Transcript 1. An Introduction to Drugs, Their Action and Discovery The basic

1. An Introduction to Drugs,
Their Action and Discovery
The basic concepts in Medicinal Chemistry
Dr Seemal Jelani
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Introduction
Primary objective－ design and discovery of new
compounds that are suitable for use as drugs
A team of workers－ chemistry, biology,
biochemistry, pharmacology, mathematics,
medicine and computing, amongst others
Requires of drug discovery or design－ synthesis
of the drug, a method of administration, the
development of tests and procedures to establish
how it operates in the body, and a safety
assessment
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 Drug discovery may also require
fundamental research into the biological
and chemical nature of the diseased state.
 Medicinal chemists need to have an
outline knowledge of the above
mentioned aspects.
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1.2 What are drugs and why do we
need new ones?
 Definition of drug －chemical substances that
are used to prevent or cure diseases in humans,
animals and plants
 Activity － pharmaceutical/pharmacological
effect on the subject, e.g. analgesic or β-blocker
 Potency － the quantitative nature of the effect
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The word “Drug” usually defined as agent used
for the psychotic effect by the media or general
public.
Even the drugs abused have their activity.
Drugs act by interfering with biological
processes, so no drug is completely safe.
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 effect – unwanted 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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 Drug resistance or tolerance
(tachyphylaxis) occurs when a drug is no
longer effective in controlling a medical
condition.
 Reasons – induced oxidases in the liver that
are able to metabolize the drug; a special
enzyme induced to metabolize the drug;
down regulated drug receptors
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Therapeutic index
 Chemotherapeutic index = Minimum
curative dose /Maximum tolerated dose
 By Ehrlich in search of a safer
antiprotozoal agent in 19th century -- more
effective drugs showed a greater
selectivity for the target microorganism
than its host
 Therapeutic index = LD50/ED50
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Evolution and revolution
 Early 19th – plant extracts and pure
isolates from medicinal plants appeared.
Some of these drugs were very toxic
 Late 19th, to find less toxic medicines than
those based on natural sources →
synthetic substances as drugs
 Early 20th synthetics dominated the main
origin of therapeutic drug origins
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Leads – the known
pharmacologically active chemicals
used in drug design and development
Analogues – the-lead related
compounds
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Therapeutic index
Paul Ehrlich and Sacachiro Hata who produced
arsphenamine in 1910 – in the search of more
effective anti-microbiotic agents: Atoxyl,
Arsphenamine (Salvarsan)
Therapeutic index 
Therapeutic index 
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Minimum curative dose
Maximum tolerated dose
ED50
LD50
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Structure–Activity Relationship (SAR)
The structure–activity relationship
(SAR) is the relationship between the
chemical or 3D structure of a molecule
and its biological activity
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QSAR – quantitative structure–activity
relationship
 1960s that Hansch and Fujita devised a
method that successfully incorporated
quantitative measurements into structure–
activity relationship determinations
 This method was refined to build
mathematical relationships between the
chemical structure and the biological
activity, known as quantitative structureactivity relationship (QSAR).
.
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The most successful uses of QSAR
has been in the development in the
1970s of the antiulcer agents
cimetidine and ranitidine.
Both SAR and QSAR are important
parts of the foundations of medicinal
chemistry
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Concept of Drug Receptor
In 1905 John Langley proposed that so-called
receptive substances in the body could accept
either a stimulating compound, which would
cause a biological response, or a non-stimulating
compound, which would prevent a biological
response.
Receptor sites usually take the form of pockets,
grooves or other cavities in the surface of certain
proteins and glycoproteins in the living
organism.
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Ligand
Ligand is a small substance, that forms a
complex with a biomolecule to serve a
biological purpose
It is a signal triggering molecule, bind to
a site on a target (protein)
The binding occurs by IMF, IB, HB, VWF
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Myoglobin (blue) with its ligand
Heme (orange) bound.
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Stereo electronic structure
 Both molecular shape and electron
distribution, is complementary with the
stereoelectronic structure of the receptor
responsible for the desired biological
action.
 The drug conformation adopted when
binds to the receptor is known as active
conformation.
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 The section of the structure of a ligand that binds
to a receptor is known as its Pharmacophore.
 E.g., the “quaternary nitrogens” that are believed
to form the Pharmacophore of the neuromuscular
blocking agent tubocrarine are separated in the
molecule by a distance of 115.3 nm.
H3CO
HO
O
H 2C
H
H3C
N+(S)
H
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N+ CH3
(R)
H CH3
CH2
2Cl-
O
OH
OCH3
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(+)-Tubocurarine chloride
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 Esters and N-substituted amides, for example, have structures
with similar shapes and electron distributions but N-substituted
amides hydrolyze more slowly than esters.
 However, changing a group or introducing a group may change
the nature of the activity of the compound.
O
O
R'
O
R'
R
Ester
N
R
H
Amide
O
N
O
N
O
N
H
NH2
NH2
Procaine
(anaesthetic)
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Procainamide
(antiarrhythmic)
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Membranes
 Drugs normally have to cross non-polar lipid
membrane barriers in order to reach their site
of action
 As the polar nature of the drug increases it
usually becomes more difficult for the
compound to cross these barriers.
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Modern Techniques
 Computerized molecular modeling (1970s) –
allows the researcher to predict the three-dimensional
shapes of molecules and target, calculate the binding
energy, and reduced the need to synthesize every
analogue of a lead compound
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 Combinatorial chemistry
 (1990s) – originated in the field of peptide chemistry but has
now been expanded to cover other areas.
 Simultaneous production of large numbers of compounds,
known as libraries, for biological testing.
 Used for structure–activity studies and to discover new lead
compounds.
 The procedures may be automated.
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1.4 Leads and analogues: some desirable
properties
1.A molecular mass less than 500;
2.A calculated value of log P* less than 5;
3.Less than ten hydrogen bond acceptor groups
(e.g. -O- and -N-, etc.);
4.Less than five hydrogen bond donor groups
(e.g. NH and OH, etc.).
⃰ P = partition coefficient of octanol/water
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Solubility
 Any compounds that are potential drug
candidates have to be soluble to some
extent in both lipid and water.
 Ideal leads and/or analogues have a
balance between their water solubility and
their lipophilicity.
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Structure
 The nature of the structures of leads and
analogues will determine their ability to bind to
receptors and other target sites.
 Binding forces between a drug and a receptor –
electrostatic bonds, such as hydrogen bonds
and van der Waals’ forces, ion pair, and
covalent bond
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 A major consideration in the selection of leads and analogues is
their stereochemistry.
 It is necessary to pharmacologically evaluate individual
enantiomers as well as any racemates.
Cl
OH
N
(Z)
(E)
H
N
N
HO
HO
7
(potency)
chloroquine
R=S form
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(potency)
OH
diethylstilbestrol
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Stablility
 Stability after administration and shelf-life
 Three strategies are commonly used for
improving a drug’s in situ stability:
1. Modifying its structure; prepare a more stable
analogue with the same pharmacological activity
2. Administering the drug as a more stable prodrug
(A biologically inactive compound that can be
metabolized in the body to produce a drug
3. Using a suitable dosage form
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Create a more stable analogue
OH
Hydrolysis
N
N
O
N
pH=7.4
OH
N
N
O
O
Pilocarpine
(active)
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N
Pilocarpic acid
(inactive)
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N
O
O
Carbamate analogue
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Prodrug formation
H
N O
P
O N
H
HN O
P
HO N
Cl
Cl
Cl
Phosphoramidate mustard
Cyclophosphamide
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Cl
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