Introduction to Medicinal Chemistry – PHS 3508

Dr. Aaron Muth

St. Albert Hall, Room B26
mutha@stjohns.edu
 Drug Discovery Process

• Potential Target Identification

• Target Validation
– Gene knockout, RNAi
• Drug Lead Identification
– Natural products, natural product analogs, natural product inspired
synthetic agents, synthetic drugs (rational design), synthetic drugs (HTS),
serendipity
• Develop SAR (Structure-Activity-Relationships)
– Structural features of a drug important to its biological activity

• Physicochemical properties of a drug

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 Physicochemical properties of a drug

• Physicochemical properties of a drug influence their

pharmacokinetics and pharmacodynamics
– Acid/base properties
– Water solubility
– Partition coefficient
– Stereochemistry

• Lipinski’s Rule of Five: a helpful guideline

– Molecular weight (MW) of 500 or less
– Fewer than 5 H-bond donating functional groups
– Fewer than 10 H-bond accepting functional groups
– Calculated logP of less than 5

Lipinski, C. et al. Adv. Drug. Del. Rev. 1997, 23, 3-25. 3

 Summary of Drug Distribution

Receptors for
Gastrointestinal track / desired effects
subcutaneous injection

Systemic circulation
Drug/
Drug Metabolites Metabolites

Liver: (site of drug

metabolism) Receptors for
Excretion of undesired effects 4

Drug/drug metabolites
 Criteria for an Ideal or Close-to-Ideal Drug
• Must be soluble in, and transported by bodily fluids
– Aqueous phase

• Pass through many membrane barriers

– Lipophilic medium

• Survive binding and storage to alternate inert sites

– Plasma proteins
• Endure metabolic modifications

• Penetrate to the site of action

• Bind to the specific receptors/targets and exert desired biological

response
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 Drug Solubility, Absorption and Distribution

Functional groups present on a drug play an important role in their

pharmacokinetics, and pharmacodynamics

• Getting the drug into the body is a

challenge
– Solubility
– Hydrophilicity – polar molecules
– Lipophilicity – nonpolar molecules
• Permeability

• Acid/base property (pKa) affects

ADME profile of a drug
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http://www.ucer.info/colitis_ph_level.html
 Ionizable Drugs in World Drug Index

Drugs with pKa outside the range of 5 – 9 tend to be strongly ionized,

and poorly absorbed through cell membrane. Why?

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Manallack, D. T. Perspect. Medicin. Chem. 2007, 1, 25–38.
 Changing the Polarity/Solubility of a Drug
• Medicinal chemists modify chemical structures of a drug to
change the polarity and pKa – addition of substructures
• Salt formation also affect solubility
– Phosphate, sulfate, citrate – increases water solubility

Basic substructures Acidic substructures

H O
O
N R
5.3 N 4.7
H 3C OH
H 10

H H O
N NH 2
N F F
H OH 2.6
-0.4 O HH
R
H N 5 O F O
H
N OH OH
3.2
F N NH 2 4.2 3.3
8
H
 Acid/Base Property of Drugs

Acidic Drugs: pKa pKb

Penicillin 2.7 11.3
Aspirin 3.5 10.5
Vitamin C 4.3 9.7
Phenobarbital 7.4 6.6
Phenytoin 8.1 5.9
Boric acid 9.2 4.8
Basic Drugs:
Caffeine 3.6 10.4
Zalcitabine 4.2 9.8
Morphine 7.9 6.1
Erythromycin 8.8 5.2
Amphetamine 9.8 4.2
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Polar, Neutral Functional Groups at Physiological pH

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 Functional Groups that are Acidic
OH O
phenol 9-11 R R

O O
sulfonamide 9-10 R S NH2 R S NH
O O

imide 9-10 O O O O

R N R' R N R'
H

N-aryl- 6-7 O
H
R S N R S N
O

sulfonamide O
R'
O
R'

O O O O O O
sulfonimide 5-6 R
S
N R' R
S
N R'
H

O O
Alkylcarboxylic 5-6 R C OH R C O
Acid O O

OH O
R R
Arylcarboxylic 4-5
acid O O
O O
sulfonic acid 0-1 R S
OH
R S
O
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Principles of Medicinal Chemistry, 7th Ed., Foye, Lemke, Williams, Roche and Zito, Eds., William & Wilkins, 2012.
 Functional Groups that are Basic

