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PHAR 2133MEDICINAL CHEMISTRY
DRUGS: AN OVERVIEW
Faculty of PharmacyCyberjaya University College of Medical
Sciences
Learning Objectives
1. To define drug.
2. To explain the 4 classification of drugs.
3. To discuss the drugs from natural sources.
4. To give examples of drugs from various natural sources.
Drugs
• Chemicals that are normally of low molecular weight.
• Interact with macromolecular targets to produce a biological
response.
• The response: -therapeutically useful as medicines.
-harmful as poisons.
• When taken in doses higher than recommended, medicinal drugs
become potential poisons.
Classification of Drugs
Classification:
1. By pharmacological effect.
2. By action on a particular biochemical process.
3. By chemical structure.
4. By molecular target.
Pharmacological Effect
• Drugs are grouped depending on the biological effect they have.
• E.g. analgesics, antipsychotics, antihypertensive, antiasthmatics,
and antibiotics.
• Useful if the need to know the full scope of drugs available for a
certain treatment.
• This type of classification contain a large and extremely varied
assortment of drugs.
• E.g. analgesics
Aspirin Morphine
Both act on different targets and have no structural relationship.
• Thus, not useful for medicinal chemists as there are many different
targets and mechanisms by which drugs can have analgesic effect.
• It is not possible to identify a common feature which is shared by all
analgesics.
Action on a Biochemical Process
• Drugs can be classified depending on whether they act on a
particular biochemical process.
• E.g. antihistamines act by inhibiting the action of the inflammatory
agent histamine in the body.
• More specific than classification according to pharmacological effect.
• However, it is still not possible to identify a common feature relating
all antihistamines.
• There are various ways in which the action of histamine can be
inhibited.
• Antihistamine is commonly used for the relief of allergies caused by
intolerance of proteins.
• The action of histamine could be inhibited by:
- blocking its attachment to histamine receptors (e.g.
cimetidine); or
- inhibiting the enzymatic activity of histidine decarboxylase;
catalyzing the transformation of histidine into histamine (e.g.
catechin) .
Cimetidine Catechin
Chemical Structure
• A third method of classifying drugs is by their chemical structure.
• In this way, drugs share a common structural feature.
• They also often share a similar pharmacological activity.
• E.g. all penicillin contain a β-lactam ring and kill bacteria by the same
mechanism.
• More useful in medicinal chemistry.
Penicillin core structure
• Other e.g. sulfonamides and steroids.
• Sulfonamides have a similar structure and are mostly antibacterial.
• However, some sulfonamides are used for the treatment of
diabetes.
• Similarly, all steroids have a tetracyclic structure, but the
pharmacological effect of different steroids can be quite different.
Molecular Target
• For the medicinal chemists, classifying drugs according to their
molecular target is the most useful.
• It allows a rational comparison of the structures involved.
• E.g. anticholinesterases are compounds that inhibit an enzyme called
acetylcholinesterase from breaking down acetylcholine.
• Thus, they have the same mechanism of action.
• So, it is valid to compare the various structures and identify common
features.
Naming of Drugs
• The majority of chemicals that are synthesized in medicinal
chemistry never make it to the market.
• Thus, they are usually referred to by codes that usually consists of
letters and numbers.
• The letters are specific to the research group undertaking the work
and the number is specific for the compound.
• E.g. Ro31-8959 is a compound prepared by Roche.
• If the compound then show a promise as a therapeutic drug, they are
taken into development and named.
• Ro31-8959 showed promise as an anti-HIV drug and was named
saquinavir.
• Finally, when it was marketed, it was given a proprietary, brand or
trade name that only Roche can use (Fortovase®).
• The proprietary name is specific for the preparation or formulation of
the drug.
• If the preparation or formulation is changed, a different name is
used.
Lead Compounds
• A lead compound is the starting point when designing a new drug.
• The compound should have some desirable property that is likely to be therapeutically useful.
• Source of lead compounds:
- natural
- synthesis
- designed using computer modeling or NMR studies.
