Medicinal Chemistry 1 - Full Version

Absorption, Distribution, Metabolism and
Excretion (ADME)
An Introduction to the Principles

Underlying Pharmacokinetics
Dr. Qosay Al-Balas

qabalas@just.edu.jo
Absorption, Distribution, Metabolism and
Excretion (ADME)
- Medicinal Chemistry: is defined as the science that deals with
the relationship between the chemical structure of the drug and
its behavior in the biological systems, added to this the aspects
of drug design and synthesis.
- Absorption: process by which the drug is transported into the

systemic circulation across biological membranes.
- Distribution: process by which a drug is transported from

systemic circulation across biological membranes.
- Metabolism: chemical modification of the drug at different

sites of the body in order to excrete it outside of the body.
- Elimination: process by which the drug or modified drug is

discarded outside body.
NH2
H S
N
N
O OH
HO O
O
Biological Activity
In order for a drug to have biological activity, there are two
conditions:
1- Reach to site of action: Governed by absorption and

distribution which in turn governed by physicochemical
properties of the drug.
2- Interact with the site of action: Governed by the chemical

structure of the drug.
Physicochemical properties: measurable characters by which the

chemical substance may interact with other systems. Such as:
water solubility, lipid solubility, partitioning behavior, vapor
pressure, and pKa. These are the major factors affect the ADME
Pharmacodynamics – what the drug does to the body
Pharmacokinetics – what the body does to the drug
What are the concepts?

What is the physiology?
What is the medicinal chemistry?
How do we improve the delivery of drugs as medicines?
The [plasma]-time Curve After Drug Administration
The Processes Involved in ADME That Control the
[plasma]-time Curve After Drug Administration
Which route?
Which formulation? Drug Administered
•Injection – aqueous or depot?
is it stable?
•Tablet - water solubility? Rapid first-pass metabolism via
site of release? Hepatic portal vein?
pH stability Pro-drug activation
enzyme stability Metabolic
Drug Absorbed
•Cream - lipophilicity? inactivation
•Aerosol - lipophilicity/stability?
Which barriers to cross? Can fast metabolism

Gut, skin, lungs? be blocked? How fast?
Stability at the site of absorption?
Pool of non-available Pool of available

Drug in the tissues Drug in the plasma Excretion
No metabolism
required?
Plasma-protein binding? Passive diffusion?
•Electrostatic charge Active transport?
Tissue-protein binding? Blood-brain barrier penetration?
Fat sequestration?
•Lipophilicity
[Volume of distribution] Drug at the site
of action
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 – esterases, amidases, cytochrome P450
Why is Medicinal Chemistry Important
in Drug ADME?
•Pharmacokinetics – what the body does to the drug

–How do you get it into the body?
–How long does it stay in the body?
–Where does it go to in the body?
–Is it metabolised to another form?
•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?
Absorption: Absorption via GIT
Factors affecting the absorption:
1- pH: affect mainly the ionizability and chemical stability
2- Surface Area [SA]: intestine has villi and microvilli that

increase the SA dramatically compared to other site of absorption
3- Enzymes: might degrade the drugs before being absorbed
4- Biomembranes: Lipid bilayer composed of phospholipids,

cholesterol and other components that make it lipophilic
Mechanism of Drug Absorption
-Passive Diffusion: movement of drugs from the area of high concentration

to the low concentration.
-Passive Diffusion: depends mainly on lipophilicity (partitioning) and the

concentration gradient.
-From GIT to the Blood, so the concentration in the blood is near to zero,
so the gradient is a continuous process.
-Active Transport: used to transport endogenous compounds such as amino

acids and neurotransmitters. The main factor of transport depends on the
structure of the drug.
-Active transport: is characterized by consuming energy and being a

saturable process.
-Ion-Pair Absorption
Barriers to Drug Absorption and Routes
of Administration
Movement of Drugs Into, Around and Out of the
Body: Ability to Diffuse Across/Partition Into
membranes
Drug Drug Drug Drug
Gut Plasma
contents Plasma Cell
Membranes have lipid character and act as barriers

to the movement of drugs within the body
Lipophilicity/ Hydrophilicity
Functional groups will determine whether a drug will

prefer to dissolve in water or diffuse into a membrane
CH2OH
O OH
OH
OH
OH
Naphthalene Glucose
O
CH3
_
O Na+
Sodium acetate
Hydrophilicity/ Water solubility
CH 3
Donor
O
H H
O
Acceptor
Acceptor
H
O
H H
O
Donor
Hydrophilicity/Water solubility
- Water Solubility: drug should have some water solubility

because:
1- Should be soluble in the gastric fluids

2- Blood which is the distribution vehicle
3- Water is the reaction medium of the biological systems
- Lipid Solubility:
- Hydrophobic nature of membranes imposes some lipid

solubility of the drugs to enable crossing. [charged molecules
does not cross]
- Feature of the molecule that increase lipophilicity.
OH
H
COOH HO N
HO
Ibuprofen Adrenaline/Epinephrine
F
Measurement of the Balance Between
Hydrophilicity and Lipophilicity is by
Determination of the Partition Coefficient:
z Partitioning
P = [Co]/[Cw]
log P = log[Co/Cw]
Determined experimentally
z log P > 2: highly lipophilic

z log P < 0: hydrophilic
Common lipophilic and hydrophilic groups
Aliphatic Aromatic Aliphatic Aromatic
-F -0.38 0.37 C6H4 1.67 1.67

-Cl 0.06 0.94 -H 0.23 0.23
-Br 0.20 1.09 -NH- -2.15 -1.03
-I 0.59 1.35 -OH -1.64 -0.44
-NO2 -1.16 -0.03 -NH2 -1.54 -1.00
-O- -1.82 -0.61 -SH -0.23 0.62
-S- -0.79 0.03 -CONH- -2.71 -1.81
-CH3 0.89 0.89 -COOH -1.11 -0.03
-CH2- 0.66 0.66 -CONH2 -2.18 -1.26
-CH< 0.43 0.43 -CN -1.27 -0.34
>C< 0.20 0.20 -CO- -1.90 -1.09
C6H5 1.90 1.90 -CO2- -1.49 -0.56
To Complicate Matters, Many Drugs are Weak
Acids or Bases, Which Means They Can Ionise
- The ionized/charged forms of drugs (salts) tend to
dissolve in water and they will not cross lipid membranes.
- The unionized/uncharged forms (free acids or bases) tend

to dissolve in organic solvents and will cross lipid
membranes.
- Drugs can therefore have both water soluble and fat

soluble properties, which means they can be formulated to
get into the body.
Oral Drug Drug transport
Admin. Drug absorption in plasma
IONISED UNIONISED IONISED

What Determines the Ratio of the Ionized
to the Unionized forms for a given drug?
1- The dissociation constant, pKa (which is fixed for a given drug)
2- The pH of the solution which the drug is in (which is variable)
We cannot change the ratio of the ionized to unionized species by

changing the pKa of the drug, but we need to take into account how
affects change.
For example, the pH in the stomach is 1-2, the small intestine pH varies
from 6-8, whilst the plasma pH is 7.4.
stomach O O
urine
gut
OH
O
100
+ H
blood and most
O O
tissues ca pH7.4
%
dissociation 50
O O
Aspirin is undissociated Aspirin is dissociated

0
1 2 3 4 5 6 7 8 9 10 in the stomach in the small intestine,
pH plasma
pH Varies in Different Body Compartments
Compartment pH
Plasma 7.35 – 7.45
Buccal cavity 6.2 – 7.2
Stomach 1.0 – 3.0
Duodenum 4.8 – 8.2
Jejunum & ileum 7.5 – 8.0
Colon 7.0 – 7.5
Drugs move between these compartments, so we need

to know how they behave according to their ionizability
Ionisation & Dissociation
- ACIDS ARE PROTON DONORS
- Our definition of an acid is a substance that can dissociate to
produce H+ and a negative ion (anion) which is called a conjugate base
i.e.:
Ka
HA H + A
Kb
ACID CONJUGATE BASE
UNIONISED IONISED
UNDISSOCIATED DISSOCIATED
-The DISSOCIATION constant for the acid, HA, is given by Ka.

