PHR 143M ­ Dr.

 Patrick Davis, Course Coordinator
PHR 5.112
475­9751
davispj@mail.utexas.edu
PHR 143P ­ Dr. Sean Kerwin, Course Coordinator
PHR 4.220E
471­5074
skerwin@mail.utexas.edu
TA’s:
Asha Nadipuram  anadipuram@mail.utexas.edu PHR 4.212; 471­7546
Bodin Tuesuwan  btuesuwan@mail.utexas.edu PHR 3.204A; 471­5859
Liping Feng  lfeng@mail.utexas.edu  PHR 3.204A; 471­5859
Scott Miller sgmiller@mail.utexas.edu PHR 4.116;  471­8860
Troy Purvis  troypurvis@hotmail.com  PHR 1.116A;  471­3027
Megan Cornwell  megs5280@mail.utexas.edu ARC 1.240;  232­2785
Hector Serrano  gilly76@aol.com  PHR 4.116;  471­8860
Class Times:

PHR 143M F 1­2pm   PHR 3.106

PHR 143P F 2­3pm PHR 3.106 (Pre­Lab)

PHR 143P Labs:
MWF 3­6pm PHR 2.116
Tu/Th  2­5pm PHR 2.116
Texts:

Lemke “Review of Organic Functional Groups” 3rd Ed (required)
Foye “Principles of Medicinal Chemistry” 5th Ed” (required)
 Overview of the Drug Discovery and
Development Process
2017 2018 1
Compound
2012 Market
2011
Phase 4
~ 5 Compounds
2010
Phase 3
2003
Phase 2
Phase 1 Development

Discovery
>10,000 Compounds
 Drug Discovery Overview

Target identification: The selection of a specific

receptor and/or properties that are expected
to lead to a new drug.
Lead identification: The selection of a specific
compound that has some of the desired
activities for a new drug.
Lead optimization: The process of designing and
synthesizing new analogs of the lead compound
in order to find a suitable drug candidate.
Promotion to Development: Selection of one
compound for eventual clinical trials (filing of IND).
Requires Scale-up synthesis, formulation, stability,
and toxicity testing prior to first human dose.

See Foye p 12-23 for more detail

 Where do the 10,000+ Compounds
Come From?

Observation
Lead
Optimization
Screening “Lead
Compound”
Rational
Design
 Where do “Lead Compounds” Come From?

• Natural Products
- Random screening and ethanopharmacology
• Screening Chemical Libraries
• Rational Design
• Existing Drugs
- Side effects: antihistamine promethazine (sedative)
chlopromazine - antipsychotic
- Metabolism Studies: azodye prontosil -> sulfonamides
 What is Medicinal Chemistry and Where Does
It Fit in this Process?
Medicinal Chemistry is broadly defined as the study of the chemistry
Related to drug discovery and drug action.

It has many components:

– Natural products chemistry
– Synthesis
– Computational Chemistry
– Enzymology/Biochemistry/Molecular Biology
It is essential during the Drug Discovery Process, in the
Selection of Leads, and Lead Optimization.
It is also essential for understanding the following properties of drugs:
­  Chemical compatibility, stability,
ADME, potency, and selectivity
 What is Medicinal Chemistry and Where Does
It Fit in this Process?
Much of Medicinal Chemistry is concerned with defining the 
relationship between the structure of a chemical compound and 
its biological activity.

Elucidating Structure­Activity Relationships 
(SAR) is a key function of medicinal chemistry

In order to study SAR, one must first understand
how structure affects physicochemical properties 
of compounds.
 Physicochemical Properties

Acid/base properties, solubility, partition

coefficient, ionization state,
Resonance and inductive effects, ionization
potential,
3D shape, stereochemisty, conformation
 Other Biological Activity
Parenteral
Oral
Administration
Administration
Receptor(s)
Intravenous for Desired
Injection Effect(s)
Gastrointestinal Tissue depots
Tract

DRUG DRUG DRUG DRUG-DRUG

METABOLITES
DRUG Serum Albumin
DRUG-DRUG DRUG-DRUG
DRUG DRUG-DRUG METABOLITES METABOLITES METABOLITES

Liver Intestinal Tract Kidney Receptor(s)

for Undesired
Excretion Effect(s)
Medicinal Chemist use their knowledge of these
relationships and of organic synthesis to design
and make new molecules with desired activities
(drugs).
1.1 Intro to Medicinal Chemistry –
Organic Functional Groups
Important REQUIRED text: Lemke
“Review of Organic Functional Groups - Intro.
to Organic Medicinal Chemistry”

Today Chapters 1-5 (p 1-22)

and Appendix B (p 132-141)

Sept. 9: Chapters 6-10, 14 (p 23-46, 79-80)

Sept. 12 Chapters 11-13 (p 47-78)

Also read Foye Chapter 2, p 37–49
 Why a Functional Group Approach?

