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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 9Chapter 9

DRUG DISCOVERY: DRUG DISCOVERY: FINDING A LEADFINDING A LEAD

Part 2: Section 9.4 Part 2: Section 9.4 (Lead compounds from the natural world)(Lead compounds from the natural world)

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ContentsContents

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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IntroductionIntroduction

4 The Lead Compound4 The Lead Compound

• A compound demonstrating a property likely to be A compound demonstrating a property likely to be therapeutically usefultherapeutically useful

• The level of activity and target selectivity are not crucialThe level of activity and target selectivity are not crucial• Used as the starting point for drug design and developmentUsed as the starting point for drug design and development• Found by design (molecular modelling or NMR) or by Found by design (molecular modelling or NMR) or by

screening compounds (natural or synthetic)screening compounds (natural or synthetic)• Need to identify a suitable test in order to find a lead Need to identify a suitable test in order to find a lead

compoundcompound• Active Principle - a compound that is isolated from a natural Active Principle - a compound that is isolated from a natural

extract and which is principally responsible for the extract’s extract and which is principally responsible for the extract’s pharmacological activity. Often used as a lead compound. pharmacological activity. Often used as a lead compound.

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4.1 Sources of Lead Compounds4.1 Sources of Lead Compounds

A) The Natural WorldA) The Natural World

B) The Synthetic WorldB) The Synthetic World

C) The Virtual WorldC) The Virtual World

Plantlife Plantlife (flowers, trees, bushes)(flowers, trees, bushes)

Micro-organisms Micro-organisms (bacteria, fungi)(bacteria, fungi)

Animal life Animal life (frogs, snakes, scorpions)(frogs, snakes, scorpions)

Biochemicals Biochemicals (Neurotransmitters, hormones)(Neurotransmitters, hormones)

Marine chemistry Marine chemistry (corals, bacteria, fish etc)(corals, bacteria, fish etc)

Chemical synthesis (traditional)Chemical synthesis (traditional)Combinatorial synthesisCombinatorial synthesis

Computer aided drug designComputer aided drug design

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4.2 Identification of Lead Compounds4.2 Identification of Lead Compounds

A) Isolation and purificationA) Isolation and purificationsolvent-solvent extractionsolvent-solvent extractionchromatographychromatographycrystallisationcrystallisation

distillationdistillation

B) Structure determinationB) Structure determinationelemental analysiselemental analysismolecular weightmolecular weightmass spectrummass spectruminfra redinfra redultra violetultra violetnmr (nmr (11H, H, 1313C, C, 22D)D)X-ray crystallographyX-ray crystallography

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANT EXTRACTSPLANT EXTRACTS

1©POPPY CAPSULEPOPPY CAPSULE

MORPHINEMORPHINE

4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANT EXTRACTSPLANT EXTRACTS

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANT EXTRACTSPLANT EXTRACTS

• OPIUMOPIUM - Morphine- Morphine

• CINCHONA BARKCINCHONA BARK - Quinine- Quinine

• YEW TREEYEW TREE - Taxol- Taxol

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANT EXTRACTSPLANT EXTRACTS

WILLOW TREE - SALICYLIC ACIDWILLOW TREE - SALICYLIC ACID

COCA BUSH - COCAINECOCA BUSH - COCAINE

AspirinAspirin

ProcaineProcaine

OH

O OHAceticanhydride O

O OH

CH3

O

NMe

O

H

H

CO2Me

CO

OC

O

N

NH2

CH3

CH3

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDSPLANTS AND ANCIENT RECORDS

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O

O

O

CH3

H

H3CO

O

CH3

H

H

H

ARTEMISININARTEMISININ

4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDSPLANTS AND ANCIENT RECORDS

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O

O

O

CH3

H

H3CO

O

CH3

H

H

H

ARTEMISININARTEMISININ

4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDSPLANTS AND ANCIENT RECORDS

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O

O

O

CH3

H

H3CO

O

CH3

H

H

H

ARTEMISININARTEMISININ

4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDSPLANTS AND ANCIENT RECORDS

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Fe

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World PLANTS AND ANCIENT RECORDSPLANTS AND ANCIENT RECORDS

THE BEATONS OF PENNYCROSSTHE BEATONS OF PENNYCROSS

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CURE for EPILEPSYCURE for EPILEPSY

Heat a cauldron of wateruntil warm to the touch

Add a liberal sprinklingof juicy spidersProduce one pedigree dogFlavour with essenceof dog turdSimmer for 20 minutesthen enjoy

THE BEATONS OF PENNYCROSSTHE BEATONS OF PENNYCROSS

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World HERBAL REMEDIES OF OLDEHERBAL REMEDIES OF OLDE

Majority may have worked through a placebo effectMajority may have worked through a placebo effect

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World VENOMS AND TOXINSVENOMS AND TOXINS

CaptoprilCaptopril(anti-hypertensive)(anti-hypertensive)

H2N CH C

CH2

O

CH2

C

OH

O

NH

CH C

CH2

O

HN

N

C

O

NH

CH C

CH2

O

CH2

CH2

NH

C

NH2

NH

N

C

O

NH

CH C

CH2

O

CH2

C

NH2

O

HN CH C

CH

O

CH3

CH2

CH3

N

C

O

N

C OH

O

CH3

C

O

N

C OHO

HS

TeprotideTeprotide

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World VENOMS AND TOXINSVENOMS AND TOXINS

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NCH3

MeO

HO

OH

CH3

NH3C

OMe

O

H3C

HO

H

TubocurarineTubocurarine(from curare)(from curare)

4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World VENOMS AND TOXINSVENOMS AND TOXINS

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NCH3

MeO

HO

OH

CH3

NH3C

OMe

O

H3C

HO

H

NO

C

O

(CH2)5 OC

OMeO

MeO

OMe

OMe

N

OMe

OMe

OMe

MeO

CH3 H

AtracuriumAtracurium(Neuromuscular blocker)(Neuromuscular blocker)

TubocurarineTubocurarine(from curare)(from curare)

4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World VENOMS AND TOXINSVENOMS AND TOXINS

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDSENDOGENOUS COMPOUNDS

NATURAL LIGANDS FOR RECEPTORSNATURAL LIGANDS FOR RECEPTORS

HO

HOADRENALINE

HN

Me

OH

HO

HO

OH

SALBUTAMOL

HN

AgonistAgonist

NH2

NH

HO

5-HYDROXYTRYPTAMINE

NMe2

NH

SUMATRIPTAN

SMeHN

O OAgonistAgonist

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDSENDOGENOUS COMPOUNDS

NATURAL LIGANDS FOR RECEPTORSNATURAL LIGANDS FOR RECEPTORS

O NH

OH

PROPRANOLOL

AntagonistAntagonistHO

HOADRENALINE

HN

Me

OH

HNN

Me

SHN NHMe

CNCIMETIDINE

HNN

NH2

HISTAMINE AntagonistAntagonist

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4.3 Lead Compounds from the Natural World4.3 Lead Compounds from the Natural World ENDOGENOUS COMPOUNDSENDOGENOUS COMPOUNDS

NATURAL SUBSTRATES FOR ENZYMESNATURAL SUBSTRATES FOR ENZYMES

EnkephalinsEnkephalins Enkephalinase inhibitorsEnkephalinase inhibitors

PeptidesPeptides Protease inhibitorsProtease inhibitors

H2NN

HO

CO2HH

L-Phe-L-Pro

HN

NH

N

N

OCONH2

HO

H

H

OHH

H

H NH

O

SAQUINAVIR