Conversely, the reverse of the reaction would be the ASSOCIATION
constant for the conjugate base, A-, which we could refer to as Kb.
- In other words, acids are proton donors and their conjugate

bases are proton acceptors.
- BASES ARE PROTON ACCEPTORS
- Bases can accept a proton to form the positively charged
cation, referred to as the conjugate acid of the base.
Kb
B + H BH
Ka
BASE CONJUGATE ACID
UNIONISED IONISED
DISSOCIATED UNDISSOCIATED
- The ASSOCIATION constant for the base (B) is referred to as

Kb, Similarly, the DISSOCIATION constant for the conjugate
acid of the base (BH+) is referred to as Ka.
- Consequently, we can say that a conjugate acid is a substance that can
dissociate to produce H+ and a neutral molecule:
Ka
BH B + H
Kb
CONJUGATE ACID BASE
IONISED UNIONISED
UNDISSOCIATED DISSOCIATED
- In this way, when we can quote Ka values for both acids and bases
(conjugate acids),
- Ka values tell us how DISSOCIATED an acid or conjugate acid
(base) is, which indicates how strong or weak the acid or
conjugate acid is.
You can’t tell from the pKa value whether the

species in question is acidic or basic
To apply these rules, you must be able to recognise

acidic and basic functional groups
Do not confuse pKa with pH – pH is simply a

measure of the [H+] concentration
pH = 1 is an acidic environment
pKa = 1 DOES NOT mean an acidic molecule
pH = 14 is a basic environment
pKa = 1 DOES NOT mean a basic molecule
Remember what pKa is – a dissociation constant

and a measure of where the equilibrium lies
For acids: a high pka means the species is predominantly

unionised, is a bad proton donor, and a weak acid
a low pka means the species is predominantly ionised,

is a good proton donor, and a strong acid
For bases: a high pka means the species is predominantly

ionised, is a good proton acceptor, and a strong base
a low pka means the species is predominantly

unionised, is a bad proton acceptor, and a weak base
So Why Are pKa Values for Acids and Bases
Relevant and Important to Pharmaceutical
Scientists?
- ONLY THE UNIONISED FORM OF A DRUG

CAN PARTITION ACROSS BIOLOGICAL
MEMBRANES (providing the unionized form is
lipophilic)
- [required for drug absorption into the body]
- THE IONISED FORM TENDS TO BE MORE

WATER SOLUBLE
- [required fro drug administration and
distribution in plasma]
Partitioning of Acids and Bases
non-ionised
organic
layer
aqueous
non-ionised ionised layer
• The equilibrium in the aqueous layer is

determined by the pKa of the compound in
question, and the pH of the solution, as we have
already demonstrated.
Consider drugs that are acids, for example RCOOH, which has a
pKa of 4.0
Gut Contents Biological
Membrane
RCOOH RCOOH Drug Absorption
H + RCOO X 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?
Now consider a drug that is basic, with a pKa of 7.0
Biological
Gut Contents
Membrane
H + RNH2 RNH2 Drug Absorption
RNH3 X No Drug
Absorption
• Where is the likely site of absorption?

• When we were calculating where we would expect our acidic or basic
drug to be absorbed from, we were assuming that the unionized from
of the drug would partition into the lipid membrane.
• However, this may not be the case: the unionized form of a drug may
still be hydrophilic. An unioinised hydrophilic drug would therefore
not partition very readily into the body.
H
H NH2
H NH3
H O
H O HO
HO HO H
H OH
HO H
H OH
H O
H
H O HO
H
HO
H H
H H OH
OH H
H OH
H
H OH O
O
HO
HO
• We therefore have to account for the partitioning properties of our

unionized drug when determining whether we expect absorption to
occur.
Distribution
Similar to Drug absorption except the factor of pH as there is no
difference between pH of blood and cell compartments.
- Physicochemical properties that are responsible for the

distribution.
- Passive diffusion is the main process with little drugs

transported by active transport.
Distribution
- Drug will be fully distributed to all the blood within one minute,
but the drug will not evenly distributed to the organs as this is
dependent on the blood supply.
- Drug escape the blood to tissues through capillaries [90-150 A],

only the protein bound are not leaving.
- Once reached the cell, the drug may act on the surface or
should cross the cell membrane or even cross the nuclear
membrane to reach the nucleic acids.
- Lipophilicity of some drugs make the estimated dose is difficult

to calculate as the drug partition to the fat tissues, e.g.
Barbiturates.
- BBB is a fatty barrier lining capillaries preventing polar drugs

cross toward brain except by pinocytosis such as insulin
Pharmacodynamics:
what the drug does to the body
N
How The Body Works
Main systems of the body are:
Both use
- CNS: - Sympathetic neurotransmitters,
- Parasympathetic adrenaline, acetylcholine
- Signals move through [polarization-depolarization]
mechanism
- Liver: - Detoxification process

- Storage device
- Hormones: - From where they produced

- How they work
To understand all of this you have to understand the molecular

level of body organization
Wikipedia: cell
Drug Targets
- Macromolecules:
1- Lipids
2- Carbohydrates
3- proteins
4- nucleic acids
- For a drug to have an action, it should interact [bind] with one of

these molecules at different ways.
- The place of interaction is called the binding site; which is a

curvature or canyon at the surface of the enzyme. ***
- Two types of interaction are of importance:

1- Irreversible - covalent bonding (HOW)
2- Reversible – by different types of interactions
How Binding Takes Place
- Binding occur through points of attachment, e.g. mountain
climbing.
- For a chemical compound, the attachment points

are the functional groups.
- Functional groups use their electronic & shape characters

to perform their binding.
- Bonds could be inter-molecular or intra-molecular.
- If we talk about reversible binding, binding of drug to receptor

should be in equilibrium state.
drug has enough power to bind for certain period in order to

deliver a task, then leaves to give chance for another drug
molecule to do the same or different task
Points of Attachment
Protein
Ligand
How Binding Takes place
- The receptor and drug are fully solvated in water molecules, as

the cell is full of water, so the drug should displace water
before making any interactions with the receptor.
- Displacement of water obey the second law of energy:
ΔG= ΔH-T ΔS
How Binding Takes place
- For the interaction to take place ΔG value should be negative, and
this is affected by enthalpy and entropy values; ΔH should be more
negative [related to interaction energy], while ΔS should be positive
to make ΔG value more negative [water molecules]
- Much polar functional groups on the compound, more solvation of

the drug, more energy needed to desolvate to allow interaction.
Another Consideration
- Why there is a lot of rings in most of the drugs?

