Medicinal Chemistry I

1435h
Topic 1:
Drug Structure &
Pharmacological Activity
Dr. Munjed Ibrahim

Drabumalik67@gmail.com

1
 Resources
Text
• Reading
• Foye, Lemke & Williams, 6thed, Chapter 2
• Foye, Williams & Lemke, 5thed, Chapter 2

• Suggested additional reading

• An Introduction to Medicinal Chemistry, Patrick L. G., 3ed
• Cairns Chs 1 & 2
• Delgado & Remers Ch 2, pp 10 - 20, 30 - 33.
• Foye, 4th ed Chs 3 & 4
• Watson Ch 2

2
 Objectives
 Relationship of Functional Groups to Pharmacological Activity
(SARs)

 Physiochemical Properties of drug molecules

 Acid - base properties of drug molecules
 pH and pKa (Henderson-Hassalbach Equation)
 ionisation and absorption
 Water and lipid Solubility (hydrogen and ion bonds)
 Predicting water solubility
• Empirical approach
• Analytical Approach
 Partition coefficient
• absorption/distribution

 Stereochemistry and pharmacological activity

 Optical isomerism (enantiomers and distereomers)
 Conformation isomers
 Geometric isomers (cis and trans)

 Isosterism and Bioisosterism

 drug design
3
 Sites of Drug Action
1. Enzyme inhibition
 Enzyme inhibition may be reversible or non-reversible; competitive or non-competitive
SUBSTRATE SUBSTRATE

2. Drug-Receptor interaction
 A receptor is the specific chemical constituents of the cell with which a drug
interacts to produce its pharmacological effects
ENZYME
This is usually through specific drug receptor sites known toENZYME
be located on the
membrane

3. Non-specific interactions
 Drugs act exclusively by physical means outside of cells
 These sites include external surfaces of skin and gastrointestinal tract.
 Drugs also act outside of cell membranes by chemical interactions
Neutralization of stomach acid by antacids is a good example

4
 Mode of Drug Action
 It is important to distinguish between actions of drugs and their effects.

 Actions of drugs are the biochemicals, physiological mechanisms by which the chemical
produces a response in living organisms.

 The effect is the observable consequence of a drug action. For example, the action of
penicillin is to interfere with cell wall synthesis in bacteria and the effect is the death of bacteria

 One major problem of pharmacology is that no drug produces a single effect.

 The primary effect is the desired therapeutic effect.

 Secondary effects are all other effects beside the desired effect which may be either
beneficial (good) or harmful (side effects, bad!!).

Drugs are chosen to exploit differences between normal metabolic processes and any
abnormalities, which may be present. Since the differences may not be very great, drugs may be
nonspecific in action and alter normal functions as well as the undesirable ones, this leads to
side effects

The biological effects observed after a drug has been administered are the result of interaction
between that chemical and some part of the organism. Mechanisms of drug action

5
 Mechanisms of Actions of Drugs
The fundamental mechanisms of drug action can be distinguished into
following categories
SUBSTRATE
1. Through Enzymes SUBSTRATE

 Enzymes are very important targets of drug action because almost all
biological reactions are carried out under the influence of enzymes. Drugs
may either increase or decrease enzymatic reactions.
Ex: ENZYME ENZYME
• Physostigmine and neostigmine compete with acetylcholine for
cholinesterase

2. Through Receptors

 A large number of drugs act through specific macromolecular

components of the cell, which regulate critical functions like enzymatic
activity, permeability, structural features, template function
6
Receptors and Drug
Action
Binding 
regions

Drug Binding 
groups
Pharmacological
response Intermolecular 
bonds

Binding site

Binding Drug

site
Drug

Macromolecular target Macromolecular target

Unbound drug Bound drug

An Introduction to Medicinal Chemistry, Patrick, Third Edition

7
 Drug-Receptor Interactions
vdw
interaction

Drug
H­bond
Active site
H ionic
O Phe
bond
Ser
CO2

Asp

receptor

• Receptors/enzymes are proteins, so they are amino acids (Asp, Phe, Ser)
• amino acids contain:
 carboxylic acids (ionic interaction)
 amines (ionic interaction)
 hydroxyl (hydrogen bond)
8
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Mechanisms of Actions of Drugs
3. Chemical Properties

• The drugs react extracellularly according to simple chemical

reactions like neutralization, chelation, oxidation etc.

