Chapter 4 Drugs Design and Synthesis (23!3!2013)

7/30/2019 Chapter 4 Drugs Design and Synthesis (23!3!2013)

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Drug discovery:and Synthesis

Chapter 4


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Drugchemical substances that are used to

prevent or cure diseases in humans, animals andplants

Activitypharmaceutical/pharmacologicaleffect on the subject, e.g. analgesic or-blocker

Potency the quantitative nature of the effect


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Drug is any substance presented for treating,curing or preventing disease in human beings

or in animals. It may also be used for making a

medical diagnosis or for restoring, correcting,

or modifying physiological functions.


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Receptors are macromolecules involved inchemical signaling between and within cells; they

may be located on the cell surface membrane orwithin the cytoplasm. Receptors get informationfrom drugs or enzymes or hormones etc.

Ligands Molecules (eg. drugs, hormones,neurotransmitters) that bind to a receptor arecalled ligands. A ligand may activate or

inactivate a receptor; activation may increaseor decrease a particular cell function


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Agonists : Agonist drugs activate receptors toproduce the desired response. Conventionalagonists increase the proportion of activatedreceptors.

Drugs + ReceptorDesire effect orpositive response

Many hormones, neurotransmitters (eg, acetylcholine,histamine, norepinephrine), and drugs (eg, morphine,phenylephrine , isoproterenol , act as agonists.

Increased binding = increased effectDecrease binding = decrease effect


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Antagonists :Agonist drugs deactivate receptors to produce theundesired desired response.

Antagonists: pharmacological efficacy = zeroProduce no effect on receptorDont change activity state of receptor


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Prodrugs


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Primary objective-design and discovery of newcompounds that are suitable for use as drugs.

A team of workers

chemistry, biology, biochemistry, pharmacology,

mathematics, medicine and computing, amongstothers

Requires of drug discovery or designsynthesisof the drug, a method of administration, thedevelopment of tests and procedures toestablish how it operates in the body, and asafety assessment


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Drug discovery:

1-Choosing the disease

(like Cancer, HIV, Asthma,

Brain tumor).

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I- Choosing the disease

Pharmaceutical companies tend to concentrate ondeveloping drugs for diseases which are prevalent in

developed countries, and aim to produce compounds

with better properties than existing drugs.

Pharmaceutical companies have to consider economic

factors as well as medical ones when they decide which

disease to target when designing a new drug.

A huge investment has to be made towards the research

and development of a new drug.

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I- Choosing the disease Therefore, companies must ensure that they get a good

financial return for their investment.

As a result, research projects tend to focus on diseasesthat are important in the developed world, because it is

the best market for new drugs.

Thus, research is carried out on ailments such as migraine,

depression, ulcers, obesity, flu, cancer and cardiovascular

disease.

Less is carried out on the tropical diseases of the

developed world. Only when such diseases start to make

an impact in richer countries, the pharmaceutical

companies sit up and take notice.

Example: research in antimalarial drugs has increased due

to increase in tourism to more exotic countries and thespread of malaria into southern states of US.

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Drug discovery: Finding a lead

2-Finding a lead compound

Combinatorial synthesis

Computer aided design

Computerized searching of structural

databases

Designing lead compounds by NMR

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Prototype having desired activity but also other

undesirable characteristics, e.g., toxicity, other

activities, insolubility, metabolism problems, oral

bioavailability

Need to identify a suitable test in order tofind a lead compoundActive Principle - a compound that is isolated

from a natural extract and which is principallyresponsible for the extracts pharmacologicalactivity. Often used as a lead compound.

What is mean of Lead compound ?.


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Lead Compounds from the Natural World

PLANT EXTRACTS

OPIUM - Morphine

CINCHONA BARK- Quinine

YEW TREE - Taxol


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O

O

O

CH3

H

H3CO

O

CH3

H

H

HARTEMISININ

Lead Compounds from the Natural World

PLANTS AND ANCIENT RECORDS


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That is, suitable quantity to cure or excess to be

poisonous! E.g. aspirin, paracetamol can be

toxic if excesses.