Organic Medicinal

Functional Group Functional Group

Interconversions Metabolism/
Degradation

Functional Group Functional Group

Reactions Interactions
Historical Perspective: "One functional group - One biological
activity"
H3C
N CH3 N+ CH3
m
u
s
O
c
HO OH HO O OH
l
Morphine - analgesic N-Methylmorphine e

r
N N+
CH3 H3C CH3 e
N N l
Nicotine - stimulant N-Methylnicotine a
x
H3C N H3C N+ CH3
a
n
H H t
OH OH
O O
s
O O
Atropine - mydriatic N-Methylatropine
Current understanding of SAR focuses on the chemical
Nature of drugs in total (e.g, the overall electronic structure);
however, functional group analysis is still a useful approach
due to its relative simplicity and the uniformity of the electronic
structure of functional groups in molecules.
 The Drug Skeletons (Frameworks):

Alkanes
Alkenes
Alkynes
Aromatic Hydrocarbons
Aromatic Heterocycles (Heteroaromatics)
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Drug Molecule Evaluation
Analysis of Individual Functional Groups:
Name
Shape
Hydrophobic/Hydrophilic Character
Polar vs. Non-polar Character
Acid/Base Character
Binding Interactions
Chemical/Enzymatic Stability

Analysis of the Whole Molecule

Functional Group Interactions
Functional Group Balance: Physicochemical Prop.
Ionization State
Drug Combinations: Chemical Interactions
 Hydrocarbons - Alkanes
Alkanes - CnH2n+2 bp =
H

methane - CH4 H
H
- 161 °C
H

ethane - C2H6 H H
H
- 89°C

H H

CH3
H H
- 42 °C
propane - C3H8 H H
H
Understanding the Physical Properties of Alkanes
Dispersion Interaction - van der Waals attraction
“instantaneous” dipoles

Averaged over time, the electron density

on the surface of an alkane is uniform
+– +– But at any one moment, the distribution is
uneven. Some areas are electron-rich (dark)
While others are electron poor (light).
– +
+ – Electron poor areas of one molecule
can induce a complementary electron-
rich area in an adjacent molecule.
The result is an attraction between the two.
The larger the molecule (the greater the # of electrons) -
The stronger the attraction
Dispersion Interaction - van der Waals attraction
“instantaneous” dipoles

This attractive force is rather weak and highly dependent

On the distance between the two molecules - it is
Only important when the molecules are very close
Together.
 Alkanes

Effect of Branching: bp =

n-Butane
- 0.5 °C
CH3CH2CH2CH3

- 12 °C
iso-Butane

(CH3)3CH
 Alkanes

Effect of Branching: bp =

n-Butane
- 0.5 °C

effective dispersion interaction between mols.

iso-Butane
- 12 °C

Less dispersion interaction between mols.

 Hydrocarbons
Van der Waals interactions determine
the physical properties of hydrocarbons.
All organic drugs are hydrocarbon based -
The physical properties of drugs are determined
by the hydrocarbon-like skeleton of these drugs
modified by functional groups.

Example - the branching effect that tends to decrease

bp in simple alkanes is the same effect that
causes drugs with branched alkyl side chains to be
more water soluble than those with linear alkyl side
chains (of the same # of atoms).
Remember:

Water solubility - How well does water interact

with molecules Vs. molecules interact with H
each other (crystal packing). O
H
O
O H H

H H
H

H O
O

H H
H

H O

H H
For two solid drugs of similar structure (e.g., functional
groups), the one with the lower mp will have
__________
HIGHER water solubility.
 Partition Coefficient (LogP)

Octanol/Water Octanol/Water
HO HO
HO
HO
OH
HO
OH drug HO
HO
OH
HO
OH

HO HO HO HO HO
HO
HO HO
HO HO HO HO HO HO
HO HO HO HO OH
OH

H H H H
O O
O
O H
H H
O H
O O
O H
H H
O H
O
H H H H H H H H

Conc. In Octanol Layer

LogP = Log
Conc. In Water Layer
For two drugs of similar structure, the drug with
More potential for intermolecular van der Waals
Interactions will have the ____________
HIGHER log P.

Lipophilicity: Preferring to interact with a lipid phase.

e.g, high log P

Hydrophilicity: Preferring to interact with water.

e.g., low log P
Example: Barbiturates

Butabarbital Butethal

O NH O
O NH O
NH
NH
O
O

Sl. Sol in water

Water insol.

logP = 1.65 logP = 1.73

 Hydrocarbons - Alkenes:
H π bond: Shared
H
Ethylene CH2=CH2 H electrons that
H
are not in the same
plane as the atoms.
Properties associated with alkenes (π bonds):
• Attack by electrophiles:
"electrophilic
oxygen" O

Electrophiles: electron-deficient chemical species

that “want” more electrons (attack nucleophiles).
Nucleophiles: electron-rich chemical species (attack
electrophiles).
 Alkenes Reactivity:
Oxidation
OH
H O2 O

R R' R R'

Alkene Hydroperoxide

Decomposition
 Alkenes:
Properties associated with alkenes (π bonds):

• Isomerization
- (E)/(Z) isomers
H3 C CH3 H3 C H
2-butene
H (Z) H H (E) CH3

Restricted bond rotation about C=C

- Double bond migration

OH OH

O O

∆9­THC ∆8­THC
 Alkenes:
Properties associated with alkenes (π bonds):

• Conjugation with other functional groups

EDG EDG

- can alter alkene’s properties

EWG EWG
Conjugation - electronic coupling of functional
groups of portions of molecules through
π electrons.

