Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 9

DRUG DISCOVERY:
FINDING A LEAD

Part 2: Section 9.4

(Lead compounds from the natural world)
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Contents

Part 2: Section 9.4 Lead compounds from the natural world

4. The Lead Compound

4.1. Sources of Lead Compounds
4.2. Identification of Lead Compounds
4.3. Lead Compounds from the Natural World (21 slides)
- Plant Extracts (4 slides)
- Plants and Ancient Records (9 slides)
- Herbal Remedies of Olde
- Venoms and Toxins (4 slides)
- Endogenous Compounds (3 Slides)

[25 slides]

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4 The Lead Compound
Introduction
• A compound demonstrating a property likely to be
therapeutically useful
• The level of activity and target selectivity are not crucial
• Used as the starting point for drug design and development
• Found by design (molecular modelling or NMR) or by
screening compounds (natural or synthetic)
• Need to identify a suitable test in order to find a lead
compound
• Active Principle - a compound that is isolated from a natural
extract and which is principally responsible for the extract’s
pharmacological activity. Often used as a lead compound.

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4.1 Sources of Lead Compounds

Plantlife (flowers, trees, bushes)

Micro-organisms (bacteria, fungi)
A) The Natural World Animal life (frogs, snakes, scorpions)
Biochemicals (Neurotransmitters, hormones)
Marine chemistry (corals, bacteria, fish etc)

B) The Synthetic World Chemical synthesis (traditional)

Combinatorial synthesis

C) The Virtual World Computer aided drug design

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4.2 Identification of Lead Compounds

A) Isolation and purification

solvent-solvent extraction
chromatography
crystallisation
distillation

B) Structure determination
elemental analysis
molecular weight
mass spectrum
infra red
ultra violet
nmr (1H, 13C, 2D)
X-ray crystallography
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4.3 Lead Compounds from the Natural World
PLANT EXTRACTS

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4.3 Lead Compounds from the Natural World
PLANT EXTRACTS

MORPHINE

POPPY CAPSULE ©1
4.3 Lead Compounds from the Natural World
PLANT EXTRACTS

• OPIUM - Morphine

• CINCHONA BARK - Quinine

• YEW TREE - Taxol

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4.3 Lead Compounds from the Natural World
PLANT EXTRACTS

WILLOW TREE - SALICYLIC ACID

O OH O OH
Acetic
OH anhydride O CH3
Aspirin
O

COCA BUSH - COCAINE

Me
CH3
N
CO2Me
N
H
O
Procaine
O CH3 C NH2
H C O
O

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4.3 Lead Compounds from the Natural World
PLANTS AND ANCIENT RECORDS

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4.3 Lead Compounds from the Natural World
PLANTS AND ANCIENT RECORDS

CH3
H

O
H3 C
O
O

H H
O
CH3
H
O

ARTEMISININ

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4.3 Lead Compounds from the Natural World
PLANTS AND ANCIENT RECORDS

CH3
H

O
H3 C
O
O

H H
O
CH3
H
O

ARTEMISININ

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4.3 Lead Compounds from the Natural World
PLANTS AND ANCIENT RECORDS

CH3
H

O
H3 C
O
O

H H
O
CH3
H
O

ARTEMISININ

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Fe

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4.3 Lead Compounds from the Natural World
PLANTS AND ANCIENT RECORDS
THE BEATONS OF PENNYCROSS

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THE BEATONS OF PENNYCROSS

CURE for EPILEPSY

Add
Flavour
Heat
Simmera liberal
with
for 20essence
a cauldron sprinkling
ofminutes
water
Produce
of juicy
until
thendog
warm oneto pedigree
turd
enjoy the touchdog
spiders

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4.3 Lead Compounds from the Natural World
HERBAL REMEDIES OF OLDE

Majority may have worked through a placebo effect

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4.3 Lead Compounds from the Natural World
O
VENOMS AND TOXINS C OH
O
C N
Teprotide O O
H
O
C N CH C N CH C N
O H
O CH2 CH CH3
C N CH C N CH2 CH2
O O H
CH2 C O CH3
H2N CH C N CH C N
H CH2 NH2
CH2 CH2 O
CH2
CH2 C OH
NH O
C O
HN C NH C N
OH
NH2
CH3
HS

Captopril
(anti-hypertensive)

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4.3 Lead Compounds from the Natural World
VENOMS AND TOXINS

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4.3 Lead Compounds from the Natural World
MeO
VENOMS AND TOXINS CH 3
N
HO CH 3
O H

H O
H3 C
N OH
H3 C
OMe

Tubocurarine
(from curare)

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4.3 Lead Compounds from the Natural World
MeO
VENOMS AND TOXINS CH 3
N
HO CH 3
O H

H O
H3 C
N OH
H3 C
OMe

Tubocurarine
(from curare)

MeO OMe
O O
CH 3 H
N C C N
MeO O (CH 2)5 O OMe

OMe MeO
OMe OMe

Atracurium
(Neuromuscular blocker)
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4.3 Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS

NATURAL LIGANDS FOR RECEPTORS

OH OH
H
H N
HO N HO
Me Agonist
HO
HO
ADRENALINE SALBUTAMOL

NH2 NMe2

HO MeHN
S Agonist
O O
N N
H H
5-HYDROXYTRYPTAMINE SUMATRIPTAN

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4.3 Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS

NATURAL LIGANDS FOR RECEPTORS

OH O N
H
Antagonist
H
HO N OH
Me

HO
ADRENALINE PROPRANOLOL

Me
NH2 H
N NHMe
HN S
HN
N
N
HISTAMINE
CN Antagonist
CIMETIDINE

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4.3 Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS

NATURAL SUBSTRATES FOR ENZYMES

Enkephalins Enkephalinase inhibitors

Peptides Protease inhibitors

H CO2H O
N O
H H H H N
N N H
N N
H2N H H H
H O OH
O CONH2
H
L-Phe-L-Pro
SAQUINAVIR

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