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394 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Review Questions
1. Answers provided in the grid below.
Box Functional Group Name
A Aliphatic alkane; aliphatic chain
B Sulfonamide
C Aniline; aromatic amine
D Secondary alcohol (or hydroxyl)
E Aromatic hydrocarbon (or aromatic ring), phenyl ring
F Carbamate
G Ether
2. Answers provided in the grid below.
Box Functional Group Name
A Ether
B Tertiary amine
C Secondary alcohol (or hydroxyl)
D Cycloalkane; alicyclic ring
E Ester
F Quaternary ammonium bromide
G Alkene
3. Part A: Functional groups are identified in the structure shown below.
Part B: The aromatic heterocycle (1,3 diazole) and the cyano group are both electron with-
drawing groups. The cyano group will significantly decrease the magnitude of the pKa value
for the guanidine. The experimentally measured pKa value for the guanidine in cimetidine is
in the range of 6.7 to 6.9.
Part C: The guanidine is not protonated at physiologic pH because the cyano group is an
electron withdrawing group and pulls (or withdraws) electrons from the guanidine through
induction. This decreases the ability of the guanidine to attract protons (H+); therefore, its
basicity will decrease. The experimentally measured pKa values for cimetidine are all in the
range of 6.7 to 6.9. The guanidine and aromatic heterocycle are both basic in character.
At pH = 7.4, the pH > pKa for these functional groups and, therefore, the basic functional
groups are predominantly unionized in this pH environment.
4. Part A: Answers provided in the grid below.
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APPENDIX - ANSWERS TO CHAPTER QUESTIONS 395
Name of Two Oxygen
Containing Functional
Groups
Primary alcohol (or
hydroxyl)
Secondary alcohol (or
hydroxyl)
R = carbon scaffolding.
Hydrophilic and/or
Hydrophobic
Hydrophilic (OH);
hydrophobic (R)
Hydrophilic (OH);
hydrophobic (R)
Contribution to Water
Solubility and/or Lipid
Solubility
Water solubility (OH) Hydrogen bond
Lipid solubility (R)
Water solubility (OH) Hydrogen bond
Lipid solubility (R)
Hydrogen Bond
Acceptor, Donor, Both,
or Neither
acceptor and donor
acceptor and donor
Part B: The primary and secondary alcohols have hydrophilic character. These alcohols (pri-
mary and secondary) interact with water as both hydrogen bond acceptors and donors,
which means that they make a sizable contribution to the water solubility of mannitol.
Part C: The primary and secondary alcohols have hydrophilic character. The alcohols (pri-
mary and secondary) are able to interact with water as both hydrogen bond acceptors and
donors, which means that they are able to attract and interact with water.
One mechanism to relieve the swelling in the brain is to remove the excess fluid via the
blood brain barrier. Mannitol achieves this by attracting and interacting with water with its
six OH groups.
Part D: Answer provided in figure below.
5. Part A: Answers provided in the grid below.
Hydrophilic and/or
Name of Functional Group
Aromatic hydrocarbon Hydrophobic Lipid solubility
Ether Hydrophobic (R) Lipid solubility (R)
Tertiary amine Hydrophobic (R) Lipid solubility (R)
R = carbon scaffolding.
Hydrophobic
Hydrophilic (O atom) Water solubility (O atom)
Hydrophilic (N atom) Water solubility (N atom)
Contribution to Water Solubility
and/or Lipid Solubility
Part B: Diphenhydramine has two aromatic hydrocarbons that are hydrophobic in char-
acter and contribute significantly to lipid solubility and drug absorption. These features
396 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
contribute to the ability of the drug to easily absorb into the skin, which has considerable
lipid character. Please note that the ether and tertiary amine groups have R groups that do
contribute, albeit minimally, to the overall hydrophobic character of the drug.
6. Functional groups that influence the shape of each molecule have been circled.
7. Functional group and explanation provided below.
Part A: The t-butyl substituent that is part of the secondary amine is responsible for
the β receptor selectivity demonstrated by albuterol.