H
H O CH3
Hydrocarbons - Alkynes:

H H

acetylene

H H

Linear, electron rich, can be reactive

Only a few drugs are alkynes
Me
Me Me
N Me

Terbinafine (antifungal)
 Aromatic Hydrocarbons
H
H H
H
H
H H
H
Benzene H H

H H
H
H H
H

H
H

pi-cloud: resonance forms

delocalized: aromatics are not as reactive
as alkenes
Aromatic: 4n+2 pi-electrons delocalized in a ring
= Hückel’s Rule
Benzene: 3 double bonds =6 pi-electron
= (4*1)+2
 Aromatic Hydrocarbons

Naphthalene Anthracene Phenanthrene

10 π electrons 14 π electrons 14 π electrons
= (4*2)+2 = (4*3)+2 = (4*3)+2

Hückel Series:
2, 6, 10, 14, 18, …
 Aromatic Heterocycles
General Rule:

X:
N
N Lone pair
:

pyridine not in π
N lone pair is not in the π system system
-> we don't count it
6 π electrons -> aromatic

X:
N H
:

N Lone pair
H
N lone pair is in the π system is in π
pyrrole -> it counts system
6 π electrons -> aromatic
Aromatic Heterocycles

N N

pyridine pyrimidine

N O S
H

pyrrole furan thiophene

All are 6 π electron aromatic systems

Other Common Aromatic Heterocycles

H H H H
N N N N
O
N O S

imidazole oxazole isoxazole Thiazole

H S
N
N N N N

s-triazole 1,3,4-thiadiazole
Other Common Aromatic Heterocycles
N

N O N
H H
Benzofuran Benzimidazole
Indole

N
N

Quinoline Isoquinoline N

N N Acridine
N N

N N N N
H

Pteridine
Other Common Heterocycles (Not Aromatic)

H
N
N
H
N
piperidine
1H-1,4-benzodiazepine
O H
N
S
N
H N
N H
H morpholine piperazine
phenothiazine
 Properties of Aromatics

Physical properties are similar to structurally related

alkenes

Charge-transfer and cation-π interactions:

Electron-
Rich aromatic Charge-
Transfer
+ O
O Complex
O

Electron- O

poor aromatic

Electron-
R
Rich aromatic cation-
+ R π
N Complex
cation N
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Halogens
Br

methylbromide H
H H

iodoform CHI3

Halothane CF3CHBrCl
 Halogens
Increased sterics (size) relative to Hydrogen

Can be reactive (alkylators) except when halogen

is attached to aromatic ring)
­
Br

Br H
H R
R H
H Nu

Nu:
 Halogens
Are lipophillic (Remember vdW attraction increases
with # of electrons)

Cl
∆(log P) = +0.71
Log P = 2.13 Log P = 2.84

So each chlorine added to a drug increases Log P by ~0.7

We can derive a simple equation for predicting the log P of
A drug:
Log Pdrug = πskeleton + πfunct. Group 1 + πfunct. Group 2 + ..
or
Log Pdrug = Σ πfragments
 Halogens

πC (aliphatic) = +0.5 Halothane CF3CHBrCl

πPh = +2.0 2 C (aliphatic) = 2 x 0.5 = 1
πF = +0.14 3 Fluorine = 3 x 0.14 = 0.42
πCl = +0.5 1 Chlorine = 0.5
πBr = +0.86 1 Bromine = 0.82
Predicted LogP = 2.74

There are more accurate ways to predict LogP, but the

π values still provide a good estimate for the effect
of individual functional groups on the lipophilic/hydrophilic
Balance of a drug.
 Halogens

Dipoles

-q +q
r

dipole moment = q x r (coulomb meters)

1 debye (D) = 3.336 x 10-30 coulomb meters

Where do dipoles come from? Bond Dipoles:
In molecular hydrogen (H2) there is no permanent
dipole H H =
 Halogens

Dipoles

In hydrogen chloride, there is a dipole:

+q ­q

H Cl

H Cl

The chlorine atom “wants” electrons much more than

the hydrogen atom. The chlorine atom has a partial
negative charge (-q) and the hydrogen is left with a
partial positive (+q). A permanent dipole results.
The dipole can be denoted with an arrow:
 Halogens

Average Electronegativities of Selected Elements.

H
(2.21)
Li C N O F
(0.98) (2.55) (3.04) (3.44) (3.98)
Na P S Cl
(0.93) (2.19) (2.58) (3.16)
K Br
(0.82) (2.96)
I
(2.66)

For an average C–H bond, the dipole is:

C H
Halogens
Bond Dipole Resultant
Moment (D) Dipole
Moment (D)

Hydrogen Chloride H Cl H-Cl, 1.05 1.05

H
C H
Methane H H -C, 0.2 0
H
H
Ammonia N :
H H-N, 1.5 1.5
H

H
Water O :
H H-O, 1.6 1.8
:
Cl
Chloromethane C H
H C-Cl, 1.7 2.0
H
 Halogens in Drugs:

Halogenated hydrocarbons can be more polar than

Simple hydrocarbons due to the molecular dipoles that
can result from halogen-carbon bond dipoles. In all but the
Simplest halogenated hydrocarbons, this effect is typically
Small due to the size of the halogens (prevents effective
Dipole-dipole interactions) and the number of other bond
dipoles involved.

Polarity: relative measure of a compounds ability to

interact with a polar phase by favorable H-bond
and molecular dipoles or ionic interactions.
Halogens in Drugs:

Cl

Halogens attached to aromatic rings withdraw electron

Density from the aromatic ring, making it less easily
Attacked by electrophiles (metabolized).
 Halogens in Drugs:

A few drugs contain halogens, particular F, Cl, and Br.