entropy issue
Ordered water particles on
hydrophobic surface
Bonding Forces
- Electrostatic or ionic forces:
- Happen between fully opposite charges
- If more than one force are there, ionic is considered the main
determinant
The main determinant factors for the strength are:

- As the distance increase, the strength decrease [other forces
are affected to higher extent with distance]
- It obeys coulomb law
- Nature of the environment, better in hydrophobic media

(WHY)
Bonding Forces
- In biological systems, it happen between residues have
carboxylate group; acidic (aspartic acid & glutamic acid) and
basic groups such as Histidine, Lysine and Arginine.
- In biological systems, the pH is 7.4, while the pKa of Lysine =

10.5, so the prominent form of this group is …………., pKa of
aspartic acid is 3.86, so the prominent form is …………..
Bonding Forces
- Hydrogen Bonds
-Should have H-Bond acceptor and H-Bond donor.
-The acceptor posses a partial………….charge.
-Mainly depend on electronegativity.
-An important factor is related to orbital interaction (sigma bond

characters), so angle is important.
-Distance between 1.5-2.2 A
-NH2, OH, form one or two H-bonds depending on the number of

electron pairs
http://www.youtube.com/watch?v=58Vn1dldevE
Bonding Forces
- Fluorine, very electronegative that hinders the electrons to be
available for H-bond acceptor compared to O,N.
- Increase electron density, better H-Bond acceptor, so anions

better than neutral compounds e.g. aromatic and alkyl amines
- H-Bond acceptors are better if the H is more electron deficient

by attachment to more electron deficient atom such as
quaternary ammonium compounds.
Bonding Forces
- Dipole- Dipole and Ion-Dipole interaction
- Formed between permanent dipoles on both drug and binding
site.
- Permanent dipoles occur in functional groups such as……………..
- Ion-dipole occur where one of the poles is an ion and the other
is permanent dipole.
Bonding Forces
- Van der Waals interactions
- Involve interaction of the hydrophobic areas in molecules.
- Formed through temporary dipole formation, so this one induce

others to be formed temporarily
Bonding Forces/ Irreversible
- Happen through formation of covalent bond.
- For covalent bond formation, there should be two poles; the
electrophile and the nucleophile.
- Nucleophiles in biology have the following functional groups:

- Thiol in the amino acid ………………
- Hydroxyl in the amino acid…………..……..
- Amine in the amino acid……………..
- Carboxylate in the amino acid……….……..
- Electrophiles
- Epoxide ring
- Alkyl group attached to halogen
- Positively charged centre
- Aziridinum ion
Bonding Forces/ Covalent
Drug Targets/Lipids
- Small number of drugs act on lipid targets, mainly by disruption
of the lipid structure of cell membranes.
- Anesthetics, antifungal Amphotericin B

Drug Targets/Carbohydrates
- Polyhydroxyl structures (polar), such as glucose, mannose,

starch, etc…
- Important role in cell recognition, regulation and growth.
- Some are found bound to proteins, and so called glycoproteins or

proteoglycan.
- For example: bacteria and viruses have to recognize host cells

before attacking them, which occur via carbohydrates.
- Designing a drug that binds to these sugars could block the

invader to attack the cells.
Drug Targets/Proteins
- Primary structure of proteins is formed through linking amino
acid through peptide bond.
- Peptide bond is planar and non-rotatable due to resonance

effect of the amide bond.
-Secondary structure determine the ordered structures such as α-
helix or β-turn due to the interaction of amino acid chain residues.
-Tertiary structure is the three dimensional structure of the protein

and it is important in determining the function and interaction with
drugs.
-Conformation of the protein is determined by the intramolecular

forces between the parts of the protein.***
-Covalent bonds happen between two Cysteine residues (thiol side

chains) and called disulphide linkage [oxidation].
Bonding in Proteins
- For the tertiary and quaternary structures, the most important
bonding interactions is Van der Wall ones, not in magnitude for
each bond but in number.
- Polar residues oriented to the surface

- The inside of the active site usually hydrophobic in
nature.
- Vaspressin and Oxytocin contain disulphide linkage that is

considered the most important bonding force. [Why?]
Proteins could be
1- Enzymes 2- Receptors
3- Carrier 4- Structural
- Carrier Proteins: used to transfer amino acids and

neurotransmitters and other biological vital molecules.
- Recognition sites on the surface are necessary to select the
needed molecule to be transferred.
- Drugs that target these proteins such as cocaine, tricyclic
antidepressant.
- Structural proteins:
such as tubulin which has a role in cell proliferation, inhibited by

Colchicine and cause depolymerization of microtubules.
Drug Targets/Enzymes
- Created for the purpose of performing reactions that are
impossible to be done in vivo.
- Normally reaction happen in equilibrium; reversible in nature.
- Its role to reduce the activation energy of chemical reactions

[How?].
How enzymes work
- Provide surface for substrates to perform reactions
- Fixing in position
- Bring reactants near to each other

- Increase the chance of meeting
- Facilitate the formation of transition state
- Weakening the bonds of reactants

- Force to change the conformation
- Proper orientation
- Participate in reaction
- The hydrophobic character of the active site help the
reaction to take place.[ avoid water]
- Certain amino acids could behave as catalytic or binding role
How enzymes work
- Binding of substrate to the active site happens with the same
bonding forces described before.
- Structure of the active site and the substrate determine the

type of bonding experienced
- From the natural substrate or active drug structure you can

have an idea about some details in the active site, as the relation
is complementary one.
Binding in Enzymes
- Old theory: Fischer’s Key and Lock:
- The enzyme and the substrates or [inhibitors] are rigid
structures.
- There is one optimum substrate and the others are less

effectively activated [Drawback, incorrect]
- Koshland’s theory of induced fit:

- The substrate and more obvious the enzyme change their
shapes in order to optimize the binding to some limit.
This theory succeeded to explain why there is a range of
substrates and inhibitors that the enzyme could
accommodate.
- Moulding process is performed to maximize the interaction
between the two which could cause weakening of substrate bonds
and may break them
Lock and Key representation
Induced fit diagram

Acid-Base Chemistry in Enzymes
-- Histidine amino acid contains imidazole ring.
- Imidazole possesses pyrrole and pyridine like nitrogens.
- Pka= 6.0-7.0.
- Dipole momentum is 3.7D in gas, but in solution differ by

concentration due to presence of H-bonding.
- Annular Tautomeric equilibrium

1.502
136.9 134.9
0.884
1.056
135.8 132.6
1.056 1.502
137.8
Acid-Base Chemistry in Enzymes
- At physiological pH histidine is …………(% ionized)
- Proton Bank, can take and donate protons as needed.
- Activate water as nucleophile
His His
NH NH
N N
His
N
H N H
His
N O H O
H H
N
H Mal-ACP O O
ACP Acp
S R O
Acp
S
O
S
O
Cys Cys
H H Phe
N N H N
Phe N H
Nucleophiles in Enzymes
- Serine, Threonine and Cysteine possess a hydroxyl [OH] and
thiol [SH] groups respectively and behave as nucleophiles
- Considered stronger than water as nucleophiles, why?
- Presence of neighboring groups help to activate them as

nucleophiles by accumulating the charge on them.
- Helix frying effect increase the reactivity of thiols and

hydroxyl groups by donating more electrons.
- Water could act as a nucleophile at later stage as liberating the

product from the enzyme if the reaction is reversible.
- Aspartic acid or glutamic acid could be nucleophiles?