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Principles of Medicinal Chemistry, 7th Ed., Foye, Lemke, Williams, Roche and Zito, Eds., William & Wilkins, 2012.
 Sample Exercise: Functional Groups

O O
O O Cl Me
S O
H 3C NH N
O NH S

OH Clopidogrel
Tirofiban
(Plavix)

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 Sample Exercise: Acidic/Basic Functional Groups at
Physiological pH

O O O
OH O O O S
O NH N N
S N H
N N
Me N H H O H 2N
H

O Me
Me N
O O Me
H 2N Me N
CH3 N
O O
O N CH3 O N N
O H Me
OH 14
 Acid/Base Chemistry

• Bronsted-Lowry acid-based theory:

– Acids are classified as compounds that donate a proton/hydrogen ion (H+)
– Bases are classified as compounds that accept a proton or generate a
hydroxide ion (OH-)

CH3COOH + H2O CH3COO + H3O

Acid Base Conjugate Conjugate

base acid

CH3NH2 + H2O CH3NH3 + OH

Base Acid Conjugate Conjugate

acid base
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 Ka and pKa

• Ka is the acid dissociation constant

• pKa = -logKa
• Acidity is typically represented by pKa
• Weak acids have large pKa values (not complete dissociation)
• Strong acids have a pKa of less than -2
– Completely dissociates in water

Example: O

OH

O 16

Aspirin
 Henderson-Hasselbach Equation

17

Principles of Medicinal Chemistry, 7th Ed., Foye, Lemke, Williams, Roche and Zito, Eds., William & Wilkins, 2012.
 Percent Ionization Formula

• pH and pKa values can be used to calculate percent ionization of

a drug
• Percent ionization is related to how well a drug can pass through
cell membrane – absorption in gastrointestinal track
• Plasma membrane is a lipid-bilayer
– Ionized molecules do not cross the membrane
– Unionized/neutral molecules do cross the membrane – passive transport

Percent Ionization of a Drug is calculated by using eq. 1

for HA acid and eq. 2 for BH+ acids
eq. 1) % ionization = 100/1+10(pKa-pH)
eq. 2) % ionization = 100/1+10(pH-pKa)
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 Percent Ionization (%I) Formula

Percent Ionization of a Drug is calculated by using eq. 1

for HA acid and eq. 2 for BH+ acids
eq. 1) % ionization = 100/1+10(pKa-pH)
eq. 2) % ionization = 100/1+10(pH-pKa)

• What do we need to calculate %I?

– Is the drug an acid or a base?
– pKa of the drug (pH at which the number of ionized molecules=number
of unionized molecules)
– pH of the environment/medium where the drug is dissolved
• Stomach, intestine, plasma

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 Ionization of a Drug

HO Me HO Me
N N H
+H
O O
-H
H H
HO HO
Morphine
pKa = 7.87

O Me H O
Me N S
N Me
N O
O N Me
O N N O O
Me H O
O H 3C O

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 Calculating %I

Calculate the %I of phenylpropanolamine (pKa 9.4) at

physiological pH (pH = 7.4).

OH OH
+H
NH 2 NH 3
-H
CH3 CH3

Base form Conjugate acid

(B) (BH+)

Using eq.2:
(pH-pKa)
% ionization = 100/1+10
(7.4-9.4) (-2)
% ionization = 100 / (1 + 10 ) = 100/(1+10 )
= 100/(1+0.01) = 100/1.01 = 99% 21
 Calculating %I
HO Me HO Me
N N H
+H
O O
-H
H H
HO HO
Morphine
pKa = 7.87

Determine the percent ionized for morphine at pH 5? Discuss if they

would be well absorbed from this pH environment.

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 Calculating %I
OH O
Me Me
O O O
O
CH3 CH3
N -H
N
O +H O

Cl Cl
Indomethacin
pKa = 4.5

Determine the %I of indomethacin at pH 5? Discuss if they would be

well absorbed from these pH environments.

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 Summary

• Acidic drugs become more ionized in basic pH

• Basic drugs become more ionized in acidic pH

Acidic drug Basic drug

Acidic pH Non-ionized Ionized

environment
Basic pH Ionized Non-ionized
environment

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 Lipophilicity

• Lipophilicity is the most important physical property of a drug in

relation to its ADME profile
• It is often an important factor in all of the following:
– Solubility Biliary and renal clearance
– Absorption CNS penetration
– Plasma protein binding Storage in tissues
– Metabolic clearance Bioavailability
– Volume of distribution Toxicity (promiscuous binding)
– Enzyme/receptor binding Binding to drug transporters

• Too non-polar to too polar molecules – NOT IDEAL DRUG

• How can we determine lipophilicity of molecule?

