Functional groups and molecular

properties
Why are functional groups important in medicinal
chemistry?
functional groups are specific groups of atoms
within molecules that are responsible for the
characteristic properties and chemical
reactions of molecules.

• Functional groups affect the properties of drugs

• Physical properties – water and lipid solubility, acidity/basicity

• Pharmacokinetics – what the body does to the drug; absorption,

distribution, metabolism, excretion (ADME)

• Pharmacodynamics – what the drug does to the body;

mechanism of action, effects of the drug on biological target,
affinity, activity
Why are functional groups important in medicinal
chemistry?

FUNCTIONAL GROUPS AFFECT:

• Water/lipid solubility
• Route of administration
• Interaction with target
• Mechanism of action
• Route of metabolism and excretion
• Duration of action
• Adverse effects and toxicity
Why are functional groups important in medicinal
chemistry?

Every atom in the molecule is part of a functional group

Why are functional groups important in medicinal
chemistry?

Some functional groups may be more important than others

• Additional methyl group in bethanechol allows selective interaction with
muscarinic receptors, prevents degradation by acetylcholinesterase
• Lovastatin and Simvastatin have essentially identical pharmacological
properties
• Methyl group in lovastatin is not as important as it is in bethanecol
Why are functional groups important in medicinal
chemistry?

Functional groups may be altered to enhance activity, increase

absorption, decrease adverse effects etc.

• OH group in acyclovir causes poor oral absorption

• Modification with a valine ester improves oral absorption
Identify functional groups

AZT
Three important effects of functional groups

• Electronic Effects
• Solubility
• Steric Effects

• Hydroxyl group affects electron density on the ring. How?

• Water solubility is affected. How?
• OH group is sterically larger than H
 Electronic effects
a) Resonance effects

Electrons are shared among a group of atoms that have adjacent double bonds and
lone pair electrons
 Electronic effects
b) Inductive effects

• Electronegativity is important here.

• The larger the electronegativity the greater the ability to withdraw electrons

• F, O, Cl, N have largest electronegativity

• With the exception of F, Oxygen withdraws electrons from all other atoms
• O, N and halogens will withdraw electrons from all other atoms
• C inductively withdraws electrons from H
 Electronic effects

How does the OH group in analog A and analog B affect the electronics of the
aromatic ring?
 Electron donating groups

• Some electron donating groups can also function as nucleophilic groups

• Nucleophilic groups may be involved in hydrogen-bonding or irreversible binding to targets
 Electron withdrawing groups

• Halogens withdraw electrons by induction

• OH, OR and SH groups will have electron withdrawing effects (inductive)
unless they are next to an aromatic ring or double bond system
 Electron withdrawing groups

Electron withdrawing groups can function as electrophiles (eg nitrogen mustards)

Electronic effects can impact therapeutic benefit

• Penicillin V has better oral bioavailability that penicillin G

• Ether oxygen influences electron flow towards aromatic ring
 Electronic effects can impact therapeutic benefit

• In the acidic environment of the stomach, penicillin G is inactivated due to

opening of the lactam ring by nucleophilic attack of the amide carbonyl
oxygen.
• The ether oxygen in penicillin V withdraws electrons from the amide
carbonyl, thus reducing the propensity to nucleophilically attack and open
the lactam ring.
• Penicillin V can be used orally but penicillin G has to be administered
intramuscularly (IM) or intravenously (IV)
 Functional groups and water solubility

Why is water solubility important?

• The body is approximately 65% water

• “Like dissolves like”
• Lipid solubility is also important. Cell membranes are largely
lipophilic; drugs have to cross cell membranes

Fine balance!

• Water/lipid solubility affects

- route(s) of administration
- distribution
- metabolism
- duration of action
- routes of elimination (excretion)
 Water Soluble functional groups

• Functional groups that enhance water solubility – hydrophilic groups

• What properties affect water solubility?
- ability to ionize (acid-base properties important here)
- ability to hydrogen bond with water
• Acidic and basic functional groups are ionizable
 Acidic functional groups

• The acidic hydrogens are highlighted

• The functional group will
exist predominantly in its
protonated form at pH
below its pKa

• The functional group will

exist predominantly in its
deprotonated form at pH
above its pKa
 Basic functional groups

• Generally contain a nitrogen atom that is capable of being protonated

 Hydrogen bonding

• Essentially hydrogen is a “bridge” between two electronegative atoms

• H-bond donor is covalently attached to hydrogen
Hydrogen bonding
Hydrogen bonding
 Lipid soluble functional groups
Groups that are not ionizable (not acidic/basic) or that cannot H-bond tend
to impart some degree of lipid solubility to the molecule
 pKas of selected drugs

Most drugs are weak acids or weak bases

The effect of pH on solubility of acidic and basic drugs

Henderson-Hasselbach equation for weak monobasic acidic drugs:

• The more ionized the drug is, the more water soluble it is
• The more non-ionized the drug is, the more lipid soluble it is
Qn. Calculate the degree of ionization of aspirin in a) the stomach and b) the intestine
given that the pKa of aspirin is 3.5, the pH of the stomach is 1 and the pH of the
intestine is 6.