• Suitable tests are required to search for lead compounds.
• Tests could be designed:
- to detect physiological or cellular effects.
- to detect the binding of the compound with a macromolecular
target such as receptor.
Natural Sources
• Natural world is rich in potential lead compounds.
• E.g. plants, trees, snakes, lizards, frogs, fungi, corals, and fish.
• Many of the active compounds produced in nature are secondary
metabolites.
• Secondary metabolites: organic compounds that are not directly
involved in the normal growth, development, or reproduction of an
organism.
• This means that they are not crucial to the early growth and
development of the organism.
• Only produced once the organism is mature.
• Many of the secondary metabolites is classified as alkaloids.
• Alkaloids contain amine functional groups and are basic.
Flora
• E.g. plant, bushes and trees.
• Have long been a source of biologically active compounds.
• Either used directly in medicine or as lead compounds for the
development of other drugs.
• E.g. morphine (poppies), anti-malarial compound quinine (bark of the
cinchona tree).
• More recent, the anticancer drug taxol, was extracted from the yew
tree.
Poppy
• These compounds are useful medicines by themselves.
• However, they are also being used as lead compounds in the
design of other pharmaceutically useful compounds.
• The world’s flora still provides a huge potential for the discovery of
new lead compounds.
• There are thousands of plant species that are yet to be discovered.
Animals
• Insulin, adrenalin.
• Several interesting drugs developed from venoms and toxins acting
as lead compounds.
• The lethality of the poisons demonstrates that they have a strong
interaction with receptors or enzymes in the body.
• Thus, poisons provide excellent lead compounds for the design of
drugs that act on those target molecules.
• Some particularly useful lead compounds include the venoms of
snakes and spiders.
• The venoms themselves are not particularly useful in medicine.
• They are highly potent polypeptide structures that are difficult to
administer due to their susceptibility to hydrolysis.
• The understanding of the poisons allows medicinal chemists to
design simpler molecules that are:
- easier to synthesize.
- more stable in the presence of digestive and metabolic
enzymes.
- administered at dose levels that will have a beneficial effect.
• E.g. antihypertensive agent captopril, was developed from teprotide,
which is found in snake venom.
TeprotideCaptopril
Microorganisms
• A popular source of antibiotics.
• E.g. penicillin, streptomycin, chloramphenicol, and the tetracyclines.
• Fungi is a good source of antibiotics.
• Other e.g. asperlicin is a lead compound at developing anti-anxiety
agents, lovastatin is the lead compound for drugs that lower
cholesterol levels.
Marine Chemistry
• Recently developed.
• Yielded some highly potent compounds from corals, sponges, fish,
jellyfish, and marine microrganisms.
• Many are used as lead compounds for novel antiviral or antitumor
drugs.
Using Natural Sources
Advantages Disadvantages
More likely to produce a lead compound than a search of randomly synthesized compounds.
A slow process (collection – extraction – separation – purification).
More likely that a completely novel structures will be found.
Active compounds are often highly complex in structure – difficult to synthesize. Reliability on the natural source for the lead compound.
The Pacific Yew
• The Pacific yew (Taxus brevifolia Nutt.) is a medicinal drug that is used to produce paclitaxel (taxol).
• In 1962, several samples were collected at random and screened.
• A potent cytotoxic effect was documented in one in vitro system.
• After a lengthy development process, clinical studies started 13 years later in 1984.
• Another 10 years is taken before paclitaxel was approved in the treatment of anthracycline-resistant metastasizing mammary carcinomas.
Foliage and fruit
Bark
• In the meantime, the compound has been approved for a variety of
other cancers and semi-synthetic derivatives were also employed.
• From collection in the wild, the compound now is produced
commercially using in vitro cultivation.
• The reasons:
- Pacific yew is a very slow-growing species.
- Produces the active ingredients only in very small amounts.
- Isolation is from the bark, thus the tree needs to be felled.
- Increased in requirement with the progress in clinical development.
• The species will extinct if the source of the active compound is only
from the wild.
QUESTIONS??
THANK YOU