Part B: The 8α substituent is responsible for fulvestrant binding to, but not activating,
the estrogen receptor.
8. The only structural difference between these two molecules is the presence of a tertiary
amine in the parent drug and an N-methylated secondary amine in the active metabolite.
The parent drug (with the tertiary amine) selectively inhibits the reuptake of serotonin. The
active metabolite (desmethyl metabolite) selectively inhibits the reuptake of norepinephrine. This change in the number of methyl substituents represents a change in the steric
character of the molecule.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 397
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9. Part A: The portion of the molecule designated as “C” is the amino acid valine. The side
chain of this amino acid is hydrophobic in character and improves the ability of the drug to
be absorbed across lipophilic membranes. This characteristic decreases the water solubility
of the drug.
Part B: The portions of the molecule designated as “A” and “B” resemble the side chain of
the amino acid phenylalanine. The side chain of this amino acid is hydrophobic in character and interacts with hydrophobic regions present within the biological target. The most
likely interactions would be with the side chains of the aromatic amino acids phenylalanine,
tyrosine, and tryptophan; however, it could also interact with the side chains of the aliphatic amino acids alanine, valine, leucine, and isoleucine. The ritonavir side chains “A” and
“B” can also participate in π-π stacking interactions with the side chains of phenylalanine,
tyrosine, tryptophan, and histidine present within the biological target. It is also possible
for these side chains to participate in cation-π interactions with lysine and arginine that are
ionized at physiologic pH.
Part A: The box represents the side chain of the amino acid mimic. The circle represents the
10.
carbonyl carbon of the amino acid mimic. In the case of aliskiren, the side chain mimics the
side chain of valine, and the carbonyl has been replaced with a secondary alcohol.
Part B: The next sequence [→,
, ] is a mimic of the amino acid valine.
Part C: There are likely to be van der Waals and hydrophobic interactions between renin and
the amino acid side chains of Leu and Val that are “docked” in the renin enzyme pockets.
Part D:
11. Functional group A: This is a methoxy group (a methyl ether). Because it is directly attached
to the aromatic ring, it acts as an electron donating group through resonance.
Functional group B: This is a tertiary amine that will most likely be ionized at physiologic
pH. Because it is more electronegative than its surrounding carbon and hydrogen atoms
(and most likely carries a positive charge), it acts as an electron withdrawing group through
induction.
Functional group C: This is a tertiary hydroxyl group (or tertiary alcohol). Because it is not
directly attached to an aromatic ring, it cannot donate electrons. Due to its electronegativity, it acts as an electron withdrawing group through induction.
12. Part A: Tyrosine (Tyr)—Aspartic Acid (Asp)—Valine (Val)—Glutamine (Gln)
Part B: Tyrosine: This side chain is one of the largest seen in amino acids and thus is involved
in dictating the overall conformation of the peptide. Although the phenyl ring is hydrophobic, the phenolic hydroxyl group can act as both a hydrogen bond donor and acceptor and
thus contribute to the overall water solubility.
398 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Aspartic Acid: This side chain is acidic and will most likely be ionized at physiologic pH,
which enhances the overall water solubility of the peptide. It will most likely reside in a
water-soluble pocket of the overall peptide.
Valine: This is an aliphatic, lipid-soluble, hydrocarbon side chain. It contributes to the over-
all lipid solubility of the peptide and can contribute to lipid-soluble pockets within the peptide. Additionally, the isopropyl side chain can impart some steric bulk that may influence
the overall conformation of the molecule.
Glutamine: Overall, this side chain is normally classified as a polar, water-soluble side chain
due to its ability to act as both a hydrogen bond donor and acceptor. The two methylene
carbon atoms allow the amide to be oriented in different locations and may contribute a
little to the overall lipid solubility of the peptide.