• Aspirin is only slightly ionized in the stomach but is significantly more ionized in the
intestine
• Aspirin will be more readily absorbed in the stomach since drugs cross membranes
more easily in their non-ionized form
• Other factors may also affect absorption
 Lipophilic
Membrane
Stomach Blood
pH 1 - 3 R-H R-H

R-CO2H R-CO2H

R-NH3

Similarly,

Henderson-Hasselbach equation for weak monoacidic basic drugs:

Weakly basic drugs (eg caffeine) tend to be more readily absorbed in the intestine
 Drug lipophilicity - Partition coefficient
• A measure of the extent to which a compound distributes itself between
two immiscible phases
• This can be roughly approximated for biological systems using organic
solvent/aqueous solvent mixtures.
• Octanol/water is commonly used

Also expressed as:

• A low P value means that the compound is less lipophilic

• A high P value means that the compound is more lipophilic (hydrophobic)
• Expressed as logP- high logP means high lipophilicity.
 To improve water solubility (chemically)
2. Add polar groups

• Groups that ionize are better for water solubility than groups that do not
ionize. Eg. COOH, phosphate (PO32-), sulphonic acid (SO3H)
• The more polar groups, the better

Qn
Which is more ionizable CH3OH or CH3OCH3?
Which is more water soluble CH3OH or CH3OCH3?
The more H-bonds possible - the more water sol.

H H
O O H H
H O
H

Alchohol O 3 H-Bonds H H
R H
Primary amine R N H O
3 H-Bonds
O H
H H
H H
O
H H
O O
H H

Aldehyde / ketone O 2 H-Bonds

R' H
R R' Secondary amine R N H O
2 H-Bonds
H

H H H H
O O O
H H
R'
Ester O 3 H-Bonds 1 H-Bonds
Secondary amine R N R''
R
R O
H H
H H O
O
 Predicting water solubility - Empirical
Water solubilization of functional groups
Functional group Monofunctional comp. Polyfunctional
Ex. monofunctional comp.
comp. methanol - pentanol/hexanol
are soluble
Alcohol 5 – 6 carbons 3 – 4 carbons

Phenol 6–7 3–4 Terbinafine

Antifungal agent
Ether 4–5 2
N
Aldehyde 4–5 2

Ketone 5–6 2

Amine 6–7 3
21 C-atom, tertiary amine solubilize 6 - 7 C atoms
Carboxylic acid 5–6 3 Insolubile (neutral form)

Ester 6 3
Corresponding acid (cationic) solubile
Amide 6 2-3

(soluble: >10 mg/mL)

Charge: 1 charge - 20-30 C
 Water solubilization of functional groups

Functional group Monofunctional comp. Polyfunctional

comp.
Ex. polyfunctional comp.
Alcohol 5 – 6 carbons 3 – 4 carbons

Phenol 6–7 3–4

Betaxolol
Betablokker
Ether 4–5 2
Ether: 2
Aldehyde 4–5 2 O N
H Ether: 2
OH
Ketone 5–6 2 Alchohol: 3-4

Amine 2
Amine 6–7 3 O
Tot: 9 - 10
Carboxylic acid 5–6 3 (notsoluble
solubile)
18 C
18 C-atomer
atoms Not
Ester 6 3

Amide 6 2-3

Charge: 1 charge - 20-30 C

 Steric effects

• Size and shape of functional groups affect binding to biological target

• Modification of steric effects in a molecule may provide therapeutic
benefits such as:
- increased selectivity for target
- enhanced binding with target
- favorable alteration of metabolism
 Steric effects
a) Selectivity

• b1 adrenergic receptor agonists cause vascular and smooth muscle

contraction
• b2 adrenergic receptor agonists cause bronchial smooth muscle relaxation
• b1 antagonists are useful for treating hypertension and cardiovascular
disorders
• b2 agonists are used to treat asthma and chronic obstructive pulmonary
disorder (COPD)
• Atenolol is a selective b1 receptor antagonist; albuterol is a selective b2
receptor agonist
• Presence of additional methyl group is important for b2 selectivity of albuterol
 Steric effects
b) Enhanced binding

• Drug has to adopt an orientation which is complimentary to the 3-D shape

of the target
• Energy is released when a drug molecule binds to a target can be used to
allow it to rotate bonds etc to fit the target (especially for “flexible”
molecules)
• However, if the energy required for such rotations is greater than the
energy released due to binding interactions, the overall binding affinity of
the drug is significantly reduced.
• Enhanced binding interactions may be improved by decreasing
conformational flexibility
 Steric effects
b) Enhanced binding

• Lower phenyl ring is important for interaction with the enzyme

(cyclooxygenase)
• The lower phenyl ring in fenoprofen is free to rotate
• Diclofenac is sterically locked into an active conformation by the two Cl
groups
• More energy is required for fenoprofen to bind; diclofenac has a higher
affinity for the enzyme
• Dose for diclofenac is 50 mg BID or TID
• Dose for fenoprofen is 400 to 600 mg TID or QID
 c) altered metabolism

• Enzymes are involved in the metabolic breakdown of drugs in the body

• Obstructing the binding interaction between the drug and the metabolizing
enzyme can prevent or slow down drug metabolism
• One approach is to sterically block the functional group being metabolized