Nucleophiles in Enzymes
Helix frying: accumulation of

Partial negative charge on one side
of the helix and positive charge
at the other side
Cofactors
- Are non-peptide substances that are required to speed up
reactions, could be metals [metal ion activator] such as Zn, Fe,
Cu by forming coordinate bond or small organic groups such as
NADH, NADPH [coenzymes].
- Their attachment to the enzyme could be covalent [called

prosthetic group] or attached by ionic and hydrogen bonding.
- Usually are water soluble (look to structure).
- NADH: used in ATP energy production reaction

- NADPH: mainly for redox reactions
Cofactors/ metals
- May be used by the enzyme to maintain its stability.
- Less weakly metal binding enzymes is used for catalysis.
- One role for metals is to act as electrophilic catalysts, stabilizing

the increased electron density or negative charge that can
develop during reactions such as liver alcohol dehydrogenase
[Zn].
- Another potential function of metal ions is to provide a powerful

nucleophile at neutral pH. Coordination to a metal ion can
increase the acidity of a nucleophile with an ionizable proton.
Regulation of Enzymes
- Enzymes should have a regulatory body to initiate, slow, stop
their performance.
- Allosteric binding: product accumulation results in binding the

product to different position of the enzyme that cause
conformational changes that prevent the active site to perform
its normal job.**
- Why is the binding not in the same place?

1- Different molecule.
2- competition at he same place between substrate and
product - as if it is inhibitor.
- Regulation could be done externally such as nitrous oxide and

then transferred to the cell via messengers
- Phosphorylation by protein kinases could activate or inactivate

enzymes depending on the nature of enzyme.
Isozymes
- More than one domain in enzymes could interact in different way
[quaternary structure], then their properties are different such
as kinetic properties [Km].
- The change is due to subunit configuration, and the primary

structure could be the same or different.
- Lactate dehydrogenase has isozyme in the heart and muscles that

is twice active in the later organ.
Enzyme Inhibitors
- Competitive Reversible Inhibitors:
- Binding of the [inhibitor] to the enzyme should be stronger than

the substrate to compete to the active site, so knowledge of the
amino acids in the active site could help to design stronger
binder to the active site.
- Increasing substrate concentration will reduce the effect of the

inhibitor.
- Sulphonamides antibacterials that bind reversibly to

dihydropteroate synthase, that is the folic acid line production
line.
- Competitively bind to the active site where para-amino benzoic

acid binds.
- Expected to have structural similarity to the substrate.

Enzyme Inhibitors
- Non-competitive irreversible inhibitors:
- Inhibitor that bind to the active site residues permanently and

the strongest when the binding is covalent.
- Penicillins bind to the bacterial enzymes irreversibly,

bactericidals.
- Aspirin binds to serine residue of COX enzyme.
- Non-competitive reversible inhibitors [Allosteric]: -
- Bind to different site, so there is no necessary resemblance to

the substrate and the high levels of the substrate not affect
the inhibitory effect.
- [6-mercaptopurine], anticancer
Enzyme Inhibitors
Transition state analogues inhibitors: -
- Design a drug that is similar to the transition state, so it is bound

irreversibly to the active site even without covalent bonding
because the transition state found to be the most fixed
structure compared to substrate or product.
- Renin inhibitors and viral protease inhibitors.

Enzyme Inhibitors/ Suicide substrate
- Special case of irreversible inhibitors as the normal substrate will
be converted in the active site to highly reactive species that
alkylate the enzyme and finish it permanently.
- Presence of an activating group in the structure cause this

phenomena.
- Has an advantage that they are selective and will not act as
suicide inhibitors until reach the active site.
- Clavulanic acid act as a suicide substrate for bacteria.
- 5-fluorouracil, act as anticancer agent converted to reactive 5-

flourodeoxyuracil monophosphate.
- Presence of more isozymes give the advantage to selectively

inhibit one form rather than the other. e.g: COX1 and COX2.
Enzyme Kinetics
- Mechaelis- Menton Equation
Rate =
Km is the concentration of substrate at which half of the active sites of the

enzymes are filled.
Km is the measure of how strong the substrate bind to the enzyme inversely.
Km is dependent pH, temperature and ionic strength.
Enzyme Kinetics
- Lineweaver Burk plots:
reciprocals
Receptors
- Mostly membrane bound proteins, that selectively bind to small
molecules called ligands.
- Generally are integral proteins.
- Composed of two parts, the recognition and

the amplification sites.
- Ligand receptor interaction happen using the

same bonding types that are used for
drug-enzyme interaction.
- Their presence is a method of communication between the different

parts of the body (synapses, vasodilatation).
Receptors/ Communication Agents
- Receptors receive endogenous chemical compounds such as
neurotransmitters (seratonin, acetylcholine) and hormones,
aminoacids, lipids (prostaglandins) and others.
- The surface of receptors contain as in enzymes hollows, ravines that

are considered the Binding Site.
- Drug that act on these receptors could be either blocking the action
of the receptor (Antagonist) or act as if they are the normal exciting
agents (Agonist).
- As in enzymes, ligand binding induces conformational changes at

receptor that in turn the message will be conveyed in different ways
(ion flux, transfer a message to inside cell).
Agonist Design
- Required when there is a shortage of the endogenous chemical
compound and we require to compensate for this shortage.
- To design an agonist you have to know:

- The geometry and topography of the active site and /or.
- The chemical structure preferably (3D structure) of the
normal substrate that act upon.
- Thorough dissection for the Ligand or the Binding site will enable us
to have an idea about:
- The important binding groups.
- The correct position of the binding groups that are related to
their arrangement and distances.
- The right size of the binding groups and sites (ISOSTERS)
- Before enrolling in agonist design, you have to know the role of each
functional group in terms of binding (Chemistry wise)
Functional Groups Binding Role
- Alcohols and phenols:
- Act as H-bond donor and acceptor with directional preference
that is related to the tetrahedral geometry of the oxygen atom.
- Their importance can be tested by methylation or esterification

of the hydroxyl group which obviously remove their H-donor
properties and retard the H- accepting characters (How?).
- Esterification will not necessarily give better H-accepting

properties due to presence of two oxygen atoms instead of one.
The reason is that the position of the new oxygen is not
necessarily the same as the other oxygen, and the resonance
effect will reduce the electron density over the other interacting
oxygen.
- Aromatic Ring and alkene:
- Planar, hydrophobic and participate in van der Wall interactions with

hydrophobic areas within the active site.
- Benzene importance is compared by cyclohexane analogue which is

v expected to be less effective binder due to:
- Loss of planarity.
- The axial Hs will shield the cyclohexane ring to be in proximity to
the hydrophobic region.
- Unable to bind in slots as what occur in benzene ring (Bulkier).
- Incapable to form induced dipole interactions with ammonium ion.
Vs
- Ketones and Aldehydes:
- Planar hydrogen bond acceptor in which the oxygen is sp2

hybridized, so the lone pair of electrons are found in the same
plane.
- Participate in dipole-dipole or dipole-ion interactions.
- Tested by its reduction to the corresponding alcohol

(tetrahedral geometry).
- Reduction will result in weakening of the binding properties, and

if the oxygen is expected to have the same role as keton
(acceptor) then ether analogue could be studied.
- Amines:
- Could be H-donor and H-acceptor.
- Aromatic and hetero-aromatic amines act as H-donor due the

busyness of the lone pair of electrons in the aromatic system.
- If ionized, it will be stronger H-donor with loss of H-accepting

power.
- Converting it to amides will rule out the possibility of H-

accepting and ionic bonding character. (resonance will remove the
lone pair of electrons from N).
- Secondary amide still have H, but due to steric factors it will

hinder to be as H-donor.
- Amides:
- Bind active site through hydrogen bonding (carbonyl as acceptor

and NH as only donor if the amide is primary or secondary).
- Could be tested by N-methylated amide, primary/secondary
amine, tertiary amine, ketone, alkene, carboxylic acids.
- all except 1, 2 amine could test if H- bond donor.
- alkenes and amines check if H- bond acceptor.
- All the above groups except alkene are not safe for testing amides
as all could rotate in contrast to amides.
- Alkenes are good tester as both H-donor and acceptor, but

difficult to synthesize.
- Lactams could form intermolecular H-bonding.