 Aluminium hydroxide neutralizes acid in stomach

Toxic heavy metals can be eliminated by chelating agents like

EDTA, BAL, penicillamine etc.

9
 Functional Groups and Pharmacological Activity
(Agonist, Antagonists)
 If acetylcholine interacts with its receptor, then molecules that
are structurally similar to acetylcholine would also interact with
SUBSTRATE SUBSTRATE
the receptor
acetylcholine "antagonist"

• Antagonists are
generally larger in
size than the
ENZYME natural substrate
ENZYME
acetylcholine + receptor acetylcholine blocked
from receptor

 This is sort of a “lock & key” approach, wherein if you stop

acetylcholine from binding to its receptor (by using another
molecule that is similar in structure) then you will stop the effect of
acetylcholine

i.e. acetylcholine causes muscles to contract, if you stop it from

10
binding to its receptor, muscles will therefore relax
Functional Groups and Pharmacological Activity
 One feature that soon became apparent to the early scientists was that
small changes in structure resulted in significant changes in biological
activity:
H3C
pyrrolidine quaternary CH3 CH3
ammonium phenol N N
pyridine X

N N X

CH3 H3C CH3

N N
HO O OH HO O OH
Nicotine N-Methylnicotine Morphine N-Methylmorphine
(insecticide) (muscle relaxant) (analgesic) (muscle relaxant)

 Crum-Brown & Fraser (1869) postulated that “muscle-relaxant activity”

was related to quaternary ammonium groups (this was later proved wrong
when acetylcholine was discovered)

O CH3

N
CH3 O CH3
CH3
Acetylcholine 11
(muscle contractant)
 Functional Groups and Pharmacological Activity
 The discovery of acetylcholine (& its activity) prompted questions as to
how a given functional group could have two different biological
activities H3C
pyrrolidine quaternary CH3 CH3
ammonium phenol N N
pyridine X

N N X

CH3 H3C CH3

N N
HO O OH HO O OH
Nicotine N-Methylnicotine Morphine N-Methylmorphine
(insecticide) (muscle relaxant) (analgesic) (muscle relaxant)

O CH3

N
CH3 O CH3
CH3
Acetylcholine
(muscle contractant)

 In the early 20th century, scientists speculated that this could be

achieved if “drug receptors” were present
 If acetylcholine interacts with its receptor, then molecules that are
structurally similar to acetylcholine would also interact with the receptor 12
 Physiochemical
Properties
Acid-Base: Conjugate pair theory
 Common acidic and basic functional groups
• W&L Table 2.1 and 2.2 respectively
• Shows acids and their conjugate
bases together with pKa
 Be able to identify these from structures

13
Acidic groups Table 2.1 (page 29)

Acidic groups (page 29)

14
Basic groups Table 2.2 (page 30)

15
Neutral groups Table 2.3 (page 30)

16
 Physiochemical Properties – Acids & Bases
 The human body is composed of ~75% water (55 L of water)
 For an average drug (MW ~200; dose = 20 mg), this equates to a drug
concentration of ~1.8 x 10-6M (i.e. a very dilute solution!)
 For dilute solutions we use the Brönsted–Lowry theory to predict
the behaviors of acids & bases
 An Acid is any substance capable of yielding a proton (H+)
 A base is any substance capable of accepting a proton (H+)

CH3COOH + H2O CH3COO + H3O

acid base conjugate conjugate
base acid

CH3NH2 + H2O CH3NH3 + HO

base acid conjugate conjugate
acid base
 Please refer to Table 2.1 (pg. 29, Foye), Table 2.2 (pg. 30, Foye), and
Table 2.3 (pg. 30, Foye)
17
 Physiochemical Properties – Acids & Bases
 Some drugs have both acidic and basic functional groups, and therefore
can act as a base, an acid, or amphoteric (= both acidic & basic
properties) neutral
Ciprofloxacin
aryl amine O acidic
weakly basic F CO2H

alkyl amine N N
basic aromatic amine
HN weakly basic

 The location of the compound in the body will determine the overall charge of the
compound

O O O
F CO2H F
O

N N N N
H H
N N
H H
stomach (pH 1.0 to 3.0) Duodenum (pH ~ 4) 18
 Relative Acid Strength (pKa)
(Henderson–Hassalbach)
 Henderson-Hasselbach Equation relates pH and pKa (acid
strength)
[conj. base]
pH  pK a  log
[acid ]

 This equation (the Henderson–Hassalbach eqn) allows us to

calculate the percent ionisation of a given molecule at a given
pH

 since pKa is a constant for a given molecule, at a known pH

(e.g. physiological) the concentration of the acidic and basic
forms of a given drug will be able to be calculated

But why is this important??