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Side effectunwanted effect usually; however, they

are not always non-beneficial

For example, the drowsiness side effect of anti-

histamine may help sleep.


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Isolation and purification Structural determination

Lead compound

Lead modified by synthesis

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Sources of Lead Compounds

A) The Natural World

B) The Synthetic World

C) The Virtual World

Plant life (flowers, trees, bushes)Micro-organisms (bacteria, fungi)

Animal life (frogs, snakes, scorpions)

Biochemicals (Neurotransmitters, hormones)

Marine chemistry (corals, bacteria, fish etc)

Chemical synthesis (traditional)


Computer aided drug design


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Drug discovery:

2-Finding a lead compound

Screening of natural products (the plantkingdom, the microbial world, the marine world,

animal sources, venoms and toxins)

Medical folklore

Screening synthetic compound libraries

Existing drugs

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Isolation and purification

If a lead compound is present in a mixture of other compounds it

has to be isolated and purified.

The isolation and purification depends upon structure, stability, and

quantity of the compound.

e.g. Fleming recognized penicillin, qualities & non-toxic to human

but could not use it clinically because he was unable to purify it. He

could isolate it in aqueous solution, but when he tried to remove

water the drug was destroyed.

Purification and isolation of penicillins were possible until

development of new experimental procedure such as freeze-drying

and chromatography. 22


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Finding a lead compound

Existingdrugs

A) Me too drugs: Many companies use established drugs from their

competitors as a lead compound in order to design a drug. By

modifying the structure in such way that avoids the patent restrictions,

retain the activity, and improved the therapeutic properties.

For example i) Captopril (Anti-hypertension) used as lead compound

by different companies to produce their own anti-hypertension drugs.

ii) Modern penicillins are more selective, more potent and more

stable than original penicillins 23


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Finding a lead compound1-Screening of natural products

Natural products are a rich source of biologically active

compounds.

Many of todays medicines are either obtained directly from a

natural source or were developed from a lead compound

originally obtained from a natural source.

The compound responsible for that activity is known as the

active principle.

Most biologically active natural products are secondarymetabolites with quite complex structures. This has advantage in

that they are extremely novel compounds.

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1-Screening of natural products

2-The microbial world: microorganisms such as bacteria and fungi are

rich for lead compounds (e.g. Antgimicrobial Drugs: pencillins,

cephalosporines, tetracyclines, aminoglycosides, chloramphenicol,

rifamycins).

3-The marine world: coral, sponges, fish and marine microorganisms

have biological potent chemicals, with interesting, anti-inflammatory,

antiviral, and anticancer activity. E.g Curacin A (anti-tumour, from marine

cyanobacterium)

4-Animal sources: antibiotic peptides were extracted from the skin of

African clawed frog.

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1-Screening of natural products

But the disadvantage of their complexity makes their synthesis difficult and

the compound needs to be extracted from its natural source (i.e. costly &

inefficient process).

As a result, there is a need to design simpler analogues of the lead

compounds .

Natural products can be obtained from different sources such as:

1-The plant kingdom: It is rich source of lead compounds (e.g.

morphine, cocaine, digitalis, quinine, tubocurarine, nicotine and muscarine,

paclitaxel (Taxol, recent anticancer), either useful drugs as morphine or

basis for synthetic ).Plants continue to remain a promising source of new

drugs.

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Finding a lead compound2- Medical folklore

Berries, leaves and roots used by local healer or shaman as

medicines. Many are useless or dangerous and if they work this

may be due to Palcebo Effect.

Some of these extracts indeed have a real effect. (e.g. quinine

(cinchona), reserpine (Rauwolfia), atropine (atropa beladona),

morphine (opium poppy), digitalis (foxglove), emetine (ipeca),cocaine (coca).