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 Lipophilicity/Partition Coefficient/Absorption

As biological membranes are highly lipophilic, drug diffusion

through these lipid membranes are partition coefficient dependent.

For Example:

Drug PC % absorbed (in rat colon)

Barbital 0.75 12 Me
Phenobarbital 4.8 20 Me
Me Me
Pentobarbital 28.0 30 O O O O
Secobarbital 50.7 40 HN NH HN NH
O O
Barbital Secobarbital
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 Partition Coefficient

Lipophilicity is measured by the partition coefficient, P – usually

expressed as logP
P
Drug(aqueous) Drug(octanol)

P = [drug](octanol) / [drug](aqueous)

P is a measure of relative affinity of a molecule for the lipid and

aqueous phase in the absence of ionization

1-Octanol is commonly used to mimic the lipid phase:

– It has polar and nonpolar regions
– P is easy to measure
– P often correlates well with biological properties
– Works well for calculation of P using computational methods 27
 Distribution Coefficient

• For molecules that ionize in water, the observed partitioning

between water and octanol depends on pH

Drug(aqueous) Drug(octanol)
[AH](oct) + [A-](oct)
D=
[AH](aqu).+ [A-](aqu)

• Distribution coefficient, D is generally expressed as logD at a

given pH (typically 7.4)

• It is a function of both the lipophilicity of the unionized drug and

the degree of ionization at the given pH

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 Water Solubility of Drugs

• Aqueous solubility of drugs depends on:

– Ionization of functional groups (i.e., acids and bases)
– Hydrogen bond (H-bond) forming ability of groups

• How do you improve aqueous solubility?

– Reduce partition coefficient (logP)
• Addition of ionizable groups, H-bonding, polar groups
– Reduce crystal packing
• Chemical substitutions that prevent molecules from tightly packing together

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 Polar Functional Groups and H-Bonds
H H H
O H
O
H
H O
H
O H H
N
H O

O R R'
H
H

Common functional groups and their H-bonding potential

O O
R O R R' R H
H O
3 2 5

H R' R'
R N R N R N
H H R"
3 2 1
Besides oxygen, and nitrogen, what is another atom that is capable of 30

H-bonding?
Water Solubility of Salts of Drugs

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 Water Solubility Prediction – I
Lemke’s method
Water solubilizing potential of organic functional groups when present in a
mono- or polyfunctional molecule (Table 2.5 in the textbook)
_________________________________________________________
Functional Monofunctional Polyfunctional
Group Molecule Molecule
_________________________________________________________
Alcohol 5 to 6 carbons 3 to 4 carbons
Phenol 6 to 7 carbons 3 to 4 carbons
Ether 4 to 5 carbons 2 carbons
Aldehyde 4 to 5 carbons 2 carbons
Ketone 5 to 6 carbons 2 carbons
Amine 6 to 7 carbons 3 carbons
Carboxylic acid 5 to 6 carbons 3 carbons
Ester 6 carbons 3 carbons
Amide 6 carbons 2 to 3 carbons
Urea, Carbamate 2 carbons 32
 Lemke’s Approach

• It is based on the carbon-solubilizing potential of various organic

functional groups
• If the solubilizing potential is greater than the number of carbon
atoms → molecule is considered water soluble

Total number of carbons = 22

Solubilizing potential from three functional groups = 9 33
 Sample Problems

OH

Functional Group Polyfunctional O

Molecule H 3C O
Aliphatic -OH 3 carbons
Phenolic -OH 3 carbons
Ether 2 carbons OH
Aldehyde 2 carbons O
Ketone 2 carbons
Me N
Amine 3 carbons H
Carboxylic acid 3 carbons
Ester 3 carbons
Amide 2 carbons HO Me
Urea, Carbamate 2 carbons N
Salt formation 20 carbons
O