(Due to the relative instability of the carbon-iodine
bond, There are fewer iodine-containing drugs)
In some cases (e.g., nitrogen mustards) the halogen and
its reactivity is required for drug action.
Most halogen substituents are on aromatic rings, where
they have the effect of blocking/decreasing
metabolism while increasing lipophilicity.
 Halogens in Drugs
Summary:
Analysis of Halogen Functional Groups:
Shape: Spherical, large: F < Cl < Br < I
Hydrophobic: F < Cl < Br < I
Slightly Polar due to bond dipoles
Neutral
Binding Interactions: Increased size and potential for
vdW interactions
Can be chemically unstable (aliphatic), decrease
metabolism (aromatic)
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Alcohols
Solubility
bp    (g/100mL H2O)
methanol CH3OH
66 °C ∞
:

O
Me
H

1-butanol CH3CH2CH2CH2OH 117  °C 7.9

a primary alcohol
2-butanol CH3CH2CH(OH)CH3 100 °C   12.5
a secondary alcohol 82 °C    ∞ 
tert-butanol (CH3)3COH

137 °C 2.3
a tertiary alcohol
1-pentanol CH3CH2CH2CH2CH2OH
 Alcohols

Hydrogen bonding:
Each Hydroxyl group
R
Can donate one and
H O Accept two H-bonds
O H = 3 potential H-bonds
R

Compare the bp of ethane (-89 °C) to methanol (66 °C).

What does this tell us about the strength of
Hydrogen bonds versus van der Waals interactions?
vdW interaction (C - C) ~ 0.5 kcal/mole
H-bond ~ 2-5 kcal/mole
 Alcohols

Hydrogen bonding:

R
H O
O H
R

Alcohols and hydroxyl-containing drugs are polar due to

The ability to H-bond.
 Alcohols

Water Solubility: in simple alcohols, each Hydroxyl group

can "solubilize" 5–6 carbons.

In polyfunctional drugs, each hydroxyl group can

solubilize 3–4 carbons.

Lipophilicity: πaliphatic OH = -1.0

 Homologation: Alcohols

n = 7 (n-octanol)

CNS
Depressant
Activity

1 4 7 10

n
CH3(CH2)nOH
 Other Biological Activity
Oral Parenteral
Administration Administration
Receptor(s)
Intravenous for Desired
Injection Effect(s)
Gastrointestinal Tissue depots
Tract

DRUG DRUG DRUG DRUG-DRUG

METABOLITES
DRUG Serum Albumin
DRUG-DRUG DRUG-DRUG
DRUG DRUG-DRUG METABOLITES METABOLITES METABOLITES

Liver Intestinal Tract Kidney Receptor(s)

for Undesired
Excretion Effect(s)
Octanol and Biological Membranes
O

O
n O

O
=
n O–
O
P O
O R

OH ~
H2O
 Alcohols - Metabolism

Oxidation:
R' = H
R Oxidation R R
OH O Oxidation O

R' R' Reduction OH

Reduction
Alcohol R' = H  Aldehyde Acid
R ≠ H  Ketone
 Alcohols - Metabolism

Conjugation:

HO R' enzyme HO2C

O
HO
O R'
R HO
OH
R
 Hydroxyl Groups in Drugs:

A number of drugs contain the hydroxyl group. In some

cases, the hydroxyl group is essential
for receptor interaction (H-bonding).
The hydroxyl group can increase water solubility
and decrease logP.
The hydroxyl group can be prone to metabolic
transformations.
 Hydroxyl Groups in Drugs
Summary:
Analysis of Hydroxyl Functional Group:
Shape: Similar in size to a methyl group.
Hydrophilic
Polar due to H-bond potential (3)
Neutral
Binding Interactions: H-bonding
Can be metabolically unstable
 Ethers

Diethyl ether O Immiscible w/ water

O
Tetrahydrofuran
O

1,4-dioxane Miscible w/ water

O
(Soluble in water
O
in all proportions)
oxirane (epoxide)
 Ethers - Properties

Ethers are not as polar as alcohols

Water Solubility: in simple ethers, the ether group

can "solubilize" 4–5 carbons.

In polyfunctional drugs, each ether group can

solubilize ~2 carbons.

Lipophilicity: πether = -1.0 (excludes the added carbon(s))

 OH OH
N N
Me Me
O O

Me
OH O

morphine codeine

logP = 0.89 logP = 1.19

 Ethers

Chemistry
peroxide formation (low MW ethers)
O OH
O air
O

explosive!!

Hydrolysis (strained ethers = epoxides)

H2O:

HO
O
OH
 Ethers

Metabolism
Enzymatic De-alkylation
enzyme
R CH3 R
O OH
enzyme
S­adenosyl­
methionine
(SAM)
:
 Ethers in Drugs

Ether functional group is present in many drugs.

It provides increased polarity for interaction with
Receptor functional groups and is more metabolically
Stable than the corresponding alcohol functional
Group.
 Ether Groups in Drugs
Summary:

Analysis of Ether Functional Group:

Shape: Ether oxygen similar is size to CH2 group.
Hydrophilic
Slightly Polar due to H-bond potential (2)
Neutral
Binding Interactions: H-bonding, dipole, vdW
Metabolically stable, except for possible dealkylation
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Phenols - Hydroxylated Aromatic
Compounds
OH Solubility = 9.3g/100mL

Compare: OH 3.6 g/mL

phenol

OH
OH OH

OH HO
OH
catechol
resorcinol hydroquinone
 Phenols - Hydroxylated Aromatic
Compounds
OH ­
O
+
+      H

phenol
phenolate

The ability of phenols to give up a proton to water

Distinguishes them from aliphatic alcohols:
Phenols are (weakly) acidic.

