Chapter 10 Manipulating Molecules and Designing Drugs

How are effective drugs designed?

Herbal remedies: Is “natural” safer than synthetic?

How harmful are illicit drugs?

Is our society becoming dependent on prescription drugs?

A wonder drug?

The classic white willow tree, Salix alba, provides more than just shade and shelter for natures animals.

Salicin is the key ingredient that is isolated from the tree and converted into one of our most reliable and heavily used drugs, aspirin!

10.1

White willow tree

It is used as an antipyretic-fever reduction.

It is used as an analgesic-pain reliever, and as an anti-inflammatory agent.

salicyn

Semi-synthesis of aspirin: from natural

product to marketed drug

10.1

White willow tree

Possible side effects: 1. Heartburn 2. Nausea 3. Reye’s Syndrom 4. Ringing in ears 5. Rash, itch 6. Shortness of breath

Salicylic acid

acetic acid anhydride acetylsalicylic acid

(aspirin)

acetic acid

Would this drug make it through FDA scrutiny today?

Organic Chemistry – The Study of Carbon Compounds

There are over 12 million known organic compounds.

Why carbon? Carbon has the remarkable ability to bond in multiple ways:

10.2

10.2

Some different ways to represent molecular structures:

Structural formula Ball-and-stick formula Space-filling model

10.2

Representing molecular structures with line-angle drawings:

C

C

C

C

C

C

H

HH

H

H

H

H H H

H H

H

H

H

C

C

C C

C

H H

H

H

H

HH

H

H

H

=

=

Each vertex (or end of a line) represents a carbon with an appropriate number of hydrogen atoms.

iso hexane, or 2-methyl pentane

cyclopentane

10.2

10.2

Representations of benzene (C6H6), an important part of many drug molecules.

10.3

Functional groups - arrangements of groups of atoms which impart characteristic physical and chemical properties.

10.3

More Important Functional groups

The presence and orientation of functional groups are responsible for the action of all drugs. See Chapter 9 for more info on functional groups.

10.3

Ester Formation

C

O

O

OH

C

O

O CH3

HH

H OH

this O attaches here

This OH and this H form H2O

C

O

O

OH

C

O

CH3

+

Ester functional groups are often found in drugs, flavorings, and fragrances.

10.3

What are the functional groups in the aspirin molecule?

1. Benzene ring

2. Carboxylic acid

3. Ester

10.3

Salt Formation

The salt forms are often preferred as drugs: • Increased water solubility • No odor • Higher melting points (longer shelf life)

CH CH NH

CH3OH CH3

CH CH NH2Cl-

CH3OH CH3

H Cl+

Pseudoephedrine freebase

Pseudoephedrine hydrochloride

Functional groups may impart a polar aspect to a molecule.

A polar molecule has partial charge separation.

d- = “partial negative” d+ = “partial positive”

Examples of polar molecules

10.3

10.4

Hormones, our chemical messengers, are produced by the body’s endocrine glands.

Hormones encompass a wide range of functions and a similarly wide range of chemical composition and structure.

Enzymes are proteins that act as biochemical catalysts, influencing the rates of chemical reactions.

Aspirin works by inhibiting the production of certain enzymes responsible for producing specific hormones.

10.4

Drugs may be broadly classified as:

1. Those that cause a physiological response in the body.

2. Those that kill foreign invading organisms.

aspirin

anticancer drugs

morphine

antibiotics

antifungal agents

10.4

Aspirin, revisited – mode of action COX enzymes Prostaglandin production COX -1: liver function, stomach lining COX-2: fever, pain sensation, inflammation

10.5

Drug Discovery-serendipity

Sir Alexander Fleming, British bacteriologist

Working with Staphylococcus-a bacteria.

A colleague working in same building was working with Penicillium notatum-a fungus that produces penicillin.

Series of chance occurrences, and penicillin was discovered.

Actual photo of petri dish Flemming showing inhibition of growth of bacteria where penicillin landed on the dish.

Drug Discovery-serendipity

S

N

CH3

CH3

COOHO

N

H

PhOCH2

O

Penicillin V

“In the fields of observation, chance favors only the prepared mind” -Louis Pasteur

10.5

How many functional groups can you identify in the structure above?

The lock and key model.

A substrate is a substance whose reactions are catalyzed by an enzyme. Here you see a drug occupying the receptor site of the natural substrate.

10.5

Drug interactions at the cellular level

10.5

The functional groups and their placement in three-dimensional space determines to a large degree a molecule’s biological activity.

The portion of a molecule that determines the biological effects of a drug is called the pharmacophore.