Objectives

 Relationship of Functional Groups to Pharmacological Activity (SARs)

Medicinal Chemistry 1
 Physiochemical Properties of drug molecules
Acid - base properties of drug molecules
Ionisation and Water Solubility

 pH and pKa (Henderson-Hassalbach Equation)
 ionisation and absorption

pka, pH and LogP 


Water and lipid Solubility (hydrogen and ion bonds)
Predicting water solubility
• Empirical approach
• Analytical Approach
 Partition coefficient
• absorption/distribution

 Stereochemistry and pharmacological activity

 Optical isomerism (enantiomers and distereomers)
 Conformation isomers
 Geometric isomers (cis and trans)

 Isosterism and Bioisosterism

1  drug design 2

Sites of Drug Action Receptors and Drug Action

1. Enzyme inhibition
Binding
 Enzyme inhibition may be reversible or non-reversible; competitive or non- regions

competitive
Drug Binding
groups
Pharmacological
2. Drug-Receptor interaction response Intermolecular
bonds
 A receptor is the specific chemical constituents of the cell with which a drug
interacts to produce its pharmacological effects
This is usually through specific drug receptor sites known to be located on the Binding site

membrane
Binding Drug

site
Drug
3. Non-specific interactions
 Drugs act exclusively by physical means outside of cells
 These sites include external surfaces of skin and gastrointestinal tract.
Macromolecular target Macromolecular target
 Drugs also act outside of cell membranes by chemical interactions
Neutralization of stomach acid by antacids is a good example
Unbound drug Bound drug
3 4
An Introduction to Medicinal Chemistry, Patrick, Third Edition
 Mechanisms of Actions of Drugs
Drug-Receptor Interactions
3. Chemical Properties

vdw
interaction
• The drugs react extracellularly according to simple
chemical reactions like neutralization, chelation, oxidation
Drug
H-bond etc.
Active site
H ionic
Phe
 Aluminium hydroxide neutralizes acid in stomach
O
bond
Ser
CO2

Asp
Toxic heavy metals can be eliminated by chelating agents
like EDTA, BAL, penicillamine etc.
receptor

• Receptors/enzymes are proteins, so they are amino acids (Asp, Phe, Ser)
• amino acids contain:
 carboxylic acids (ionic interaction)
 amines (ionic interaction)
 hydroxyl (hydrogen bond) 5 6
An Introduction to Medicinal Chemistry, Patrick, Third Edition

Functional Groups and Pharmacological Activity Physiochemical Properties – Acids & Bases
(Agonist, Antagonists)
 The human body is composed of ~75% water (55 L of water)
 If acetylcholine interacts with its receptor, then molecules that are  For an average drug (MW ~200; dose = 20 mg), this equates to a drug
structurally similar to acetylcholine would also interact with the receptor concentration of ~1.8 x 10-6M (i.e. a very dilute solution!)

acetylcholine "antagonist"  For dilute solutions we use the Brönsted–Lowry theory to predict the
behaviors of acids & bases
• Antagonists are  An Acid is any substance capable of yielding a proton (H+)
generally larger in
size than the  A base is any substance capable of accepting a proton (H+)
natural substrate
CH3COOH + H 2O CH3COO + H 3O
acetylcholine + receptor acetylcholine blocked
from receptor acid base conjugate conjugate
base acid

 This is sort of a “lock & key” approach, wherein if you stop acetylcholine
from binding to its receptor (by using another molecule that is similar in CH3NH2 + H 2O CH3NH3 + HO
structure) then you will stop the effect of acetylcholine conjugate conjugate
base acid
acid base
i.e. acetylcholine causes muscles to contract, if you stop it from binding  Please refer to Table 2.1 (pg. 29, Foye), Table 2.2 (pg. 30, Foye), and Table 2.3
to its receptor, muscles will therefore relax 7 (pg. 30, Foye) 8
 Physiochemical Properties – Acids & Bases Relative Acid Strength (pKa)
 Some drugs have both acidic and basic functional groups, and therefore can act as (Henderson–Hassalbach)
a base, an acid, or amphoteric (= both acidic & basic properties)
neutral
 Henderson-Hasselbach Equation relates pH and pKa (acid strength)
Ciprofloxacin

aryl amine O acidic [conj. base]

weakly basic F CO2H pH  pK a  log
alkyl amine
[ acid ]
N N
basic
HN
aromatic amine
weakly basic
 This equation (the Henderson–Hassalbach eqn) allows us to calculate the
percent ionisation of a given molecule at a given pH

 The location of the compound in the body will determine the overall charge  since pKa is a constant for a given molecule, at a known pH (e.g.
of the compound physiological) the concentration of the acidic and basic forms of a given drug
will be able to be calculated
O O O
F CO2H F
O But why is this important??
H
N N
H
N N  percent ionisation (clue to absorption of drug and activity/interactions)
N N
H H
9 10
stomach (pH 1.0 to 3.0) Duodenum (pH ~ 4)

Relative Acid Strength (pKa) Relative Acid Strength (pKa)