This accounts for the increased water solubility of phenols

Relative to alcohols - the phenolate species, being charged
Is much more water soluble.
 Understanding Acid-Base Properties

What makes one acid “more acidic” than another?

BH <=> B – + H+
Or, where does this equilibrium lie for two “BH” acids?
Or, what is the ∆G associated with this reaction?

To understand from the medicinal chemistry view

We must be able to relate the answers to these
Questions to the STRUCTURE of BH.
Acidity in Solution (Water)

(BH)sol <=> (B –) sol + (H+) sol

[(B –) sol] [(H+) sol]

Ka =

[(BH) sol]
pKa = - log (Ka) pH = - log [(H+) sol]
Understanding Functional Group Acidity and
Structural Effects
Look at relative acidity - Compare two BH acids:
B1H <=> B1 – + H+
B2H <=> B2 – + H+
Look at the energetics of this equilibrium and focus
on the forces which tend to stabilize or destabilize
the charged species:

B – + H+ Common to all BH
Focus on this!

If B2- is more stable than B1-, the pKa of B2H will

LOWER
be ________ than the pKa of B1H.
 Phenols
OH ­
O
+ pKa ~ 16
+      H
cyclohexanol

OH ­
O
+
+      H pKa ~ 10
phenol

– O O
O O

– –
The resonance stabilization of the phenolate anion makes phenols
A million times more acidic than alcohols.
 Phenols

OH ­
O
+
+      H pKa ~ 10
phenol
To what extent is phenol ionized at pH 7?
Henderson-Hassalbach Equation:

[BH]
pKa = pH + log _____

[B-]
Phenol is
[BH] [BH] ~0.1% ionized
10 = 7 + log = 1,000 at pH 7.
[B ]
-
[B-] Phenol is a
Very weak acid.
 Phenols

Substituent Effects

O O–
H
+ H+
R R

UP
If R = electron donating group, pKa goes ______
relative to R = H.

If R is electron withdrawing group, pKa

DOWN
goes _______
relative to R = H.
 Phenols
Properties

Water Solubility: in simple phenols, each phenolic hydroxyl

group can "solubilize" 6–7 carbons.

In polyfunctional drugs, each phenolic hydroxyl group

can solubilize 3–4 carbons.

Lipophilicity: πphenol OH = -1.0

NOTE: πphenyl = +2.0

 Phenols

Chemical Instability

Oxidation (NOTE: different from alcohols)

O O

O O
H Air

p-quinone o-quinone
 Phenols - Metabolism
Conjugation (Similar to alcohols)
OH Enzyme
­
O O
S
O O

Methylation
OH Enzyme O
CH3
OH
OH

Oxidation
OH Enzyme OH

OH
 Phenols in Drugs

A number of drugs have phenol functional groups.

In some cases, these functional groups are essential
for receptor interaction.
Phenol functional groups can increase water solubility
but do not prevent passive diffusion through
membranes.
Phenol functional groups are prone to metabolic
transformations and chemical instability.
 Phenol Groups in Drugs
Summary:

Analysis of Phenol Functional Group:

Shape: Phenol OH is similar in size to CH3 group.
Hydrophilic
Polar due to H-bond potential (3) and ionization
Very weak acid
Binding Interactions: H-bonding, dipole, ionic
Chemically and Metabolically unstable.
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Thiols (Sulfhydryls)

CH3C2SH
Ethanthiol (Ethyl mercaptan)

bp = 37°C
Solubility 1.5g/100mL H2O
Compare ethanol: bp =78°C, miscible with water

Sulfur in thiols is large, lipophilic

Thiols do not form strong H-bonds
 Thiols are weak acids

CH3CH2OH < => CH3CH2O – + H+ pKa ~ 16

CH3CH2SH < => CH3CH2S – + H+ pKa ~ 10

Thiols form good ligands for metal ions, especially zinc

O
H
thiol S N

HO2C

captopril
 Thiols - Chemical Reactivity

air R or R'
S H S S
R R
thiol disulfide
Thiols are prone to oxidative disulfide formation.
Mixed disulfides can form when thiols react with
Disulfides.
Thiols - Chemical Reactivity

R or R'
S H S S
R R
thiol disulfide

Thiols are prone to disulfide formation. They are

Also associated with a variety of side effects.
Very few drugs contain the thiol functional group.
 Thiols in Drugs

Very few drugs have thiol functional groups.

Thiol functional groups are weakly acidic, and serve as

ligands for metal ions.

Thiol functional groups are chemically unstable

(disulfide) and associated with side effects.
 Thiol Groups in Drugs
Summary:

Analysis of Thiol Functional Group:

Shape: SH is similar in size to ethyl group.
Hydrophobic&hydrophilic (πthiol = 0)
weakly polar
Very weak acid
Binding Interactions: metal ion coordination
Chemically unstable.
Thioethers
S
R R'

S
Me Me

90°

Large, lipophilic, decreased bond angle relative

To ethers (112°)
 Thioethers

oxidation O oxidation O O
S
R R' S S
R R' R R'
thioether sulfoxide sulfone

Unlike ethers, thioethers are prone to (metabolic)

oxidation to sulfoxides (tetrahedral!) and less
often, sulfones
 Thioethers

S S

:
Lone pair involved in resonance, O
Less available for oxidation

S S

How readily is thiophene oxidized to the

corresponding sulfoxide?
Thioethers in drugs

A number drugs contain thioether groups, especially

as part of an aromatic ring (e.g., thiophene,
phenothiazine).
The increase in lipophilicity can offset the metabolic
instability
 Thioether Groups in Drugs
Summary:

Analysis of Thioether Functional Group:

Shape: S is similar in size to ethyl group, 90° bond
angles.
hydrophilic (πthiol = 0)
non-polar
neutral
Binding Interactions: vdW
metabolically unstable.
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Amines
:

N
methylamine Me
H H

(a primary amine)

NH2
HO
Serotonin (5-hydroxytrypamine - 5-HT)
N
H

OH

NHMe
Ephedrine
Me
(a secondary amine)
 Amines - Properties
triethylamine N Solubility = 14g/100mL
(a tertiary amine)

Amines can donate (1° and 2°) and accept H-bonds.