- Quaternary Ammonium Salts:
- Ionized group that could form ionic bonding with carboxylates or

induced dipole interaction (Face of the ring is negative and positive
at the edges).
- Tested by synthesizing a tertiary amine instead (but could be

protonated, so amides are better testers).
- Acetylcholine contains quaternary ammonium group.
- Carboxylic acids:
- Act as H-donor and acceptor, but could be as carboxylate moiety
which in turn will be ionic bond pole or strong H-acceptor.
- Tested by synthesizing analogues such as ethers, alcohols and

ketons.
Esters:
- 4 sites as good H-acceptor, and could be tested by converting to
ethers.
- Faced by the problem of esterases in the body.
- Esters could be protected from hydrolysis by electronic or steric
factors.
- Could be used deliberately to make pro-drugs.
- Alkyl and Aryl Halides:

- Chemically reactive species and considered good leaving groups, so
react with any nucleophile covalently.
- Alkyl fluorides are not reactive as C-F is strong bond, and used to
replace H because has the same size [used to protect from
metabolism].
- Aryl halides are not alkylating agents but affect the binding of
the aromatic ring as they considered electron withdrawing
groups.
- Tested by their counterparts that lack the halide moiety.
- Thiols:
- The SH group is considered a good ligand for zinc ion, and is
incorporated in drugs that target enzymes contain zinc as a
cofactor.
- Tested by their counterpart alcohol which is less reactivity to
metals.
- Heterocycles:
- Very important as they form variety of bonding with the
active site [mainly H-bonding]
Agonist Design
- The designed agonist should contain all the necessary binding
groups that the natural substrate posses in order to have the
optimum response [Take in consideration the pharmacodynamic
properties].
- In a series of agonists, there should be a great similarity in

structure between these molecules.
- Chirality is an important factor that should be taken in

consideration as enantiomers or diasteromers do not bind in the
same way as receptors are enantiospecific.
Agonist Design
- One of the enantiomers will bind and the other will have no role in the
therapeutic activity or cause side effects.
Antagonist Design
- Antagonist for the binding site:
- They act by having some or all the binding groups but fail to induce
an effect which could be achieved by:
- inability to change the receptor conformation or,

- distort the receptor in wrong way.
- Competitive antagonists are not necessarily have great similarity

to the substrate or to each other.
- These differences in structure are justified by the fact that

antagonist is required to bind to sites near the active site that
prevent physically the substrate to reach target.
- In general, Antagonists are bulkier than agonists. And it is easier

to make compound that block receptor site than molecule have
specific interactions to induce conformational changes.
Antagonist Design
- Addition of competitive antagonist shifts the curve to the right.
- Allosteric antagonist: bind in different site

and could alter the shape of the active site
(called non-competitive antagonist).
- It is independent of the amount added of the substrate [Kd not

changing]
- Umbrella effect: design of an competitive inhibitor that exploit the

neighboring areas of binding sites which consequently will retard the
binding of normal substrates.
- The same bonding interactions could be used to for this design

[ionic, van der Wall, H-bonding].
Competitive Versus Noncompetitive
Antagonist
Partial Agonist
- A compound that cant be defined surly as agonist or antagonist. It
act as agonist but not reach to the same level of substrate
response.
- It should bind to the same binding site with low ability to induce
change.
- It could bind partially to the binding site, but the other part will
bind as antagonist.
- Could be used to distinguish between different types of sub-

receptor.
Buprenorphine ,
used for opioid addiction
Morphine
Inverse Agonist
- It is common to antagonist in that bind to the receptor binding site
and prevent the normal substrate to act; however, it differs from
the antagonist in that it exert an action that is opposite to the
substrate.
- It may act by preventing inherent activity to some receptors such

as GABA and dihydropteridine.
- Not necessarily bind to the same site of substrate and no need to

have structural similarity to substrate.
- Examples:
- Valium (diazepam): is an anticonvulsant while β-carboline is an
inverse agonist and induce convulsion.
Desensitization & sensitization
- When a drug bind to receptor strongly it will act as agonist, then for
this long time of binding the effect will be inversed and become
antagonist.
- Phosphorylation of the active site residues such as hydroxyl or phenol

will change the conformation and inactivate it.
- When ligand leave, dephosphorylation will occur.
- If no leave of the ligand, the receptor will be enocytosed and

metabolized.
- Desensitization will occur by reducing the receptors as the there is

continuous activation by the tight binding.
- Sensitization, occur when there is continuous use of antagonist, so

cell produce more receptors.
1991 - Burger A.
• Compounds or groups that possess
near-equal molecular shapes and
volumes, approximately the same
distribution of electrons, and which
exhibit similar physical properties... .
Bioisosterism
- Isosteres: Atoms or group of atoms which have the same valency
(number of outer shell electrons) and have chemical or physical
similarities.
- Bioisoster: it include both classical and non-classical isosters, and it

is a group that can be used to replace another group while retaining
the desired biological activity.
- Used to replace a functional group that is important for binding but

problematic in a way or another.
- Used in drug design to vary the character of the molecule in rational

way with respect to features such as size, polarity, electronic
distribution and bonding.
- Uses:
- Determine the importance of some binding groups
- Investigate the type of binding some groups posses.
Bioisosterism
- Example: propranolol is a β-blocker that has an ether linkage; its
replacement by CH=CH, SCH2, CH2CH2, will eliminate activity. But
replacement with NHCH2 retain activity.
O N
H
OH
O
- F is replaced by H because they have similar H(F)
HN
size properties but different electronic behavior.
[no effect of size] O N
H
- 5-flourouracil is consumed by the substrate as it has the same size

as Uracil, but the C-F bond is strong and not broken as if it is H.
Bioisosterism
Sultopride:
Dopamine antagonist was improved by replacing the amide by

pyrrole ring has led to increase activity and selectivity of D3
over D2.
N N
O NH
NH
OMe
OMe
EtO2S
EtO2S
Bioisosterism
- Transition state isosteres: are moieties that are used to mimic the
crucial features of the transition state but which are stable.
- Tetrazole is a bioisoster of carboxylic acid, its replacement in the

first compound has led to the discovery of losartan (angiotensin II
inhibitor).
- Planar, ionized, pKa= 4.7
- More lipophilic resist metabolism
Bioisosterism
- Univalent isostere:
- CH3, NH2, OH, F, Cl, SH
- Br, i-Pr
- I, t-Bu
- Bivalent isostere:
- Trivalent isostere:
- Ring equivalents:
-
N
H
S O N
-
Nonclassical isosteres
- Carbonyl group:
NC CN O
O O O O O CN NOH NOCH3
S S N
S
O N
- Carboxylic acid group:
O O R O O CN O O O O O O
S N S OH S N S S S S
OH N N Ar N Ar N Ar
O H O O H H H O H O O H O
O OH OH
H
O S HO O N X N OH N N
N N N N O N N N
N N N N
O H O
OH OH OH
OH OH
N N
N N F F
OH
- Amide:
- Ester:
- Hydroxyl group:
- Catechol:
O
HO N O O S
HN
N X N
HO H HO HO
HO
X= O, NR
- Halogens:
- Benzene:
- Spacer:
Affinity, efficacy, and Potency
- Affinity: how strongly the drug bind to the receptor; depends on the
molecular complementary of drug and receptor.
- Measured by radio-ligand labeling.
- Efficacy: the maximum biological effect the drug can produce.
- Potency: the amount of drug needed to achieve defined biological

effect.
- (Scatchard plot, Schild analysis ) refer to book.
- An agonist is something which binds with both affinity and efficacy.
- An antagonist is something which binds with affinity but no efficacy.