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2-Medical folklore 3-Screening synthetic compound libraries

4-Existing drugs (Me too drugs & Enhancing the side effects)

5-Starting from natural ligand or modulator (natural ligands for

receptors, natural substrates for enzymes, enzyme products aslead compounds, natural modulators as lead compounds)

6-Combinatorial synthesis

7-Computer aided design

8-Computerized searching of structural databases 9-Designing lead compounds by NMR

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ANALYSIS OF DRUGS

ANALYSIS OF DRUGS by NMR,IR, UV, EI-MS, HREIMS,HMBC, HSQC, COSY, NOEY


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Drug discovery: Synthesis

3-Identifying a bioassay Choice of bioassay In vitro test

In vivo tests

Test validity

High-through screening

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A combination of tests is often used in

research programs


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in vivoTests

Carried out on live animals or humans Measure an observed physiological effect

Measure a drugs ability to interact with its target and its ability

to reach that target

Can identify possible side effects Transgenic animals - genetically modified animals

Drug potency-concentration of drug required to produce 50% of

the maximum possible effect


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Tests not carried out on animals/humans

Target molecules (e.g. isolated enzymes or receptors)Cells (e.g. cloned cells)

Tissues (e.g. muscle tissue)

Organs

Micro-organisms (for antibacterial agents)

More suitable for routine testing Used in high throughput screening

Measure the interaction of a drug with the target but not the

ability of the drug to reach the target

Results are easier to rationalise - less factors involved Does not demonstrate a physiological or clinical effect

Does not identify possible side effects

in vi t roTests


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III-Identifying a bioassay

4-Test validity

Sometimes the validity of testing procedure is easy and clear. For

example, the antibacterial drug can be tested by its effect on

killing bacteria. Local anaesthetics are tested by their effect on

blocking action potential in isolated nerve.

In other cases, the testing procedure is more difficult. For

example, there is no animal model for antipsychotic drug.

Thus, validity of the test should be carried out.

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III-Identifying a bioassay

6-Screening by NMR

5-The identification of weakly binding molecules allows the

possibility of using them as building blocks for the construction of

larger molecules that bind more strongly. 6-Screening can be done on a new protein without needing to

know its function.

NMR screening also has limitations, the main one being that at

least 200 mg of the protein required.

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III-Identifying a bioassay5-High throughput screening (HTS)

HTS involves the miniaturization and automation of in vitro tests

such that a large number of tests can be carried out in a short

period of time.

It involves testing of large number of compounds versus a large

number of targets. The test should produce easily measurable

effect. This effect may be cell growth, an enzyme catalyzed

reaction which produces a color change (may be a dye).

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III-Identifying a bioassay6-Screening by NMR

There are, several advantages in using NMR as a detectionsystem:

1-It is possible to screen 1000 small molecular weight compounds

a day with one machine.

2-The method can detect weak binding which would be missedby conventional screening methods.

3-It can identify the binding of small molecules to different

regions of binding site.

4-It is complementary to HTS. The later may give false-positiveresults, but these can be checked by NMR to ensure that the

compounds concerned are binding in the correct binding site.

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2-Choosing a drug target Drug targets

Discovering drug targets

Target specificity and selectivity between species

Target specificity and selectivity within the body

Targeting drugs to specific organs and tissues

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II- Choosing a drug target

1- Drug targets

Once a therapeutic area has been identified the next stage is to

identify a suitable drug target (e.g. receptor, enzyme or nucleic acid)

Understanding which biomacromolecules are involved in a particular

disease state is very important.

This will allow the medicinal chemist whether agonist or antagonist to

be designed for a particular receptor or whether inhibitors should be

designed for a particular enzyme.

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3. DRUG TARGETS

A) LIPIDS

Cell Membrane Lipids

B) PROTEINS

Receptors

Enzymes

Carrier Proteins

Structural Proteins (tubulin)

C)NUCLEIC ACIDS

DNA

RNA

D) CARBOHYDRATES

Cell surface carbohydrates

Antigens and recognition molecules


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2. DRUG TARGETS

Between species

Antibacterial and antiviral agents Identify targets which are unique to the invading pathogen.

Within the body

Selectivity between different enzymes, receptors etc.

