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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
A) The Natural World
Plantlife (flowers, trees, bushes)
Micro-organisms (bacteria, fungi)
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
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4.3 Lead Compounds from the Natural World
PLANT EXTRACTS
•
OPIUM
•
CINCHONA BARK - Quinine
•
YEW TREE
- Morphine
- Taxol
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4.3 Lead Compounds from the Natural World
PLANT EXTRACTS
WILLOW TREE - SALICYLIC ACID
O
O
OH
OH
OH
Acetic
anhydride
O
CH3
Aspirin
O
COCA BUSH - COCAINE
Me
N
CH3
CO2Me
H
N
O
CH3
C
H
Procaine
O
C
NH2
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
a liberal
sprinkling
Flavour
with
Heat
Simmer
a cauldron
for 20essence
ofminutes
water
Produce
one
juicy
spiders
of dog
turd
until
then
warm
enjoy
to pedigree
the touchdog
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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
Teprotide
O
O
H2N CH C
N CH C
H
CH2
CH2
CH2
C O
OH
HN
N
O
O
C
N CH C
H
CH2
CH2
N
O
O
C
N CH C
H
CH2
N
O
H
N CH C
N
CH CH3
CH2
CH2
C O
CH3
NH2
O
CH2
C OH
NH
O
C NH
C
NH2
HS
N
CH3
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
N
HO
O
H3 C
H3 C
H
CH 3
CH 3
H
O
N
OH
OMe
Tubocurarine
(from curare)
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4.3 Lead Compounds from the Natural World
MeO
VENOMS AND TOXINS
HO
O
H3 C
H3 C
H
CH 3
N
CH 3
H
O
N
OH
OMe
Tubocurarine
(from curare)
MeO
MeO
N
CH 3
O
O
C
C
O
OMe
OMe
(CH 2)5
O
OMe
H
N
OMe
MeO
OMe
Atracurium
(Neuromuscular blocker)
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4.3 Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS
NATURAL LIGANDS FOR RECEPTORS
OH
HO
OH
H
N
Me
HO
H
N
Agonist
HO
HO
ADRENALINE
SALBUTAMOL
NH2
HO
NMe2
MeHN
N
H
5-HYDROXYTRYPTAMINE
O
Agonist
S
O
N
H
SUMATRIPTAN
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4.3 Lead Compounds from the Natural World
ENDOGENOUS COMPOUNDS
NATURAL LIGANDS FOR RECEPTORS
OH
H
N
HO
O
OH
Antagonist
N
H
Me
HO
ADRENALINE
PROPRANOLOL
Me
NH2
HN
N
HISTAMINE
S
HN
N
H
N
NHMe
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
H2N
O
N
H H
N
N
H
O
L-Phe-L-Pro
O
O
H
N
H H
CONH2
H
N
OH
N
H
H
H
SAQUINAVIR
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