PHAR 2133 MEDICINAL CHEMISTRY DRUGS: AN OVERVIEW Faculty of Pharmacy Cyberjaya 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 AspirinMorphine 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. Ro is a compound prepared by Roche. If the compound then show a promise as a therapeutic drug, they are taken into development and named.

Ro 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.

Teprotide Captopril

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 AdvantagesDisadvantages 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 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.

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