19
 Relative Acid Strength (pKa)
 Look at the sulphonamides (antibacterial)
 Why is the following true?
lipo- relative half
pKa solubility activity life
R=H 10.5 10.5 1 9
O
sulfanilamide
H2N S N R N
H R= 6.4 26 140 17
O N
sulfadiazine

 These compounds are only active in their ionised forms

 Despite only minor differences in half-life and lipo-solubility, there is a huge
difference in activity

 This is due to their respective pKa values:

 For sulfadiazine, at pH 7.4 it is ~80% ionised
 For sulfanilamide, at pH 7.4 it is only 0.03% ionised
 The difference in pKa is due to the electron withdrawing nature of the
sulfonamide nitrogen substituent, thereby stabilising the ionised form:

O H N O N O N
-H+
NH2 S N NH2 S N NH2 S N
O N O N O N 20
Ionisation of Drugs
 For an acid drug:

100
% ionisation 
1  10 ( pK a  pH )

 For a basic drug:

100
% ionisation 
1  10 ( pH  pK a )
21
 Example: %ionisation for
aspirin
• pKa of aspirin (acetylsalicylic acid) is 3.5
• Physiological pH = 7.4 CO2H CO2
O O
For an acid drug O O
CH3
100 CH3

% ionisation  ( pK a  pH )
acetylsalicylic acid
1  10 (Aspirin)

100 100
% ionisation  ( 3 .5  7 .4 )

1  10 1  10 ( 3.9 )
100 100
 
1  0.000126 1.000126
 99.99% 22
Rule of Thumb (acids)
• Weak acids
• pH = pKa compound ~ 50% ionised
• pH = pKa + 1 compound ~ 90%
ionised
• pH = pKa + 2 compound ~ 99%
ionised
• pH = pKa + 3 compound ~ 99.9%
ionised
• pKa of aspirin is 3.5 • pH
• pH = pKa + 4 compound ~= pKa+ 4
99.99%
• Physiological pH =
ionised
7.4

%ionisation= 99.99% 23
 Rule of Thumb (bases)
• Weak bases
• pH = pKa compound ~50%ionised
• pH = pKa - 1 compound ~ 90% ionised
• pH = pKa - 2 compound ~ 99% ionised
• pH = pKa - 3 compound ~ 99.9% ionised
• pH = pKa - 4 compound ~ 99.99%
OH
ionised
OH
NH3
NH2 H

CH3
• pH = pKa- 2
CH3
phenypropanolamine

• pKa of phenylpropanolamine is
9.4
• Physiological pH = 7.4 %ionisation= 99% ionised
24
 Physical Properties
(water and lipid solubility)
• Partition coefficient
• lipophilic vs. hydrophilic character of drug
• determines water solubility of drug
substances
• affects drug distribution
• confers target-drug binding interactions

[compound] o
P
[compound ]w
25
Water Solubility

26
Water Solubility
 Given that we are ~75% water, the solubility
of a drug in water directly affects the route of
administration, distribution, and elimination
(ADME).

 The most important two key factors that

influence this are:

 Hydrogen bonding: more H-bonds => 

solubility
 Ionisation: dissociable ions =>  solubility
27
Predicting Water Solubility
 Empirical Approach
 Analytical Approach

28
 Predicting Water Solubility
Empirical Approach
 Lemke has developed an approach to predicting water solubility based upon
the “solubilising potential” of various functional groups, versus the number of
carbons Functional Polyfunctional
Monofunctional
Group molecule molecule
alcohol R OH 5 to 6 carbons 3 to 4 carbons
phenol Ar OH 6 to 7 carbons 3 to 4 carbons

ether R O R 4 to 5 carbons 2 carbons

aldehyde O 4 to 5 carbons 2 carbons

ketone R R' 5 to 6 carbons 2 carbons
amine R NH2 6 to 7 carbons 3 carbons

carboxylic acid 5 to 6 carbons 3 carbons

O
ester (R' = OR) 6 carbons 2 to 3 carbons
R R'
amide (R' = NHR) 6 carbons 2 carbons

29
 Given that most drugs are polyfunctional, the second column is most
 Predicting Water Solubility
The Empirical Approach – a working example
alkyl amine
(3 carbons)
N
CO2CH2CH3
aryl amine
(3 carbons) ester
H2N
(3 carbons)

Anileridine
(Narcotic analgesic)

 We get a total “solubilising potential” of 9 carbons using this theory.