Nucleic Acids as Drug Targets
DNA Bases
- Purines: Heterocyclic aromatic compounds that are composed of
pyrimidine attached to imidazole.
Guanine
Adenine
- Pyrimidines: there are three bases for the DNA and RNA?
DNA Bases
- (Cytosine, Thymine, and Uracil)
- Back to slide 1, you should be able to know the strength of the H-

donors and acceptors and the reason behind this strength or
weakness.
Drugs Act on DNA
- Drugs classified as Intercalating, alkylating and Chain cutters.
- Intercalating:
- They must contain flat part of the molecule [Aromatic and
Heteroaromatic].
- Act by sliding between the DNA strands disturbing the helix structure
and retard transcription and replication.
- Examples: Proflavine, Dactinomycin, and Doxorubicin.
- Intercalator could be minor groove binder or major groove binder.
- Proflavine is an aminoacridine derivative that possess yellow color, and

used as antibacterial agent.
- Used topically as it is toxic to the host cells systemically.

Drugs Act on DNA
- Actinomycin D (Dactinomycin): naturally occurring antibiotic, posses
flat phenoxazone ring that bind to the minor groove.
- Prefer the binding to G-C pairs and between two adjacent G-G units.
- Form stable complex that prevent DNA-RNA dependent

polymerase to unwind the DNA which eventually cause cell apoptosis
and death.
Pentapeptide portion
Drugs Act on DNA
- Doxorubicin:
- Naturally occurring antibiotics group called Anthracyclines.
- They are major groove binders and slide using the three flat cycles.
- The positively ionized amine group interacts with the negatively

phosphate groups.
- They inhibit Topoisomerase II. Very important enzyme for replication

of DNA.
- Hydroxyquinone moiety chelates iron, then produce reactive oxygen

species which breakage of the DNA strands.
Drugs Act on DNA
- Alkylating agents:
- Highly electrophilic compounds that react with nucleophiles in the
DNA such as ………. to form covalent bonds.
- Examples are : Nitrogen mustard (Chlormethine), Nitrosoureas

(Lomustine), and Cisplatin.
Drugs Act on DNA
- Chain Cutters:
- Cut the strands of the DNA, and prevent the DNA ligase from
repairing the damage.
- They act by forming oxygen radicals and peroxy species.
- Example: Calicheamicin γ1, isolated from bacteria, binds to the

minor groove and cuts the DNA by forming highly reactive
species radical species.
Trisulfide
Enediyne moiety
Drugs Act on DNA
- Flouroquinolones:
- Form complex with DNA and with the enzyme topoisomerase
IV; and enzyme used to reduce tension through unwinding
DNA for replication.
- Nalidixic acid the first agent of this group, enoxacin,

ciprofloxacin.
- They act by forming ternary complex [Quinolones, DNA,

topoisomerase], so the cut DNA will not be sealed.
Binding to Enzyme
Ciprofloxacin
Pharmacokinetics-Metabolism
Metabolism
- Biochemical modification or degradation, usually through specialized

enzymatic systems, often converts lipophilic chemical compounds
into more readily excreted polar products.
- Non-specific enzymes such as Cytochrome P450 enzymes, add polar

functional groups to wide variety of drugs.
- Other group of enzymes unmask already polar groups such as

methoxy group that when demethylated will give hydroxyl group.
- Reactions are classified as Phase-I or Phase-2; Phase-I are

Oxidation, reduction and hydrolysis. (functionalisations)
Metabolism
- The main site of these reactions is the liver but could be found in
gut wall, blood plasma and other tissues.
- Oxidation mainly targeted groups such as N-methyl derivatives,

aromatic rings, terminal position of alkyl groups and the least
hindered position of alicyclic rings (is an organic compound that is
both aliphatic and cyclic. They contain one or more all-carbon
rings which may be either saturated or unsaturated, but do not
have aromatic character).
- Reduction occur to groups such as Nitro, Azo, and Carbonyl
- Amides and esters are prone to hydrolysis.

Metabolism
- Drugs in general could be exposed to more than one reaction of
metabolism.
- Knowledge of the metabolic pathways enable the medicinal chemist

to know the products expected to be formed.
- Phase-II reactions occur mainly in the liver, and most of them are
conjugation reactions – polar conjugates are attached to polar
groups found in the drug. (conjugation reactions)
- Both Phase-I, Phase-II are species specific, so what is found in vivo

studies as metabolites in rats not necessarily the same as humans.
- Also both of these reactions are regio-specific and stereo-selective.

Metabolism
- Cytochrome P450 system: The most important enzymes in

metabolism and are positioned in liver cells.
- These are haemoproteins (contain heme and iron), act by catalyzing
reactions that split molecular oxygen, one for the drug and the
other as water molecule. [belong to enzymes called
monooxygenases].
- There are 33 enzymes of P450, classified to four groups CYP1 -

CYP4.
- Sub-groups classified by letter then by number such as CYP3A4.
- Most drugs in current use are metabolized by five primary CYP

enzymes (CYP3A, CYP2D6, CYP2C, CYP1A2, and CYP2E1).
- The isozyme CYP3A4 is particularly important in drug metabolism
and is responsible of most drugs.
Metabolism-Oxidation
- Oxidation occurs to carbons that are exposed or activated; methyl
groups of a carbon skeleton easily accessible to enzyme as they are
exposed and form alcohol upon oxidation.
- Long chains aliphatic compounds will have the last and the
penultimate carbons will be highly exposed.
- Aliphatic rings also will be oxidized to positions that are exposed.
- Carbon atoms next to sp2 or sp centers are activated and prone to

oxidation. ***
- Carbon atoms that are α-position to a heteroatom which form

unstable metabolite that immediately hydrolyzed and cause
dealkylation of amines, ethers and thioethers or dehalogenation of
alkyl halides. [Aldehyde]
- Oxidation of unsaturated systems such as double bonds, triple
bonds and aromatic systems. Alkenes for an epoxide then
deactivated by epoxide hydrase to form diol.
- If the epoxide escaped the enzyme it will react with

nucleophiles in the body and cause toxicity.
- Aromatic rings in the same way they form epoxide intermediate

that could be :
- Rearrangement by which a hydride will be transferred to

form a phenol, normally at para position.
- Deactivated by epoxide hydrolase to form diol.
- React with glutathione S-transferase [conjugation].
- If the aromatic epoxide evaded the enzyme, it has proven to be

