolites are drawn below. On the
lines below each metabolite, list the Phase I and/or Phase II metabolic transformation(s)
that must occur to form each metabolite drawn. Next to the name of each transformation,
indicate whether it is a Phase I or Phase II transformation.
NOTE: The number of lines has nothing to do with the number of transformations required.
If you use the same transformation more than once, then indicate with the designation 2X,
3X, etc.
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11. Evaluate each of the following metabolic transformations and determine which phase II
transformation has occurred. Which metabolic enzyme is responsible for catalyzing each of
these transformations?
310 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
12. Shown below is the structure of indomethacin in the form that exists at physiologic pH.
For each of the listed metabolic transformations, determine whether indomethacin can
undergo each transformation. If your answer is “YES,” then draw the appropriate metabolite; if your answer is “NO,” then provide a brief explanation as to why this transformation
cannot occur.
Pathways:
A. Oxidative deamination
B. Oxidative O-dealkylation
C. Aromatic hydroxylation
D. Glucuronide conjugation
E. Amino acid conjugation
F. Hydrolysis
G. Oxidative dehalogenation
STRUCTURE ACTIVITY
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RELATIONSHIPS AND
BASIC CONCEPTS IN
9
DRUG DESIGN
LEARNING OBJECTIVES
After completing this chapter, students will be able to
• Explain the meaning of the term structure activity relationships and provide examples of
this concept.
• Compare the structures of two or more similar drug molecules and explain how the
differences in their functional groups and/or structures could affect their pharmacological,
physicochemical, or therapeutic activity (i.e., predict/understand structure activity
relationships).
• Explain, in general, the potential advantages of developing analogs of an existing drug
molecule.
• Provide specific advantages of each of the molecular modification concepts discussed.
• Apply the concepts discussed in this chapter to perform rational drug design to create
analogs of a given drug molecule.
The structure of a drug molecule is defined by the relative locations/placements and stereochemical orientations of its functional groups. Each of the previous chapters has focused on selected
characteristics of functional groups and has included a variety of examples of how each of these
characteristics is important for the overall physiochemical, pharmacological, and therapeutic activity of a drug molecule.
This chapter is designed to be a capstone chapter with two primary objectives. The first objective is to define and provide examples of structure activity relationships (SARs). Many of the examples provided in previous chapters are revisited here with an emphasis on their role in establishing
SARs for specific drug classes. Additional examples are also introduced. The second objective is to
provide a brief overview of some of the common strategies that are used in rational drug design.
In the design of new drug molecules, the primary emphasis is placed on common simple molecular
modifications/replacements of existing functional groups. The advantages that each of these types
of modifications can provide are also discussed.
DOI 10.37573/9781585286959.009
311
312 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
STRUCTURE ACTIVITY RELATIONSHIPS
Overview: What Is Meant by the Term
Structure Activity Relationship
A structure activity relationship (SAR) is a common term used when discussing the medicinal chemistry of a drug molecule. Throughout previous chapters, we examined the overall structure of an
individual drug molecule in terms of its component functional groups and the various properties
that they possess, which can represent key elements of SARs. In Chapter 2, we learned that each
atom within a drug molecule is part of a specific functional group and that some of these functional
groups are more important than others. Each functional group has specific electronic, solubility,
and steric properties that have an effect on the overall pharmacological and therapeutic actions. In
Chapter 3, we reviewed acidic and basic functional groups and the importance of knowing the acid/
base character of a drug molecule. This knowledge helped us to examine the proper application of
the Henderson-Hasselbalch equation to solve pH/pKa problems in Chapter 4. In that chapter, the
primary goal was to determine if one or more functional groups found within a drug molecule are
either predominantly ionized or unionized in a given physiologic environment. From an application
standpoint, we learned that functional group ionization affects solubility, duration of action, the
ability of a drug molecule to interact with its biological target, and the potential to cause or limit
a specific drug interaction. Chapter 5 further explored water and lipid solubility. We examined the
advantages of water- and lipid-soluble salts, the need for an overall balance between water and lipid
solubility within the structure of a drug molecule, strategies for optimizing solubility to meet a therapeutic need, and the benefits of both water and lipid solubility. In Chapter 6, we explored the types
of covalent and noncovalent bonds that can form between the functional groups present on a drug
molecule and those present on its biological target(s). In Chapter 7, we considered the stereochemical orientation of functional groups, looked at both configurational and conformational isomers, and
identified specific examples of how these isomers can affect drug activity. Finally, in Chapter 8 we
reviewed the metabolic transformations that alter specific functional groups to enhance drug elimination, alter the drug’s pharmacological activity, or ensure that toxic metabolites are neutralized.