 Since the molecule contains 22 carbons, it suggests that the molecule is
insoluble in water (USP has water solubility listed as <1g per 10,000ml)
 However, if we make the hydrochloride salt, then the compound
becomes water soluble
 Lemke estimates that a charge (either anionic or cationic)
contributes a “solubilising potential” of between 20 and 30
30
carbons
 Predicting Water Solubility
Analytical Approach
 The alternative approach for predicting water solubility utilises
the “logP” of molecules
 Essentially, logP is a measure of lipophilicity (hydrophobic)
properties of a molecule
 It is determined by measuring the “partition coefficient”
between water and octanol for a given molecule (i.e. the
solubility of the compound in octanol versus the solubility of the
compound in water)

 Octanol is used as a mimic of the characteristics of a lipid

membrane (polar at one end, long hydrocarbon chain at the
other)

LogP is calculated by adding the contributions from each

functional group in the molecule
31
 Predicting Water Solubility
Analytical Approach-a working example
Fragment π value N
C (aliphatic) + 0.5 CO2CH2CH3

Phenyl + 2.0 H2N

Cl + 0.5
S +0
O (hydroxyl, ether) – 1.0 2 x amines – 2.0

N (amine) – 1.0 9 x aliphatic carbon + 4.5

IMHB + 0.65 2 x phenyl rings + 4.0

O=C–O (carboxyl) – 0.7 1 x ester – 0.7

O=C–N (amide) – 0.7 logP + 5.8

 Water solubility is defined (by the USP) as greater than 3.3%, or a logP
<+ 0.5
 Therefore, anileridine, with a logP greater than + 0.5 is considered
insoluble
 The “ionisation state” of a molecule not only influences water
32
solubility, but also its ability to cross biological barriers or be absorbed
Stereochemistry and
Biological Activity

33
 Stereochemistry and Biological Activity
 The physicochemical properties of a drug are not only influenced by which
functional groups are present, but also by the spatial arrangement of groups.

 The spatial arrangement of groups is especially important when dealing with

biological systems, since receptors are susceptible to the shape of a
molecule.

 Stereoisomers contain the same number and kinds of atoms, the same
arrangement of bonds, but a different spatial arrangement of atoms.
 A carbon atom with four different substituents is an asymmetric
molecules.

 Stereochemistry is primary:
– Optical isomerism (Enantiomers, Diastereomers)
– Geometric isomerism
– Conformational isomerism

34
 Designation of stereoisomerism
 Cahn, Ingold & Prelog (1956) devised a system of nomenclature for
stereoisomer
 Prioritise atoms around a chiral centre, based
1 upon the atomic weight of
the atom
anti-clockwise S 4
2

 Once you have assigned priority from 1 (= highest) to 4 (= lowest), then

“look from the chiral centre towards the lowest priority and count from 1 to 3
 If you count clockwise it is “R”
 If you count anticlockwise it is “S”
1
4

R
2

3 35
 Optical Isomers & Biological Activity
 Whilst enantiomers have identical physical properties, they can
have very different biological properties (e.g. (+)-asparagine is
sweet, whilst
(–)-aspargine is tasteless). This was one of the earliest
observation by in 1886).

 Easson-Stedman hypothesis states that the more potent enantiomer

must be involved in a minimum of three interactions with the receptor
and that the less potent enantiomer only interacts with two sites
This difference is due to the asymmetry of receptor – ligand
interactions D A

A C D C
B B

biological
receptor
36
 Selective Reactivity -
Enantiomers
 R-(-)-epinephrine vs. S-(+)-epinephrine
– each enantiomer maps to the receptor site differently – (see
Foye, Fig 2.19, page 41)

S, Epinephrine
R, Epinephrine
OH
H H3C
H3C N OH
N OH 
 H H
H H OH H
OH
OH

Flat area Flat area

Anionic site Anionic site

Receptor Receptor
HB HB
37
 Diastereomers – Asymmetric
Centres
Diastereomers:
 Stereoisomers with the same number and kinds of atoms, but in a
different spatial arrangement (any stereoisomers compound that is not an
enantiomer)

 These compounds have different physical and chemical properties

 These arise from compounds possessing two or more asymmetric

centres

 Consider isomethadol H
C (S) N
• 2 asymmetric carbons (S)
• 4 isomers (2 pairs of enantiomers) C
H OH
• only the (3S,5S)-isomer has analgesic activity.