H
HO
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 Examples

O OH HO Me
O N
OH
Me N O
O H
H
H 3C O
HO

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 Water Solubility Prediction – II
Table 2.6 – Hydrophilic-lipophilic Values (πV) for Organic Elements
An analytical approach Functional Group π value (aliphatic) π value (aromatic)
developed by Cates based H 0.00
upon approximate Alkane 0.50 0.56 (Me); 1.02 (Et)
calculation of logP for a Alkene 0.82
molecule - logP of a drug C6H5 (phenyl) 2.15
greater than 0.5 means Br, Cl, F, I 0.60; 0.39; -0.17, 1.0 0.86; 0.71; 0.14; 1.1
poorly water soluble; logP of IMHB 0.65
a drug ≤ 0.5 means freely NH2 (primary amine) -1.19 -1.23
water soluble. NHR (secondary amine) -0.67 0.47
NHR2 (tertiary amine) -0.30 0.18
LogP = Σπ ( hydrophobic -NHC=OR (amide) -0.97
substituent constants) Sulfur 0.0
OH -1.12 -0.67
OCH3 -0.02

IMHB = Intramolecular -OC=OR (ester) -0.27 -0.64

CHO (aldehyde) -0.65
hydrogen bond
C=OCH3 (ketone) -0.55
CO2H -0.32 36

SO2NH2 (sulfonamide) -1.82

 Water Solubility Prediction – II
Table 2.6 – Hydrophilic-lipophilic Values (πV) for Organic Elements
Functional Group π value (aliphatic) π value (aromatic)
H 3C
N O H 0.00
Alkane 0.50 0.56 (Me); 1.02 (Et)
O
H 2N Alkene 0.82
C6H5 (phenyl) 2.15 1.96
Br, Cl, F, I 0.60; 0.39; -0.17, 1.0 0.86; 0.71; 0.14; 1.1
Calculate logP for Anileridine IMHB 0.65
NH2 (primary amine) -1.19 -1.23

Fragments π Value NHR (secondary amine) -0.67 0.47

NHR2 (tertiary amine) -0.30 0.18
NH2 (aromatic) -1.2
-NHC=OR (amide) -0.97
NR2 (aliphatic) -0.3 Sulfur 0.0
9 aliphatic carbons +4.5 OH -1.12 -0.67
2 phenyl rings +4.3 OCH3 -0.02
1 ester -0.27 -OC=OR (ester) -0.27 -0.64
logP +7.0 CHO (aldehyde) -0.65
C=OCH3 (ketone) -0.55
CO2H -0.32 37

SO2NH2 (sulfonamide) -1.82

Examples

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 Examples
HO O
HN NH 2
O H
O
OH N S
Me O O O
H N
Me Me O Cl

O OH
Me
HO
OH

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 Limitations to drug distribution – site of loss

Most drug molecules do not survive to reach the site of action. They
can undergo:

• Protein binding
• Binding to neutral fats
• Drug metabolism
• Excretion

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 Limitations to Drug Distribution – Site of Loss

• Protein Binding
– Drugs bind to albumin in a reversible fashion
– Binding is due to ionic and/or nonionic bonding, and is nonselective
– Lipophilicity/acidic features on the drug generally tend to increase
protein binding
– Bound drug cannot cross the membranes – ineffective
– Bound drug cannot be metabolized or excreted, therefore protein binding
can prolong the duration of drug’s activity
• e.g. typanocides, suramin
• Clinical Significance
– Bound drug/endogenous ligands can be displaced by other drugs leading
to drug interactions
• e.g. anticoagulant warfarin is displaced from its albumin-binding sites by several
drugs such as phenylbutazone, clofibrate, sulfonamides, etc.
• e.g. protein bound bilirubin can be displaced by the sulfonamides and other organic
anions 41
 Limitations to Drug Distribution – Site of Loss

• Neutral Fats
– Make up to 20-50% of the body weight

– More lipophilic drug = more likely to deposit in neutral fats. Lipophilic

drugs deposit in neutral fats by either direct physical dissolution or by
primary deposition into membranes followed by slow redistribution to the
fatty tissue

– Ultra-short acting barbituates (e.g. thiopental) has a very short duration of

action because it is deposited in the neutral fats rapidly thereby
decreasing its plasma concentration below therapeutic levels

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 Next Class

• There will be a 7-8 question quiz

• Quiz will begin 5 minutes after the beginning of class
• The quiz will close 20 minutes after the beginning of class
• Once you begin the quiz, you will have 12 min to complete
• The quiz will only be accessible on Blackboard
• You will need to be in class to take the quiz (password)

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