alkylating agent and toxic. [electron rich aromatic rings are faster in
metabolism than electron deficient].
- Tertiary amines are oxidized to N-oxide, if there is no steric

hindrance, then immediately converted to hydroxyl amines.
- Aromatic primary amines oxidized to nitro, which are toxic.***due to

the formation of highly electrophilic intermediate that alkylate DNA
and proteins.
- Primary and secondary amides are oxidized to hydroxyl amines that

found related to toxicity and carcinogenicity.
- Thiols oxidized to disulfides or methylated to methyl sulfides then

oxidized to sulfoxides and sulphones.
- “Oxidation of aromatic moieties (arenes) to their -
corresponding phenolic metabolites (arenols)”.
- Most of the hydroxylation processes occur at para position.
- Substituents nature affect the ease of hydroxylation process, in

general, electron rich rings are hydroxylated faster, while
deactivated rings attached to (COOH, Cl, N+R3, SO2NHR)
usually resistant or slowly hydroxylated.
- If there is two aromatic rings, it is expected to hydroxylate the

electron rich ring.
Aromatic oxidation
Examples: -
- Resistant compounds to hydroxylation processes.

Aromatic oxidation
- More activated rings hydroxylated first.
- Polychlorinated dibenzo-1,4-dioxins are extremely

toxic such as (Sevesodioxin, TDCC- 2,3,7,8-
tetrachlorodibenzodioxin).
- TDCC: is a teratogenic with LD50 in rats
45 μg/kg.
- Formed as a byproduct of commercial 2,4,5-trichlorophenol.
Olifens oxidation
- Forms epoxide that is more stable than the aromatic epoxide.
- Hydrolysis of the epoxide by hydration lead to trans 1,2 diols.
- The following compounds form toxic epoxides.
Aflatoxin
Benzylic/ Allylic carbon oxidation
- “Carbon atoms attached to aromatic rings”.
- Oxidized to alcohol, aldehyde (ketone) and then carboxylic acid.
- Allylic oxidation:
Oxidation of carbon at α position to carbonyl &
imines
(C=O) and imino (C=N). -
- Oxidation of aliphatic and alicyclic carbon atoms. (Omega and ω-1).

- Alicyclic: They contain one or more all-carbon rings which may be
either saturated or unsaturated, but do not have aromatic character
Alicyclic oxidation
- Mono substituted cyclohexyl group is usually hydroxylated at
positions 3 and 4 with the possibility of cis and trans.
Carbon-Heteroatom systems oxidation
- C-N, C-O, and C-S oxidation involve two main types.

1- Hydroxylation of the α-carbon atom directly attached to
heteroatom, to produce unstable intermediate which decomposes by
cleavage the C-X bond.
2- Hydroxylation of the heteroatom (N,S only) forming N-

hydroxyl, N-oxide, sulphoxide and sulphone.
Oxime, nitrone, nitroso, imino

C-N system oxidation
- Tertiary amines: oxidative removal of alky group (oxidative N-
dealkylation) by P-450. Started by α-carbon hydroxylation to form
carbinol amine intermediate, then cleavage of C-N bond to
secondary amine and carbonyl moiety (Aldehyde or keton).
- Small alky groups are normally removed quickly, and the first is
removed faster.
Methadone to pyrrolidine ring cyclization

- Complete dealkylation reactions will lead to oxidation of primary
amine to carboxylic acid.
- t-butyl moiety is not possible to be removed because no alpha H to

be hydroxylated with the exception of t-butyl-norchlorcyclazine,
which occur through oxidation of terminal CH3 to carboxylic acid
then decarboxylated to produce H at alpha carbon.
- Tertiary alicyclic amines usually form Lactams (nicotine).
O
X X
R
R R XH
H O
H
OH
Cl Cl
N N N N
Cl COOH
Cl N N
N N
- Secondary and primary amines:
Undergo N-dealkylation, oxidative deamination, and N-oxidation
reactions.
- Carbinol amine pathway is the same for tertiary amines, then
produces primary amine.
- Examples: propranolol, methamphetamine (dealkylation to form
keton with same carbinol amine intermediate).
- Oxidative Deamination: process by which a molecule loses the
primary amine group by the same carbinol intermediate.
- Norketamine does not undergo N-deamination. (why?)
- In general, the first step is N-dealkylation, then deamination but
there is exception such as propranolol (aldehyde).
- Also some alicyclic secondary amines are transformed to their
corresponding lactams (phenmetrazine, methylphenidate).
- N-oxidation also happens but to less extent to form N-
hydroxylamine that is prone to form nitrone derivative (N-
benzyl amphetamine, phenmetrzine).
- Primary amines normally undergo oxidative deamination or by N-
oxidation. (endogenous compounds such as neurotransmitters
oxidized via monoamine oxidase [MAOs]).
- Phentermine is dependent on the possibility of alpha carbon
oxidation (structural features of alpha hydrogen availability).
- Decarboxylation step could happen first then deamination occur
(methyldopa).
- N-hydroxylation could occur first then converted to imine by
water loss, then converted to oxime which will be converted to
ketone (amphetamine).
- Primary aliphatic amines which are not possible to be oxidized at
alpha position will be N-hydroxylated and further oxidation
produced nitroso and nitro compounds. (phenteramine,
amantadine).
Aromatic amines and heterocyclic Nitrogen compounds
- Tertiary aromatic amines will undergo N-dealkylation and N-oxide

formation.
- Secondary amines undergo N-dealkylation and N-oxidation to give

N-hydroxyl amines which will oxidized again to give nitrone
derivatives, which they may hydrolyze to primary hydroxylamines.
- Tertiary and secondary aromatic amines are not common in

medicinal drugs while the primary amines are abundant (from
enzymatic reduction of aromatic nitro compounds, reductive
cleavage of azo compounds and hydrolysis of aromatic amides).
- Primary aromatic amines first produce hydroxyl derivative, then to

nitroso.
- Aromatic N-oxidation is considered a minor constitute compared to
N-acetylation and aromatic hydroxylation.
- Methemoglobinemia is a common side effect of aromatic amines

(dapsone) when converted to hydroxyl derivative. It oxidizes the
Fe+2 to Fe+3 in hemoglobin which will prevent oxygen transport
(suffocation).
- Aromatic amines are considered carcinogenic: activated by N-

oxidation to make them highly electrophilic and alkylated by DNA,
RNA.
NH N N
OH OSO3 -
N N N
N N N
GLG
N+
N
N
N
N
N
nitrenium ion
- N-oxidation of N atoms inside heterocycle occur less common to
produce N-Oxide metabolite, (trimethoprim, cotinine and
metronidazole).
Amides
- Oxidative C-N cleavage (α- carbon hydroxylation) and N-
hydroxylation reactions.
- Oxidative dealkylation occur through carbinolamide intermediate,

unstable, fragmentation to form N-dealkylated product (Diazepam).
- Lactams, in the same way by forming carbinolamide that lead to C-N

breakage (Cotinine).
- Cyclophosphamide has many metabolites, see book.
- Aromatic amides, minor extent, toxicological importance, 2-acetyl

aminoflourene (AFF) [N-oxidation, sulfonation, then nitrinum ion
production].
chlorpropamide
Cotinine Cyclophosphamide
Diazepam Flurazepam
Amides
- Acetaminophen:
O
HN CH3
Cause covalent binding with livercells, necrosis
O
N-acetylamindoquinone
O Renal excretion
HN CH 3 O
HN CH 3
O
H
O
Glucuronide
O
HN CH3
O SO O -
3
C-O System Oxidation
- Performed via microsomal mixed function oxidases.
- Oxidation involve α-oxidation to form hemiacetal or hemiketal,

followed by C-O bond breakage (phenol, alcohol) and (keton or
aldehyde).
- Small alkyl groups removed first (morphine).
- Mescaline where the 3-O demethylation is favored.
OH OH
OR2 OR2
R1 H R1 R3
C-S System Oxidation
- Undergo S-dealkylation, desulfuration, and S-Oxidation. The first
two involve C-S bond cleavage.
- S-dealkylation is proceeded in the same way as C-O and C-N

dealkylation by oxidizing the α-carbon.
- Examples are 6-(methylthio)-purine produced 6-mercaptopurine.