CHAPTER 3
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
1. Acidic and basic functional groups along with normal pKa ranges are shown below.
2. Venetoclax is an amphoteric drug because its structure contains both acidic and basic functional groups.
3. There are two main factors that contribute to the enhanced acidity of the sulfonamide
functional group. First, this functional group is directly attached to a carbonyl group. Similar
to sulfonylureas, this adjacent carbonyl enhances the acidity of the sulfonamide through
resonance stabilization of the negative charge. Once the proton leaves, the resulting negative charge can be equally delocalized to all three adjacent oxygen atoms. Second, the nitro
group on the adjacent aromatic ring can withdraw electrons from the aromatic ring through
resonance. This decreases the electron density of the aromatic ring and causes an inductive effect that withdraws electrons from the adjacent sulfonamide. The overall effect of
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 399
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this nitro group is somewhat decreased due to the ability of the aromatic amine to donate
electrons through resonance into this same aromatic ring. Because the electron withdrawing properties of the nitro group are stronger than the electron donating properties of the
aromatic amine, the net result is an electron withdrawing effect that enhances the acidity
of the sulfonamide group.
4. Five-membered rings that contain a single nitrogen atom are not basic because the lone
pair of electrons on the nitrogen atom is involved in the aromaticity or resonance delocalization of the ring and unavailable for binding to a proton. The presence of a second nitrogen atom within the five-membered ring enhances basicity, as discussed in the chapter;
however, in this case, the second nitrogen atom is in the six-membered pyridine ring. This
nitrogen atom is basic because the lone pair of electrons on the nitrogen atom is oriented
perpendicular to the plane of the aromatic electrons. Thus, the lone pair of electrons are
not involved in the aromaticity of the ring and are available to bind to a proton.
The ionized form of the tertiary amine is shown below.
5.
Checkpoint Drug 2: Elamipretide
1. Answers provided in the grid below.
Name of Functional
Group
A Guanidine Basic 12.5
B Primary amine Basic 9-11
C Amide Neutral NA
D Phenol Acidic 9-10
a
The pKa range for guanidine can dip as low as 6, especially if the functional group is attached to
one or more electron withdrawing groups, as found in the H2 antagonist class of drugs.
2. Functional group C is an amide. The carbonyl carbon is electron poor due to the electronegativity of the adjacent oxygen atom and the resulting dipole. This carbon atom looks
to its neighbor nitrogen atom for electron density. The neighboring nitrogen atom has a
nonbonding pair of electrons that is available (via resonance) to donate electron density to
the electron deficient carbon atom. Because this nonbonding pair of electrons is busy helping the neighbor electron deficient carbon atom, it is unavailable to participate as a proton
acceptor (base). By way of reminder, the electronegative oxygen atom has two pairs of
nonbonding electrons, but these electrons are held too tightly to the nucleus of the oxygen
atom to participate as a proton acceptor (base). As a result, amides are neutral in character.
Character: Acidic, Basic,
Neutral
pKa Value or Range
(NA is Acceptable)
a
400 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. The ionization states and acid/base character are provided below.
Stomach
(pH = 1)
Ionized,
Unionized, NA
A Ionized Acidic Ionized Acidic Ionized Acidic
B Ionized Acidic Ionized Acidic Ionized Acidic
C NA Neutral NA Neutral NA Neutral
D Unionized Acidic Unionized Acidic Unionized Acidic
Acid/Base
Character
at pH = 1
Intestine
(pH = 8)
Ionized,
Unionized, NA
Acid/Base
Character
at pH = 8
Urine (pH = 5)
Ionized,
Unionized, NA
Acid/Base
Character
at pH = 5
Functional group A (guanidine) is basic in character with a pKa = ∼12.5. It is ionized in all
three physiologic locations because the environmental pH < pKa of the functional group. In
its ionized form, a guanidine is a proton donor (acidic).
Functional group B (primary amine) is basic in character with a pKa range = 9 to 11. It is ion-
ized in all three physiologic locations because the environmental pH < pKa of the functional
group. In its ionized form, a primary amine is a proton donor (acidic).
Functional group C (amide) is neutral in character. It is not an ionizable functional group, so
NA should be placed in the grid.
Functional group D (phenol) is acidic in character with a pKa = 10. It is unionized in all three
physiologic locations because the environmental pH < pKa of the functional group. In its
unionized form, a phenol is a proton donor (acidic).