Water Solubility: in simple amines, each amino

group can "solubilize" 6–7 carbons.

In polyfunctional drugs, each amino group

can solubilize 3–4 carbons.
NOTE: Salt formation can increase the solubility
significantly.

Lipophilicity: πamine = -1.0

 Amines - Properties
Acidity / Basicity

Simple amines
:

NH3 + H3O+ NH4+ + H2 O

Base Conjugate Acid
Typically, we talk about the
Deprotonation of the Conjugate acid:
:
NH4+ + H2O NH3 + H 3 O+
pKa
 Amines - Properties
Amine Conjugate pKa (BH)
Acid
NH3 N+H4 9.2
CH3NH2 CH3N+H3 10.6
(CH3)2NH (CH3)2N+H2 10.7
(CH3)3N (CH3)3N+H 9.8
Little change in basicity of amines with alkyl
substitution.
 Amines - Metabolism:
Oxidation:
N N
O Amine oxide
enzyme
OH OH
O O

O O
Atropine
Atropine N-oxide
Methylation / N-dealkylation Quaterary
Ammonium
enzyme N+
N CH3 ion
CH3 H3C
N enzyme N

Nicotine N-methylnicotine
 Amines as Drugs

The amino functional group is the most common

functional group in drugs:
• Many biogenic amines are natural receptor ligands.
• Amines can exist in the unprotonated (lipophilic) form,
which enables passive diffusion through membranes,
as well as in the protonated, ionized form, which
allows for interaction with receptors (and improved
water solubility).
• The relative insensitivity of pKa to substitutent effects
allows for a wide variety of structural variation in
amine-containing drugs while maintaining desired
pKa and lipophilic/hydrophilic balance.
 Amine Groups in Drugs
Summary:

Analysis of Amine Functional Group:

Shape: N is similar in size to CH2 group, tetrahedral
hydrophilic (πamine = -1)
very polar
basic
Binding Interactions: ionic, H-Bond,
Can be metabolically unstable.
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Anilines: Properties

:
N(CH3)
2

N,N-Dimethylaniline

Solubility = 1.4g/100mL H2O

Solubilization, Hydrophilicity similar to amines

 Anilines: Properties

:
H N(CH2CH3)
N+(CH2CH3) 2

2 < =>
N,N-Diethylaniline
Conjugate
Acid pKa ~ 4 + H+

Compare to simple amines with pKa of 9-10!

 Anilines: Resonance Effects

:
N(CH2CH3) +
2
N(CH2CH3)
2
N,N-Diethylaniline
–

–
+ +
N(CH2CH3) – N(CH2CH3)
2
2
 Anilines - Metabolism

Conjugation:

H2N H
enzyme HO2C O N
HO
CO2 H OH
HO CO2 H
OH
OH
 Anilines as Drugs

The aniline functional group occurs in a number of drugs.

Although the analine group is similar to the amino group

In hydrophilicity and solubilzation, it is only very weakly
basic

The aniline group can be metabolically unstable.

 Aniline Groups in Drugs
Summary:

Analysis of Aniline Functional Group:

Shape: N is similar in size to CH2 group, planar
hydrophilic (πaniline = -1)
polar
weakly basic
Binding Interactions: H-Bond, dipolar, ionic
Can be metabolically unstable.
 Review of Functional Group pKa
(In units of Fives)

Functional Approx. pKa

Group
Alcohols ROH ~15 Neutral
Phenols PhOH ~10 Weak Acids
Amines RNH3+ ~10 Bases
Anilines PhNH3+ ~5 Weak Bases
 Other Basic Functional Groups

:
N

:
N
H
:
Pyridine Imidazole

pKa = 5 pKa = 7

Is the nitrogen lp involved Is this nitrogen lp involved

In (aromatic) resonance? in (aromatic) resonance?

Why is this “amine” so different Why is imidazole so different

From trimethyl amine? From pyridine?
Other Basic Functional Groups

H H
N+ N

N N+
H H

Resonance stabilization of the protonated form

Increases the pKa relative to pyridine
Other Basic Functional Groups

NH NH
R
R NH2 N NH2
H
Amidine
Guanidine
pKa ~ 12
pKa ~ 12

H +H H H Resonance stabilization
N N
Of the protonated form
H +H
R N R N Increases the pKa
H H Relative to simple
amines
What is the pKa of N-methylnicotine?

N+
CH3
H3C
N

Identify the basic functional group(s).

Pyridines have pKa’s ~ 5–6

 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Carbonyl Compounds

O
'R
O
R
R R’

O–

R + R’
 Aldehydes and Ketones - Properties
O O

Formaldehyde Acetaldehyde
H H Me H

O
Benzaldehyde bp 179 °C, 0.3g/100 mL H2O
H

Compare benzyl alcohol

OH
In simple carbonyl compound H
Aldehyde and ketone groups H

Solubilize 4-6 carbons.

