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