In each of the previous chapters, some of the examples helped to define a concept (i.e., these
are water-soluble salts, this is an acidic functional group) whereas others explored how the differences in specific functional groups can affect the overall pharmacological and therapeutic actions of
the respective drug molecules. These latter examples fall into the realm of SARs.
An SAR literally refers to the relationship between the chemical structure of a drug molecule
and its physicochemical, pharmacological, and therapeutic activities. The term structure refers to
both the functional groups present within a drug molecule and their stereochemical orientation
while the term activity is related to the type of pharmacological activity (i.e., agonist or antagonist,
enzyme inhibitor), the ability to be absorbed from the site of administration, the ability to interact
with a specific biological target and produce a specific pharmacological action, the ability or probability to be metabolized via a specific transformation, the duration of activity, and/or the ability to
cause a specific drug interaction or adverse effect.
The “Why” or “How” Component of an SAR Statement
A key concept to learn and remember is that each SAR statement must include a “why” or “how” component. Simply stating that “functional group X enhances activity” is of very limited value unless this
is followed with a discussion of why or how functional group X enhances the activity. Without the
“why” or “how” component, each SAR statement becomes a matter of simple memorization rather
than an application of a chemical concept. As an example, let us revisit the sulfonamide class of
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antibiotics originally discussed in Chapter 4. The structures of sulfanilamide and sulfamethoxazole
are shown below.
Both of these drugs mimic para-aminobenzoic acid (PABA) and inhibit the bacterial synthesis
of folic acid. When these two drugs are compared, it is found that sulfamethoxazole binds tighter
to the target enzyme than does sulfanilamide and is less likely to precipitate in the urine and cause
crystalluria. In looking at the two drugs, it is visually apparent that the structure of sulfamethoxazole contains an additional oxazole ring whereas sulfanilamide has an unsubstituted sulfonamide. The remaining question then becomes either “Why does this oxazole ring provide these two
beneficial effects?” or “How does this structural difference relate to the differences seen in the
above activities?” As mentioned in Chapter 4, the oxazole ring is electron-withdrawing in character.
This electron-withdrawing nature enhances the ionization and water solubility of the sulfonamide
functional group and prevents the drug from precipitating in the urine. Additionally, the enhanced
ionization allows sulfamethoxazole to better mimic PABA, hence enhancing its ability to interact
with the target enzyme. Using all of this information, we can construct two SAR statements for the
sulfonamide class of drugs.
1. Electron-withdrawing functional groups enhance the ionization of the sulfonamide functional group and therefore increase its ability to mimic PABA and inhibit the bacterial biosynthesis of folic acid.
2. Electron-withdrawing functional groups enhance the ionization of the sulfonamide functional group, increase the water solubility of the drug molecule, and decrease the chance of
precipitation in the urine.
Both of these SAR statements explain what structural feature is responsible for the beneficial
effect and offer an explanation as to why this structural feature is responsible for the beneficial
effect. Because of the structural generalities found within these statements, they are applicable to
the entire class of sulfonamide antibacterial agents and not just sulfanilamide and sulfamethoxazole. In contrast, if one were to simply identify that these beneficial effects were due to the presence
of an oxazole ring, this specific structural information does not allow for the ability to predict the
activity associated with other ring systems or functional groups.
Examples of Structure Activity Relationships
The examples used in this chapter are organized into four main sections. The purpose of these examples is solely to demonstrate specific SARs that exist within drug classes. None of the examples
presented represent a complete list of all of the SARs for a specific drug class. This information
is readily available in the references cited in Chapter 1. As you review each example, please note
that the changes in the component functional groups and/or their stereochemical orientations are
responsible for the differences in activity. In other words, the structure dictates the activity.
Structure Activity Relationships and Pharmacological Activity
The mechanism of action of a drug molecule almost always requires specific structural features for
it to interact with its biological target. Drug molecules that meet most or all of these structural
requirements are generally more active than those that do not. Many classes of drugs have SARs
that define both the minimum structural requirements for activity as well as additional structural
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