4. The guanidine of arginine, the primary amine of lysine, and the phenol of the tyrosine
derivative are all ionizable. Don’t forget that this peptide-based drug has an amino and a
carboxy terminus! In this case, the carboxy terminus carboxylic acid has been masked as an
amide, but the amino terminus primary amine is still present and is ionizable.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 401
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Review Questions
1. Acidic and basic functional groups are circled below and named in the table below.
Drug Name Acidic Functional Groups Basic Functional Groups
Olapatadine Carboxylic acid Tertiary amine
Lisinopril Carboxylic acid (×2) Primary amine
Secondary amine
Olmesartan Tetrazole Aromatic heterocycle (imidazole)
Baclofen Carboxylic acid Primary amine
Brilanestrant Carboxylic acid Aromatic heterocycle
Aplaviroc Carboxylic acid Tertiary amine
2. Acidic functional groups have been modified to show the ionized form.
402 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
3. Basic functional groups have been modified to show the ionized form.
4. Functional groups that are acidic when they are in their ionized form are identified below.
Olmesartan Lisinopril Aplaviroc
Aromatic heterocycle (imidazole) Primary amine Tertiary amine
Secondary amine
Functional groups that are basic when they are in their ionized form are identified below.
Olmesartan Lisinopril Aplaviroc
Carboxylic acid Carboxylic acid Carboxylic acid
Tetrazole
5. Amphoteric: contains at least one acidic and at least one basic functional group. All of the
drugs in Question 1 are amphoteric in nature.
6. Answers provided in the grid below.
Name of Functional
Drug Name
Besafloxacin Carboxylic acid pKa = 2.5-5 Amphoteric
Tinlorafenib Sulfonamide pKa = 4.5-11 Amphoteric
Nezulcitinib Tertiary amine (×2) pKa = 9-11 Amphoteric
Group(s)
Aniline pKa = 2-5
Primary amine pKa = 9-11
Aniline pKa = 2-5
Aromatic heterocycles
(imidazole, 1,2 diazole)
Phenol pKa = 9-10
Approximate pKa
Value(s)
pKa = 1-6
Acidic, Basic, or
Amphoteric
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 403
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7. Part A: Colestipol (Colestid®) is a polymer than contains numerous basic secondary and
tertiary amines as a component of its structure. Evaluating the entire polymeric structure,
colestipol is considered basic in character. Because colestipol dissociates into ions in solution, it is therefore classified as an electrolyte.
Part B: Drugs that contain one or more functional groups that are anionic (negatively
charged) when in an environment of pH ∼8 exchange for the chloride ion in the polymer.
The drug is then associated with the polymer and is eliminated via a fecal route. This results
in less drug available to be absorbed into the body (also less bile acids being removed),
which likely will reduce the therapeutic effectiveness of the drug because a portion of the
dose was removed by the polymer.
Part C: Atorvastatin (carboxylic acid), sampatrilat (carboxylic acids), and furosemide (car-
boxylic acid) are all likely to be anionic at pH ∼8 and therefore are sequestered by the polymeric drug.
Part A: Ionizable functional groups are listed in the table below.
8.
Drug Name Acidic Functional Groups Basic Functional Groups
Arformoterol Phenol Secondary amine
Atorvastatin Carboxylic acid
Sampatrilat Phenol Primary amine
Carboxylic acids (×2)
Sulfonamide
Furosemide Sulfonamide Aniline
Carboxylic acid
Part B: The acidic and/or basic character of each drug molecule is provided below.
Acidic Character, Basic Character, or Both Acidic
Drug Name
Arformoterol Acidic and basic character
Atorvastatin Acidic character
Sampatrilat Acidic and basic character
Furosemide Acidic and basic character
and Basic Character
9. The acidic and/or basic character of each drug molecule is provided below.
Acidic Character, Basic Character, or Both Acidic
and Basic Character
Zolmitriptan Basic character
Xemilofiban Acidic and basic character
Vilanterol Acidic and basic character
Terbutaline Acidic and basic character
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