38
 Diasteroemers & Biological Activity
 Most drugs contain more than one chiral centre, so therefore
diastereomers become important.
 Two chiral centers: up to four stereoisomers, consists of two
sets of enanatiomeric pairs. For each enantiomeric pair there
is inversion of both chiral ecnters, while in the disteroemers
there inversion in only one chiral center.

HO H H OH

NHMe (S) (R)

NHMe
(R) (S) enantiomers
Me H H Me

(–)-ephedrine (+)-ephedrine

diastereomers diastereomers

HO H H OH
NHMe NHMe
(R) (R) enantiomers (S) (S)

H Me Me H

(–)-pseudoephedrine (+)-pseudoephedrine 39
Enantiomeric Pair
Differences
• Some examples
• Isomethadol (cf methadone) - analgesic
• Acetylisomethadol - transformation induced
• Etomidate - nonbarbiturate hypnotic
• Ibuprofen - NSAID/Analgesic
• Naproxen - NSAID/Analgesic
• Verapamil - Ca channel blocker
• Warfarin - anticoagulant

40
Geometric isomers & biological activity
 Geometrical isomerism (= restricted rotation)
H H H Me Z- comes from German
“Zusammen” (= together)
Me Me Me H E- comes from German
“Entgegen” (= opposite)
cis- or Z-isomer trans- or E-isomer

• Sometimes E- and Z- becomes difficult to determine when it is

less obvious which substituents are the highest priority:

N N
1
1 N 1 2H

2 2
H N
2 1

MeO MeO
triprolidine
(a histamine antagonist)
 Thekey here is to assign the two groups on each side of the
double bond, and then “simply” see if the two highest priority
groups are on the same side or opposite sides
41
Geometric isomers & biological
activity
cis/trans isomers have different physical properties
 distribution in biologic system varies
• generally leads to distinct biological activity
• But … difficult to correlate activity differences with
stereochemistry alone
• eg different pKas of isomers => different levels of ionisation
and hence => differing penetration or absorption

42
Cis-trans Spatial arrangement of
pharmacophores
• eg Diethylstilbestrol (W&L p62)
• trans isomer more active than cis

OH HO OH

HO

trans-diethylstilbestrol cis-diethylstilbestrol

43
 Conformational Isomers
 Conformational isomerism - Eliel’s definition

 “ ... the no identical spatial arrangement of atoms in a molecule, resulting

from rotation about one or more single bonds.”

 Involves both acyclic and cyclic drug molecules

• acyclic - flexible - Newman and sawhorse models
• cyclic - rigid - chair/boat model of conformers
 cyclic molecules of more interest medicinally
H3C CH3
H3C N
* O

* O
CH3

Acetylcholine 44
 Conformational Isomers
 Endogenous  lead  compounds  often  simple  and  flexible  (e.g. 
adrenaline)
 Fit several targets due to different active conformations               
(e.g. adrenergic receptor types and subtypes)

single bond
rotation
+ +

Flexible
chain
Different conformations

 Rigidify molecule to limit conformations ­ conformational restraint
 Increases activity (more chance of desired active conformation)
 Increases selectivity (less chance of undesired active 
conformations)
 Disadvantage:
 Molecule more complex and may be more difficult to synthesise

45
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Conformational Isomers (Epinephrine)
NH2Me
H H

O O

NH2Me
H H
BOND
ROTATION

I II

O 2C

H H
NH2Me
O O
O H O 2C O H
NH2Me

H H

RECEPTOR 1 RECEPTOR 2
46
An Introduction to Medicinal Chemistry, Patrick, Third Edition
Rotatable bonds

Target inetraction site  An Introduction to Medicinal Chemistry, Patrick, Third Edition 47

 Rotatable bonds

Target interaction site 
48
An Introduction to Medicinal Chemistry, Patrick, Third Edition
Rotatable bonds

Target interaction site  An Introduction to Medicinal Chemistry, Patrick, Third Edition 49