In polyfunctional drugs, each
bp 205 °C, 4g/100 mL H2O
aldehyde or ketone group can
solubilize 2 carbons.
 Aldehydes and Ketones - Chemistry:
Hydration

O OH

+ H2O : OH
Cl3 C H Cl3C H
chloral chloral hydrate

O–

Cl3 C +
H
 Aldehydes and Ketones - Chemistry:
Hydration
OH
O
+ H2 O R
OH
R R’ R’
carbonyl Carbonyl hydrate

If R is electron withdrawing, the unfavorable dipole-dipole

Interaction with the carbonyl group destabilizes the
Carbonyl form and facilitates formation of the hydrate
 Aldehydes and Ketones - Chemistry:
Acetal/Ketal Formation

+
+ R'OH
H
O
+ R'O OH H+ R'O OR'
R'OH
R H R H R H
aldehyde alcohol hemiacetal acetal
Intramolecular:
H O

H OH
HO H
H+ OH
O
H OH HO
HO H
H OH OH
OH
CH2OH

Other Nucleophiles too (e.g., protein thiol, hydroxyl groups)

Aldehydes and Ketones - Chemistry:
Hydration
Bacterial
NH2
Enzyme NH2
HO
HO H2N HO
HO O –O O H2N
NH2 P HO O
HO NH2
OR –O O HO
OR
Aminoglycoside
Antibiotic INACTIVE

NH2 NH2
HO H2O
HO
O H2N HO
HO O H2N
OH
HO NH2 HO O
HO NH2
OR OR

Spontaneous Bacterial
Enzyme
–  HPO42­
NH2

HO
–O O H2N
P OH
–O HO O
HO NH2
O
OR
Aldehydes - Chemistry:
Reactivity

O Air O

R H R OH

Acid
R

O O

R O R
 Aldehydes /Ketones - Chemistry:
Tautomers

:
O OH

R' R'
R R
H H
Keto Enol
H
O– O+
R' R'
R
+
R –
H H
Tautomers: Differ only in the attachment of one proton
 Aldehydes /Ketones - Chemistry:
Enolization

–
O O

R'
+ H+
R'
R R
H H
Keto Enolate

pKa ~ 20 O

R'
BUT: if R’ is also R –
C=O, pKa ~ 10.
 Aldehydes /Ketones - Chemistry:
Imine formation

R"
O "R
N
NH2

R' R R' R

Ketone or Imine (Shiff’s Base)

Aldehyde (R = H)
 Aldehydes /Ketones - Metabolism:
Oxidation/Reduction

R' = H
R Oxidation R R
OH O Oxidation O

R' R' Reduction OH

Reduction
Alcohol R' = H  Aldehyde Acid
R ≠ H  Ketone
 Aldehydes / Ketones in Drugs

Very few drugs possess the aldehyde functional group due

To its chemical and metabolic instability.

A number of drugs contain the ketone functional group,

which is generally part of a ring or, if acyclic, is often
Flanked by at least one aromatic group (reduces reactivity).
O

OH OH

O O

Nabilone ∆9­THC
 Ketone/Aldehyde Groups in Drugs
Summary:

Analysis of Ketone and Aldehyde Functional Groups:

Shape: C=O is similar is size to C=CH2 group,
planar
hydrophilic
polar
neutral or weakly acidic
Binding Interactions: dipolar, H-Bond, covalent
Can be chemically and metabolically unstable.
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines
Guanidines
 Carboxylic Acids
O
Acetic acid
H3 C OH

Benzoic acid
OH

bp = 250 °C,
0.34g/100 mL H2O
In simple carboxylic acids the carboxylic acid group
Can solubilize 5-6 carbons.
In polyfunctional drugs, each carboxylic acid group can
solubilize 3 carbons.
 Carboxylic Acids

O O

OH
NaOH O– Na+

0.34g/100 mL H2O 55 g/100 mL H2O

Carboxylic acid salts are much more soluble than

Carboxylic acids.
 O

OH
pKa = 3.75
H

O
pKa = 4.76
H3 C OH

OH pKa = 4.21

O
pKa = 3.50
OH

O2 N
 Review of Inductive Effect

Carbocation Stability:

H
Least Stable + Primary
H H

+
Secondary
H3C CH3

CH3

+
Tertiary
Most Stable H3C CH3
 Ion–Dipole Interactions

An ionic center interacts favorably with a

properly aligned dipole.

+q’ -q +q
PEIon-Dipole ∝   q / r2
-q’ +q -q

For an average C–H bond, the dipole is:

C H
Inductive effect is an Ion–bond dipole effect
H CH 3
+ = + + =
H H H3 C CH 3
+
 CH bond Inductive Effect Stabilizes Positive charges

CH3

+ = Good
H3C CH3 +

CH bond Inductive Effect Destabilizes Negative charges

CH3

– = Bad
H3C CH3
–
 Review of the Inductive Effect:

Which is more inductively Stabilized?

O O
F – H C O–
C O
or H
F
F H

What are the bond dipoles involved?

 Review of the Inductive Effect:
Which is more inductively Stabilized?
(Least inductively de-stabilized)
O
O
H – O–
O
H
or
H
H

What are the bond dipoles involved?

