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Introduction to Medicinal
Chemistry
Chapter 1
What is medicinal chemistry?
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The science that deals with the discovery
or design of new therapeutic chemicals
and the development of these chemicals
into useful medicine
What is “medicine”?
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Drugs, pharmaceutics
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Media distinction between drugs that are used
in medicine and drugs that are abused
(addiction).
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A compound that interacts with a biological
system, and produces a biological response
(ideally desired and positive)
“Good” vs. “Bad” Drugs
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No medicine has only benefits or drawbacks
A “good” medicine would have to satisfy the
following criteria.: it would have to do what it is
meant to do and have no toxic or unwanted
side effects and be easy to take.
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HO
Morphine
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In low dose it is an Excellent analgesic, but have
serious side effects such as:
Addiction, tolerance (the effect of the drug
diminishes after repeated doses and so we need
to increase the size of the dose to achieve the
same results.)
Respiratory depression and it may kill if taken in
excess.
O
N
H
HO
CH3
Barbiturates
( series of synthetic compounds with
sedative properties)
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Depressants, sedatives, anesthetics
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General anesthetics in Surgery
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They are known to cross blood brain barrier
because they are fat soluble
Overdoses fatal (Pearl Harbor, wounded
persons were given these drugs before surgery
but many of them died)
H3C
O
C
Heroin
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O
O
N
O
Diamorphine
H
C
H3C
O
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One of the best painkillers (“hero”=heroic drug)
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1898: on market, but
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1903: withdrawn from market due to discovery of its
addictive properties.
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2006: still used under strict control as the drug of
choice for treating patients dying of cancer. It
reduces pain as well as it produces a euphoric effect
to treat depression in patients close to death
CH3
Everyday drugs
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Still produce a biological response
Caffeine (stimulant), in coffee, tea cocoa(when you take a cup of
coffee you are a drug user but when you crave a cup of coffee then
you are a drug addict)
Sugar reacts with the taste buds of the tongue to produce a sense
of sweetness taste
Nicotine (sedation or calming effect), in cigarettes
Alcohol is an unsatisfactory drug because it is difficult to judge the
correct dose required to gain the happiness effect without drifting
into the higher dose levels that produce un wanted side effects
such as staggering effect. Also, either happiness or depression
may result)
Food additives may cause allergies
Junk food and fizzy drinks cause hyperactivity in children (contain
chemicals that are converted in the body into neurotransmitters
leading to excess messages are transmitted in the brain leading to
disruptive (unsettling, troublesome) behavior.
Vitamins
Herbs
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Basil: 50 potential carcinogens
Cultural aspects
“Good” vs. “Bad” Drugs
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Safety of a drug depends on its :
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Dosage level
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Almost anything in excess will be toxic but in
proper dose it is a good medicine
Chronic exposure
Measure of safety of drug = therapeutic
index.
Therapeutic index
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Measure of a drug’s beneficial effects at low
dose vs. harmful effects at high dose
Comparison of dose levels which lead to toxic
effects to dose levels which lead to maximum
therapeutic effects
High therapeutic index = large margin of safety
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Marijuana = 1000
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Alcohol = 10
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Does not take chronic use into account
Medicinal Chemistry
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Under what conditions are drugs “good,” and what to they do to the body?
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Curare (Tubocurarine structure)
It was used as a deadly poison which was used by the native people of
South America to tip their arrows such that a minor arrow wound
would be fatal.
Drugs based on the tubocurarine
structure are used in surgical
operations to relax muscles.
Classification of drugs
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Four main groups (overlap)
1. By biological/pharmacological effect
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2.
Analgesics, anti-asthmatics, antipsychotics,
antihypertensives, antihistaminic, antibiotics ,etc.
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Large and varied assortment of drugs
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Many mechanisms of action
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Some drugs may have more than just one use.
By chemical structure
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Penicillins, opiates, barbiturates
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Common skeleton
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Pharmacological effects may be similar or different uses
in medicine
Classification of drugs
3. By target system
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4.
Examples: Antihistamines
Affect a certain target system in the body
Variety of structures due to large number of stages
in system (synthesis, release, receptor interaction
and removal of histamine for example)
Not all antihistamines are similar compounds
By target site of action (more specific)
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Anticholinesterases (inhibit acetylcholinesterase
enzyme in CNS)
Target enzyme or receptor with which they
interact.
Usually common mechanism
History of Medicinal Chemistry
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Studied/practiced for thousands of years
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Medicine men/witch doctors
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Roots, plants, trees, berries, herbs (medical folklore)
Often placebos (useless drugs but they worked because the patients
had a will of them to work )
Last 150 years: isolation and purification of active principles of the
remedies so Mechanism of reaction/response
1909: first chemotherapy means chemicals that directly interfere
with the proliferation of the microorganisms at concentrations
tolerated by the host-selective toxicity. by Ehrlich)
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Salvarsan (compound “606” arsenic containing compound) for syphilis
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Later replaced with penicillin (toxic fungal metabolite,1940s)
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2005: Structure determination
Aspirin
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400 BC: Hippocrates
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Chew bark of willow tree for pain (child birth and eye
infections)
Active component of willow bark = salicin
Aspirin itself has an antiinflammatory action
It is a prodrug to mask the side effect (gastric bleeding) due
to free phenolic group in salicylic acid, where the ester
group is later hydrolyzed in the body into free active drug.
O
O
OH
glucose
O
O
OH
1. Hydrolysis
2. Oxidation
OH
Ac2O
Ac
(1883: Bayer)
OH
Salisylic acid
- more effective
- no bitter taste
- gastric bleeding
O
Acetylsalicylic acid (aspirin)
- less irritating
- ester hydrolyzes to active drug
Cocaine (I)
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Active principle in South American coca bush
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Plant used as a stimulant, it is absorbed
sublingually by chewing coca leaves
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mystical/religious reasons
Isolated 1880’s
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It is the lead compound for Local Anesthetic in
dentistry
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Addiction (absorbed by mucous membrane of
the nose when its powder snorted or sniffed or
smoked) : Freud
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Used for depression; in other drug addiction
Drug development based on structure (by
simplification of structure)
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Procaine II (Novocain)