Selectivity between receptor types and subtypes

Selectivity between isozymes

Organ selectivity

TARGET SELECTIVITY


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Identify competitive or non competitive inhibitionStrength of inhibition measured as IC50IC50 = concentration of inhibitor required toreduce enzyme activity by 50%

Enzyme Inhibition Tests


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Choosing which disease to tackle is usually a matterfor companys market strategists. The science

becomes important at the next stage.

A molecular target is chosen, which is believed toinfluence a particular disease when affected by a

drug.

The greater the selectivity that can be achieved, theless chance of side effects.

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Choosing a drug target


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Choosing a drug targetTarget specificity and selectivity between species

Target specificity and selectivity is a crucial factor in modernmedicinal chemistry research

The more the selective a drug is for its target, the less chance

that it will interact with different targets and have less

undesirable side effects.

For example, penicillin target an enzyme involved in bacterial

cell wall biosynthesis. Mammalian cells does not have a cell wall,

so this enzyme is absent in human cells and penicillin has few 43

II Ch i d


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4-Target specificity and selectivity within the

body

Selectivity is also important for drug acting on targets within the body

Enzyme inhibitors should only inhibit the target enzyme and not some otherenzyme.

Receptors agonist/ antagonist should ideally interact with a specific kind of

receptor (adrenergic receptor) rather than a variety of different receptors, or

even a particular receptor type ( such as - receptor) or even a particular

receptor subtype 2- receptor.

Ideally, enzyme inhibitors should show selectivity between the various

isozymes of an enzyme. 44


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Choosing a drug targetTargeting drugs to specific organs and tissues

Targeting drugs against specific receptor subtypes often allows

drugs to be targeted against specific organ or against specific

areas of brain.

This is because the various receptor subtypes are not uniformly

distributed around the body, but are often concentrated in

particular tissues. For example, adrenergic receptors in the heart

are predominantly1 while those in the lungs are 2. If a

drug acts on either, less side effects would be observed.45


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Choosing a drug targetPitfalls

The body is a highly complex system. It is possible to

identify whether a particular enzyme or receptor plays a

role in a particular aliments.

For any given function, there are usually several

messengers, receptors, and enzymes involved in the

process

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C bi t i l th i


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Combinatorial synthesis is automated solid-phase procedureaimed at produce as many as different structures as possible in

short time as possible.

The reactions are carried out on very small scale, often in a waythat will produce mixtures of compounds.

Combinatorial synthesis aims to mimic what plants do, i.e.

produce a pool of chemicals.

One of these compounds may be prove to be a useful lead

compound.

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Computeraided design

Knowledge of target binding site aids in design of novel

compounds intended to bind with that target.

The enzyme and receptors can be crystallized and it is possible to

determine their structure (structure of protein & binding site) by

X-ray crystallography.

Molecular modelling software programs can be used to study the

binding site and to design drugs.48


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Computerized searching of structural

databases

New lead compounds can be found by carrying out computerized

searches of structural databases.

In order to carry out such search, it is necessary to know the

desired pharmacophore.

Data base searching is known as database mining.

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Synthesis of cyclopropane

Drug Synthesis

Retrosynthesis

Synthesis of Aspirin


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Synthesis of Aspirin

Diketone synthesis


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Diketone synthesis

Summary


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Summary

A lead compound is a structure which shows a useful pharmacological

activity and can act as the starting point for drug design.

Natural products are a rich source of lead compounds. The agent

responsible for biological activity of a natural extract is known as the

active principle.

Lead compound have been isolated from plants, trees, microorganisms,

animals, venoms, and toxin. A study of medical folklore indicates plants

and herbs which may contain novel lead compounds.

Lead compounds can be found by screening synthetic compounds

obtained from combinatorial syntheses and other sources.

Existing drugs can be used as a lead compounds for design of novel

structures in the same therapeutic area.

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S


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Summary

If a lead compound is present in a natural extract or acombinatorial synthetic mixture, it has to be isolated and purified

such that its structure can be determined. X- ray crystallography

and NMR spectroscopy are particular important in structure

determination.

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Summary

Documents

Chapter 4 Drugs Design and Synthesis (23!3!2013)