Dr. Bilal Al-jaidi
Medicinal Chemistry
Is the science that deals with the
design and development of
pharmaceutical agents that has a
desired biological effect on human
body and other living systems.
Drug
 Is a compound that interact with a biological target to
produce a biological response:
 Biological system: Human, bacteria, fungi,…
 Biological response: desired or undesired.
 Sugar, salt, pesticides, herbicides, can be considered
as drugs.
 Food and fizzy drinks also considered as drugs.
 Others define drugs as molecules used as medicine or
as a components in medicines to diagnose, cure or
prevent disease.
 Medicinal chemistry also involves isolation of
compounds from natural sources or the synthesis of
new molecules the trying to investigate the
relationships between the chemical structure of these
compounds and their biological activities.
The Ideal drug is:
 Not toxic.
 Effective and potent.
 Selective.
 Easily administered.
 Cheap
In Reality, There is no Ideal drug.
 Penicillin: one of the safest and most active
antibiotics……BUT….. Resistance developed to most of
them.
 Morphine: very effective pain killer….. BUT…. May
cause tolerance, addiction and respiratory depression.
 Heroin: the best pain killer we know….BUT….
addiction developed (still used in terminal cancer).
 Drug might be harmful at higher doses:
 Therapeutic index: it is the ratio of the dose
leads to toxic effect in 50% of cases to that
leads to therapeutic effect in 50% of the
cases.
 Large therapeutic index…… safer drug.
 narrow therapeutic index…… more toxic
drug.
 Poisons can be drugs at lower doses:

Arsenicals: very toxic but used as
antiprotozoal agents.
 Tubocurarine:
used as muscle relaxant.
Selective Toxicity
 Selective Drugs are those that show toxicity against
abnormal cells without affecting normal cells.
 Degrees of selectivity:



No effect on normal host cells.
Killing certain microbial strain without affecting others.
Targeting certain metabolic pathway with affecting others
Drug Targets
 they are macromolecules (receptors, enzymes, DNA or
transport proteins).
 Drugs interact and bind to the binding sites through
intermolecular bonds (ionic, H-bonds, Van Der Waals,
dipole-dipole and hydrophobic).
 The bonds mainly are weak bonds, therefore this
binding is reversible in most of the cases.
In medicinal chemistry:
 Pharmacokinetic: How the drug distribute and reach
its target (ADME) and what will happen to the drug
 Pharmacodynamic: How the drug interact with its
target.
 Pharmacodynamics – what the drug does to
the body:
– What is the therapeutic effect of the drug?
– How does it exert its effect?
– How does the drug interact with the target?
– Can the effect be modified?
 Pharmacokinetics – what the body does to the
drug:
 How do you get it into the body?
 How long does it take to exert its action?
 How long does it stay in the body?
 Where does it go to in the body?
 Is it metabolised to another form?
 How do we analyze and detect it?
The [plasma]-time curve after drug
administration
Pharmacokinetics
Which route?
Which formulation?
Drug administered
Drug absorbed
Metabolic
inactivation
Which barriers to cross?
Gut, skin, lungs?
Stability at the site of absorption?
Pool of non-available
Drug in the tissues
Plasma-protein binding?
• Electrostatic charge
Tissue-protein binding?
Fat sequestration?
• Lipophilicity
[Volume of distribution]
available
Drug in the plasma
Passive diffusion?
Active transport?
Blood-brain barrier penetration?
Drug at the site
of action
Excretion
What do we mean by:
Oral
availability
Oral
stability
Tissue
availability
Orally
active
Oral
availability
 Oral availability or bioavailability measures the
fraction of the drug being absorbed into the blood
circulation.
 Factors affecting oral availability:
 Chemical nature of drug (lipophilicity and ionization
state).
 Water solubility.
 Oral stability.
 Physiological factors.
Oral
stability
 Oral stable drugs must be:
 Chemically stable toward the GIT conditions; acidic
stomach and basic intestine.
 Enzymatically stable: stable toward the digestive and
metabolizing enzymes such as esterase, amidase and
oxidase enzymes.
 If the drug is orally unstable it will not be available to
be absorbed…..low oral availability.
Orally
activity
 Orally active agents are drugs either active locally in
the GIT lumen (such as in the case of gastroenteritis)
or must be absorbed into the blood circulation.
 Factors affecting oral activity:
 Chemical and enzymatic stability of drugs.
 The physiological nature of the GIT lumen.
 The same factors affecting the oral availability in the
case of systemically active agents.
Tissue
Availability
 Tissue availability means the amount of the drug that
reached the site of action or the target tissue.
 In most of the cases, tissue availability is lower than
the oral availability due to one of the following factors:
 Extensive drug metabolism.
 Blood protein binding.
 Rapid drug excretion.
 Fat deposition of drug.
 The many barriers the drug have to penetrate to reach
the site of action.
The molecular properties of drugs
 It is the physicochemical properties of drugs.
 These properties fundamentally affect every thing the
drug does to the body (the pharmacodynamic aspects)
and what the body does to drugs (the pharmacokinetic
aspects).
 the molecular properties also determine which dosage
form and the route of administration is suitable for the
given drug.
Molecular properties of interests
1.
2.
3.
4.
5.
Partition coefficient.
Dissociation constant (degree of ionization).
Solubility (aqueous and fat solubility).
Chemical stability.
Biological stability (metabolic profile of drugs).
Physicochemical properties of
drugs
•
Partition coefficient
• Lipophilicity/hydrophilicity
•
Ionisation/dissociation constant
• Strong or weak acids/bases
• Salt formation
•
Solubility
• Water-soluble salts
• Lipid soluble esters
•
•
•
Stability
Chemical degradation – oxidation, hydrolysis, light
Enzyme degradation (metabolism) esterases, amidases,
cytochrome P450
Pharmacokinetic properties
 Drug administration: How is the drug to be
formulated? If as an injection, is it soluble in aqueous
solution? If as a tablet, will it dissolve when released in
the gut?
 Drug absorption: can the drug pass through the
barrier membranes in the GIT? Can it pass through the
skin barriers? These barriers are made up in a large
part by lipids, so the drug must be sufficiently fatsoluble/ unionized to diffuse through them.
 Membranes have phospholipids bilayer that act as barriers
to the movement of drugs within the body
Pharmacokinetic properties
 Drug metabolism: metabolism increases the water
solubility of drugs by enzymatically introducing polar
functional groups so that they can be excreted: what is
the chemistry of the drug? How fast is it inactivated? Is
it converted into more active or even toxic
components?
 Drug excretion: the kidney excretes water-soluble
metabolites.
Pharmacodynamic properties
 It is what the drug does to the body.
 How does the drug interact with biological receptors
or enzymes and what are the factors affecting this
binding.
Lipophilicity/hydrophilicity of drugs
Acceptor
H
O
H
CH3
H
O
Donor
O
H
Acceptor
H
O
Donor
Partition coefficient
 Is the measurement of the drug water solubility.
 Partitioning means that the drug will be divided in parts
between water and oil layer.