 Rigidificati
on 
Methods ­ Introduce rings
 Bonds within ring systems are locked and cannot rotate freely
 

rotatable bonds fixed bonds

H H

O O

NHMe
NH2Me
H

FLEXIBLE RIGID MESSENGER
MESSENGER

50
An Introduction to Medicinal Chemistry, Patrick, Third Edition
Isosterism and Bioisosterism

51
 Isosterism and Bioisosterism
 A poor “drug profile” includes issues such as bioavailability,
unwanted side effects, inability to cross biological barriers,
poor pharmacokinetics.
These undesirable features could be due to specific functional
groups in the molecule.
 Modify this molecule to reduce these undesirable features
WITHOUT losing the desired biological activity with other
groups having similar properties is known as ISOSTERIC or
BIOISOSTERIC replacement.
In 1919 Langmuir first developed the concept of isosterism to
describe the similarities in physical properties among atoms
(same number of valence electrons O and S).
 In 1925 Grimm developed his hydride displacement law
(illustration of similar physical properties among closely
related functional groups)
Thus, NH2 is considered to be isosteric to OH, SH, CH3) 52
 Grimm’s isosteres -
1925
C N O F Ne

CH NH OH HF

CH2 NH2 OH2

CH3 NH3

CH4

 Descending diagonally from left to right in the table H atoms are added to
maintain the same number of valence electrons for each group of atoms
within a column.

 Each member of a vertical group is isoelectronic

53
 Isosterism
 Initially this concept related to the notion that different functional groups have the
same number of valence electrons

 NH2 and OH are considered to be isosteric to each other

 Both groups are able to participate in hydrogen bonding interactions

 However, NH2 is basic at physiological pH, which means that changing an OH to

an NH2 would give the molecule a positive charge at physiological pH (& therefore
very different pharmacokinetics)

 Some isosteric replacements do work well (e.g. replace benzene with pyridine),
but it is difficult to generalise between different biological systems
N

benzene pyridine
54
 Isosterism and Pharmacological Activity
(example)
 “isosteric replacement” replacement of functional groups, where the
chemical group considered to be important for activity is replaced by a
different chemical group which has the “same” properties

O H O H
H2N O H2N S N R
O
PABA sulfonamide

O O
H2N H2N S NHR

O O
H-bond v.d.w. H-bond v.d.w.
ionic ionic

enzyme active site enzyme active site

 These “isosteres” are important when considering issues such as water

solubility, acidity / basicity, lipophilicity, etc, since sometimes compounds
with excellent biological activity have a poor “drug profile” 55
 Bio-isosterism
 This process attempts to overcome the limitations of isosteric
replacement by considering not just the similarity in chemical structure
between functional groups, but to also look at the biological effects

• Friedman definition “bio-isosteres are functional groups or molecules

that have chemical and physical similarities producing broadly similar
biological properties”

• Burger definition: “bio-isosteres are compounds or groups that possess

near equal molecular shape and volumes, and with exhibit similar
physical properties such as hydrophobicity”.

 The key point is that the same pharmacological target is influenced by

bioisosteres as agonist or antagoinist.
 There are two general types of “bio-isosteres”

• Classical and non-classical

56
 Bio-isosterism… Classical
 (Monovalent bio-isosteres)
 A common replacement is F instead of H (in the development of
antineoplastic agent 5-fluorouracil from Uracil) O O
 van der Waal’s radii: F = 1.35Å; H = 1.2Å H F
HN HN
 (therefore very similar steric demand)
 The only real difference is electronegativity
O N O N
H H
uracil 5-fluorouracil

 Tetravalent bio-isosteres of -tocopherol:

 -tocopherol (when X= C14H29) was found to accumulate in heart tissue

 All bio-isosteric analogues (when X= NMe3, PMe3 Or SMe2) were found to

produce similar biological activity
Me
HO X = NMe3

X X = PMe3
Me O
Me
Me X = SMe2

-tocopherol X=C14H29 57
Examples of Bio-isosteres
(Classical)
O O
H F
HN HN

O N O N
H H

S N
N H
O OH
O
OH
X N
N H O
N N
H X = OH: Folic Acid
H2 N N N X = NH2: Aminopterin
58
(basis of methotrexate)
 Bioisosterism….Non-Classical

 Replace a functional group with another group which

retains the same biological activity

 Not necessarily the same valency

Example: N
antipsychotics N
Et
Et

O N
N
H
Pyrrole ring =
H bio­isostere for
OMe
OMe amide group
EtO2S
EtO2S
DU 122290
Sultopride

Improved selectivity 
for D3 receptor
An Introduction to Medicinal Chemistry, Patrick, Third Edition
over D2 receptor 59