What is the magnitude of this effect? SMALL

PEIon-dipole ∝   q / r2 C–H bond = 0.2 D
1 debye (D) = 3.336 x 10-30 coulomb meters
 Carboxylic Acids - Properties

O R
H
O O
H
R O

Hydrogen bonding (2-3)

Polar

πcarboxyl = -0.7
 Carboxylic Acids - Metabolism

Conjugation:

O O
enzyme
OH N CO2H
R R H

And other conjugation reactions

β-oxidation:

O enzyme O

R OH R OH
 Carboxylic Acids in Drugs

A large number of drugs contain the carboxylic acid

functionality.
The chemistry of the carboxylic acid functionality is
dominated by its acidity.
Carboxylic acids can be metabolically unstable.
 Carboxylic Acid Groups in Drugs
Summary:

Analysis of Carboxyl Functional Group:

Shape: Similar in size to -CH(Me)2 group , planar
hydrophilic (πcarboxyl = -0.7)
polar
weakly acidic
Binding Interactions: ionic (metal ion coordination),
H-Bond,
Can be metabolically unstable.
 Esters - Properties
O

CH3 bp = 199 °C
Methyl benzoate O
0.016g/100 mLH2O

In simple esters the ester functional group

Can solubilize 5-6 carbons.
In polyfunctional drugs, each ester group can solubilize
3 carbons.
Each ester functional group can accept up to 2
Hydrogen bonds
Polar, but neutral

πester = -0.7
 OH OH
N N
Me Me
O O

H Me
O O

morphine codeine
logP = 0.89 O logP = 1.19
O CH3
N
Me
O
O

O CH3

Heroin
logP = 1.58
 Esters - Properties

'R 'R
O O
O O
R R

Tetrahedral O–R Oxygen

Relatively free rotation about the C–O bond
 Esters - Chemistry/Metabolism:
Hydrolysis
Acid, base
O or enzyme O R
HO
R
R' O
H2O R' OH

–
OH

–
O OH
R
R O
'
Tetrahedral Intermediate
 Amides - Properties

NH2 bp = 288 °C
Benzamide 1.35 g/100 mL H2O

In simple amides the amide functional group

Can solubilize 6 carbons.
In polyfunctional drugs, each amide group can
solubilize 2-3 carbons.
Each amide functional group can accept up to 2
Hydrogen bonds and donate 0-2 H-bonds
(depending on the number of N-substituents)
Polar, but neutral
πamide = -0.7
 Amides vs. Esters

'R 'R
O O
O O
R R

'R
O
H N
R

N is planar
Restricted rotation about C–N bond
 O O–

R R
+
'R N 'R N

H H

Resonance - NOT tautomerization

N OH N O
H

Tautomerization
Amides - Chemistry/Metabolism:
Hydrolysis
H + Strong Acid
O O
or enzyme H2N
R
R
'R N
H H2O 'R OH

H2O

HO OH
+ R
R N
' HH
Tetrahedral Intermediate
 Esters and Amides - Chemistry:
Hydrolysis

Ester hydrolysis occurs more readily than amide

hydrolysis, both chemically and in vivo (esterases).
 Esters and Amides in Drugs:

Acyclic esters are most often used as pro-drugs of the

corresponding carboxylic acids.
Cyclic esters are more stable to hydrolysis, and
can be found in a variety of drugs.
Both acyclic and cyclic amide functional groups
are found in a number of drugs.

Pro-Drug: a compound that is inactive, but which

undergoes metabolic transformation to an
active form.
 Easter and Amide Groups in Drugs
Summary:

Analysis of Ester (CO2R) Functional Group:

Shape: Similar in size to -CH(Me)2 group , C=O planar,
-OR oxygen tetrahedral, relatively free C–O bond
rotation
hydrophilic (πester = -0.7)
polar
neutral
Binding Interactions: H-Bond, dipolar
Is chemically, metabolically unstable.
 Easter and Amide Groups in Drugs
Summary:

Analysis of Amide Functional Group:

Shape: Similar in size to -CH(Me)2 group , planar,
restricted C–N bond rotation
hydrophilic (πester = -0.7)
polar
neutral
Binding Interactions: H-Bond, dipolar
Can be metabolically unstable.
 QUIZ
O
Insoluble (simple amide
-> 6 carbons)
N Amide logPpred. = (2*2)+0.5+(-0.7)
Me
= 3.8

Ether
O
Alcohol / Hydroxyl group
O OH
Insoluble (OH -> 3-4 C’s, two
ethers -> 2* 2 C’s)
logPpred. = (2*2)+(4*0.5)+(2*-1)
= 4.0
O

Me
Ketone - Carbonyl group
Me
Alkene
Me
Insoluble (simple ketone -> 5-6 C’s)
logPpred. = (13*0.5)+(-0.7)
= 5.8
Carboxylic Acid - Carboxyl
CO2 H group
Insoluble (simple carboxylic acid
-> 6-7 C’s)
logPpred. =2+ (6*0.5)+(-0.7)
= 4.3
 O Ester - Carbomethoxy
MeO2 C
group
O Me

Borderline Soluble (two esters

-> 2*3 C’s)
logPpred. = (2*2)+(2*0.5)+(2*-0.7)
= 3.6
 Functional Groups
Halogens
Alcohols
Aldehydes
Ethers
Ketones
Phenols
Imines
Thiols
Carboxyic Acids
Thioethers
Esters
Sulfoxides
Amides
Sulfones
Sulfonic Acids
Amines
Sulfonamides
Amine oxides
Quaternary Ammonium ions
Anilines
Amidines Read Lemke p 77-78
Guanidines