P = [Co ]/[Cw]
LogP = Log[Co ]/[Cw].
LogP > 2 lipophilic drug.
LogP < 2 hydrophilic drug
LogP only applied for neutral compound
Low logP….. Low penetration to CNS
High logP….. Low water solubility…. Not suitable for oral
administration
Ionisation and dissociation
•
•
ACIDS ARE PROTON DONORS
acid is a substance that can dissociate to produce H+ and a negative ion
(anion) which is called a conjugate base i.e.:
•
•
BASES ARE PROTON ACCEPTORS
Bases can accept a proton to form the positively charged cation (
conjugate acid of the base).
pH in different body compartments
Plasma
Buccal cavity
Stomach
Duodenum
Jejunum & ileum
Colon
7.35 – 7.45
6.2 – 7.2
1.0 – 3.0
4.8 – 8.2
7.5 – 8.0
7.0 – 7.5
O
O
Ka
H3C
H3C
H
OH
O
[CH 3COO ][H  ]
Ka 
[CH 3COOH ]
Ka for CH3CO2H is approximately
10-5
Ka 
1
10 5
i.e. only 1 molecule in 100,000 is DISSOCIATED (ionised).
-log10Ka = pKa
So pKa for acetic acid is 5
O
O
Ka
HO
S
OH
HO
O
S
O
H
O

[ HSO4 ][H  ]
Ka 
[ H 2 SO4 ]
Ka for H2SO4 is approximately 105
105
Ka 
1
i.e. 100,000 molecules are DISSOCIATED (ionised) for every
one undissociated.
The pKa of H2SO4 is therefore -5
[ PhCH2 NH 2 ][H  ]
Ka 