 Look at the sulphonamides (antibacterial) lipo- relative half
pKa solubility activity life
 Why is the following true? R=H
O 10.5 10.5 1 9
lipo- relative half sulfanilamide
pKa solubility activity life H 2N S N R N
H R= 6.4 26 140 17
R=H 10.5 10.5 1 9 O N
O
sulfanilamide sulfadiazine
H 2N S N R N

O
H R= 6.4 26 140 17 These compounds are only active in their ionised forms
N
sulfadiazine

 These compounds are only active in their ionised forms O H O H

 Despite only minor differences in half-life and lipo-solubility, there is a huge difference H2N O H2N S N R
in activity O
PABA sulfonamide
 This is due to their respective pKa values:
O
 For sulfadiazine, at pH 7.4 it is ~80% ionised O
 For sulfanilamide, at pH 7.4 it is only 0.03% ionised
H2N H2N S NHR

O O
 The difference in pKa is due to the electron withdrawing nature of the sulfonamide H-bond v.d.w. H-bond v.d.w.
nitrogen substituent, thereby stabilising the ionised form: ionic ionic

O H O N O N enzyme active site enzyme active site

N -H+
NH2 S N NH2 S N NH2 S N
11 12
O N O N O N
 Ionisation of Drugs Example: %ionisation for aspirin
• pKa of aspirin (acetylsalicylic acid) is 3.5
 For an acid drug: • Physiological pH = 7.4
CO2H CO2
O O
For an acid drug
100 O O
% ionisation  CH3 CH3
1  10 ( pK a  pH ) % ionisation 
100
acetylsalicylic acid
1  10 ( pK a  pH ) (Aspirin)

 For a basic drug: 100 100

% ionisation  
1  10 ( 3.5  7.4 ) 1  10 ( 3.9 )
100
% ionisation  
100

100
1  10 ( pH  pK a ) 1  0.000126 1.000126
13
 99.99% 14

Rule of Thumb (acids) Rule of Thumb (bases)

• Weak bases
• Weak acids
– pH = pKa compound ~50%ionised
– pH = pKa compound ~ 50% ionised
– pH = pKa - 1 compound ~ 90% ionised
– pH = pKa + 1 compound ~ 90% ionised
– pH = pKa - 2 compound ~ 99% ionised
– pH = pKa + 2 compound ~ 99% ionised
– pH = pKa - 3 compound ~ 99.9% ionised
– pH = pKa + 3 compound ~ 99.9% ionised
– pH = pKa - 4 compound ~ 99.99% ionised
– pH = pKa + 4 compound ~ 99.99% ionised
OH OH
NH3
NH2 H
• pH = pKa- 2
• pKa of aspirin is 3.5 CH3 CH3
• pH = pKa+ 4 phenypropanolamine
• Physiological pH = 7.4
• pKa of phenylpropanolamine is 9.4
• Physiological pH = 7.4
%ionisation= 99% ionised
15 16
%ionisation= 99.99%
 Predicting Water Solubility
Water Solubility
 Empirical Approach
 Analytical Approach

17 18

Predicting Water Solubility Predicting Water Solubility

Empirical Approach The Empirical Approach – a working example
 Lemke has developed an approach to predicting water solubility based upon the
“solubilising potential” of various functional groups, versus the number of carbons alkyl amine
(3 carbons)
Functional Monofunctional Polyfunctional N
Group molecule molecule CO2CH2CH3
aryl amine
alcohol R OH 5 to 6 carbons 3 to 4 carbons (3 carbons) ester
H2N
(3 carbons)
phenol Ar OH 6 to 7 carbons 3 to 4 carbons

ether R O R 4 to 5 carbons 2 carbons Anileridine

aldehyde 4 to 5 carbons 2 carbons
(Narcotic analgesic)
O

ketone R R' 5 to 6 carbons 2 carbons  We get a total “solubilising potential” of 9 carbons using this theory.
amine R NH2 6 to 7 carbons 3 carbons
 Since the molecule contains 22 carbons, it suggests that the molecule is insoluble
carboxylic acid 5 to 6 carbons 3 carbons in water (USP has water solubility listed as <1g per 10,000ml)
O
ester (R' = OR) 6 carbons 2 to 3 carbons  However, if we make the hydrochloride salt, then the compound becomes water
amide (R' = NHR)
R R'
6 carbons 2 carbons
soluble
Lemke estimates that a charge (either anionic or cationic) contributes a
 Given that most drugs are polyfunctional, the second column is most relevant 19 “solubilising potential” of between 20 and 30 carbons 20
C (aliphatic) + 0.5 C (aliphatic) + 0.5
Phenyl + 2.0 Phenyl + 2.0
Cl + 0.5 Cl + 0.5
S +0 S +0
O (hydroxyl, ether) – 1.0 O (hydroxyl, ether) – 1.0
N (amine) – 1.0 N (amine) – 1.0
IMHB + 0.65 IMHB + 0.65
O=C–O (carboxyl) – 0.7 O=C–O (carboxyl) – 0.7
21 22
O=C–N (amide) – 0.7 O=C–N (amide) – 0.7