[ PhCH2 NH 3 ]
Ka for PhCH2NH3+ is approximately 10-9 (pKa = 9)
Ka 
i.e. only 1 molecule in 1,000,000,000 is DISSOCIATED (UNIONISED).
A weak conjugate acid does not willingly donate its proton
(1 molecule in 1,000,000,000 donates a proton)
Therefore a strong base willingly accepts a proton
(1,000,000,000 molecules accept a proton for every one)
1
10 9
pKa is a different term than pH
pH is simply a measure of the [H+] concentration in
a given solution
pH = 1 ...........the environment is acidic
pKa = 1 DOES NOT mean an acidic molecule
pH = 14 ............the environment is basic
pKa = 1 DOES NOT mean a basic molecule
You can’t tell from the pKa value whether the
species in question is acidic or basic
Weak a cid
Strong base
Cl
Cl
Cl
C
Cl
OH
COOH
Cl
C
pKa = 0.9
COO
H
Cl
O
H
Which one is the stronger acid?
pKa = 10.0
Considering Ka values relates ratio of products to reactants
Cl
Cl
C
Cl
OH
pKa = 0.9
Cl
COOH
Cl
C
COO
Ka = 10-0.9
H
[Cl3COO ][H  ]
Ka 
[Cl3COOH ]
1
K a  0 .9
10
Cl
O
pKa = 10.0
H
[ PhO ][H  ]
Ka 
[ PhOH]
Ka = 10-10
1
K a  10
10
Phenols are weaker acids than acetates
NH2
NH3
NH
H
NH2
pKa = 0.5
pKa = 9.0
H
Which one is the stronger base?
pKa = 0.5
Ka = 10-0.5
NH2
NH3
NH
[ Ph2 NH ][H  ]
Ka 
[ Ph2 NH 2 ]
1
K a  0 .5
10
H
NH2
pKa = 9.0
H
Ka = 10-9
[ PhCH2 NH 2 ][H  ]
Ka 
[ PhCH2 NH 3 ]
Ka 
1
10 9
Aromatic amines are weaker bases than aliphatic amines
• We can quantify how pH changes the ratio of
dissociated to undissociated species as follows:
pH  pKa  log10
1 0p Hp K a 
Dissociated 
Undissociated 
Dissociated 
Undissociated 
antilog pH  pKa  
Dissociated 
Undissociated 
What is the importance of studying the pKa values for
Acidic and basic drugs?
• only the unionised form of a drug can partition
across biological membranes (providing the
unionized form is lipophilic)
• the ionised form tends to be more water soluble
[required for drug administration and distribution in
plasma]
PARTITIONING OF ACIDS AND BASE
Consider drugs that are acids, for example RCOOH, which has a
pKa of 4.0
Biological
Membrane
Gut Contents
RCOOH
H
•
•
•
+
RCOO
RCOOH
X
Drug Absorption
No Drug
Absorption
If the pH shifts the balance towards the unionized/undissociated
form, the drug would be absorbed.
If the pH shifts the balance towards the ionized/dissociated form, the
drug would not be absorbed.
Assume the pH of the stomach is 2.0 and the pH of the small
intestine is 8.0. Where would you expect absorption to take place
from?
PARTITIONING OF ACIDS AND BASE
Biological
Membrane
Gut Contents
RCOOH
H
+
RCOO
RCOOH
X
+
RNH2
RNH3
No Drug
Absorption
Biological
Membrane
Gut Contents
H
Drug Absorption
RNH2
X
No Drug
Absorption
Drug Absorption
So we should expect that this compound will not be readily
absorbed though the lipophilic membranes although it is in the
unionized form
Remember the followings
For acids:
1. a high pka means the species is predominantly
unionised, is a bad proton donor, and a weak acid
2. a low pka means the species is predominantly
ionised, is a good proton donor, and a strong acid
3. pH < pKa by 2 units, 99% unionised .
4. pH > pKa by 2 units, 99% ionised
For bases:
1. a high pka means the species is predominantly
ionised, is a good proton acceptor, and a strong base
2. a low pka means the species is predominantly
unionised, is a bad proton acceptor, and a weak base
3. pH < pKa by 2 units, 99% ionised
4. pH > pKa by 2 units, 99% unionised
Common acidic functional groups in
pharmaceutical chemistry and their pKa
values
O
R
4-5
OH
10
OH
9.9
<2
O
R
NH
8-10
R
O
Common basic functional groups in
pharmaceutical chemistry and their pKa
values
R
NH2
10.0
NH2
4.6
R
NH
R
10.6-11.0
HN
N
6.5
R
N
R
R
9.8-10.8
N
5.2
Common neutral functional groups in
pharmaceutical chemistry
R
R
O
NH2
R
R
O
O
R
O
NH
O
R
O
R
HN
N
R
R
R
OH
N
H
R
Molecular properties and routes of administration
•
•
•
•
•
•
•
Oral
rectal
vaginal
topical
parenteral
Respiratory
The molecular properties of the drug must be determined before any
route can be considered, but other factors are important
Factors to consider when choosing
a route of administration
•
•
•
•
•
•
•
molecular properties of the drug
physiological nature of the route
patient compliance
onset of action
the condition being treated
systemic or local effect (side effects)
metabolism
Oral administration and absorption
•
If a drug is to be absorbed through the mucosal membranes that line
the gut, then it must be in its lipophilic unionised form to partition out
of the aqueous medium.
•
acidic drugs tend to be absorbed more rapidly from the stomach,
whilst basic drugs must pass through to the small intestine before
absorption.
•
The partition co-efficient of the unionised form will also determine
how much is absorbed.
•
The absorption phase of the dose-response curve is therefore
heavily influenced by the pKa and log P of a drug.
Oral administration and absorption
Orally administered drugs must have:
•
•
•
•
logP < 5.
No more than 10 hydrogen bond acceptors.
No more than 5 hydrogen bond donors.
A molecular weight less than 500 Dalton.
These points are called ‘’ Lipinski’s rule of five’’
•
Not more than 7 rotatable bonds.
Practice question
 Loratadine is an orally available drug, it has a pKa
of 5, answer the followings according to its
structure:
 Is it basic, acidic or neutral compound?
 Calculate the % ionization:


In stomach (pH = 2):
In intestine (pH = 8):
 Based on your calculation, from where do you think
loratadine will be absorbed?