S COOH
S SH O
S
N N N
N HN
N N N
H N S N O
H H CF3
- Desulfuration: Conversion of thiono (C=S) or (P=S) to (C=O) or P=O

respectively.
- Thiopental to pentobarbital, and parathion to paraoxon.

C-S System Oxidation
- S-Oxidation reactions:
- Sulfide to sulfoxide to sulphone.
Oxidation of Alcohols and Aldehydes
- Alcohol is produced from different metabolic pathways such
as……
- If the OH is not conjugated, it will further oxidized.
- Primary alcohol and aldehydes give facile oxidation to carboxylic

acid.
- Less important, secondary alcohol to keton, not that important

as it may be reduced again to alcohol as it is easier to be
conjugated.
- The enzyme called alcohol dehydrogenase perform reversible

reaction that converts alcohol to aldehyde and keton, using
NAD+ as a coenzyme.
- Further oxidation of aldehyde to COOH, is done by aldehyde

oxidaze and xanthine oxidize.
Other Oxidation Reactions
- Oxidative aromatization, as in norgestrol.
- Dehalogenation: halothane to trifluroacetic acid with carbinol

intermediate and HBr elimination.
- Chloroform produce phosgene (hepato and nephrotoxicty).
- Normally dehalogenation reactions produce toxic acylhalides.
OH
H H
H H
O
Reduction Reactions
- Have an important role in drugs contain carbonyl, nitro and azo
functional groups, which usually followed by conjugation reactions.
- Less common reduction reactions such as N oxides, sulphoxides, S-S

and C-C cleavage reactions.
- Aldehydes and ketones:

- Source:
- From drugs.
- Oxidative deamination reactions.
- Aldehydes to primary alcohol (but most of its reaction is oxidation to
COOH), rare case is the conversion of chloral hydrate to
trichloroethanol (then phase II).
- Ketones to secondary alcohol then to conjugation reactions.
- These reactions are normally performed by aldo-keto reductase

(NADPH) or oxidoreductase enzyme (alcohol dehydrogenase).
Reduction Reactions
- Propranolol as major metabolite after deamination is COOH
derivative and as minor is propranolol glycol.
- Chlorphenramine first dealkylated, deaminated then it could undergo

oxidation or reduction.
- Ketone reduction reactions are stereo-selective, which involve H

transfer to the carbonyl group and then one steroisomer will be
preferred over the other (Acetophenone, Warfarine).
- Examples of compounds undergo oxidative deamination to ketone and

then reduction to alcohol (amphetamine, ephedrine).
Cl
Ephedrine
Chlorphenramine Warfarine Amphetamine
Acetophenone
Reduction reactions
- Nitro and Azo compounds:
- The end product is primary amines.

- Aromatic nitro to nitroso to hydroxylamine to amine.
- Aromatic azo to hydrazo to cleavage to two aromatic amines.
- Nitro reductase and NADPH are needed for nitro reduction (7-
nitrobenzodiazepine [clonazepam, nitrazepam]).
- Prontosil (azo) to the active metabolite sulfanilamide.
- Tartrazine and amaranth cleaved by intestinal bacteria.
Sulphasalazine is hydrolyzed to sulphapyridine and 5-aminosalicylic acid.
O H
H2N N N
S
O
N NH2 O
H 2N S N HOOC N
N
O
HO
Clonazepam
Nitrazepam PRONTOSIL SULPHASALAZINE
Other Reduction Reactions
A. (N-Oxide to tertiary amines).

- reduces the polarity of the tertiary amines, so reduce excretion.
B. (Disulphide reduction).
- Disulfiram is converted to N,N-dithylthiocarbamic acid and
sulindac (sulphoxide to sulfide).
N N HO
S N
S S S SH O
S S
O
Hydrolytic Reactions
- Esters and amides:
- Occur in various tissues and plasma.
- The products are (COOH, alcohols, phenols, and amines). The result is
more polar and easier to be conjugated.
- Enzymes involved for esters are esterases in liver, kidney and plasma and
for amides amidases, esterases and deacylases.
- For drugs contain esters, hydrolysis is the major route because it is

easily cleaved.
- Examples (Aspirin, cocaine, ritaline), normally esters are prodrugs that

are activated inside the body such as clofibrate, diphenoxylate.
O
O
N
Hydrolytic reactions
- Examples of using esters as prodrugs:”
- Clindamycin & Chloramphenicol: as palmitate ester to hide the bitter
taste of these drugs.
- Geocillin, improve poor oral absorption of carbenicillin [Indanyl ester].
- Prednisolone hemisuccuinate sodium salt for I.V injection.
- Amides hydrolyzed slowly compared to esters (procaine, procainamide).
- Other examples: indomethacin and prazocin.

Hydrolytic reactions
- Other Hydrolysis reactions:
- Hydrolysis of proteins and hormones at their terminal amino acid groups

by aminopeptidases; insulin, GH, prolactin, and PTH.
- Hydrolysis of epoxides, and areneoxides.
- Hydrolysis of phosphate esters, carbamate esters, and cardiac

glycosides.
Phase II: conjugation reactions
- Aims to produce water soluble moiety, but not necessarily abolish
parent compound activity.
- Adds polar, small, endogenous and ionizable group to phase I

metabolite or parent xenobiotics such as (glucuronic acid, sulfate,
glycine, glutamine).
- Generally, these metabolites are nontoxic and not active.
- Other phase-II reactions such as acetylation and methylation are

not increasing water solubility, rather they act to terminate or
attenuate pharmacological activity.
- The conjugated residues are first activated as coenzyme before

transfer and attachment by transferase enzymes.
Phase II: Glucuronic acid conjugation
- The most common conjugation pathway due to:
- Readily available D-glucuronic acid (from D-glucose).
- Many functional groups can be united with glucuronic acid.
- Its ionized carboxylic acid and the polar OHs increase water solubility
to high extent.
- β-glucuronides formation involves two steps:

- Synthesis of activated coenzyme (UDPGA)
- Transfer of glucuronyl moiety to the xenbiotic by UDP-
glucuronyltransferases.
- One step of glucuronation is sufficient to excrete a compound, so

di- process is not common.
- Common features of the binding are :

- occur at C1 of the glucuronic acid.
- The acceptor has the formula HXR, that the OH of
glucuronic acid will leave.
- There are many functional groups that can be glucuronated:
- O- glucuronation: hydroxy and carboxy.
- Hydroxy: alcoholic or phenolic are the most common FGs that undergo
glucuronation.
- Less common hydroxy groups undergo glucuronation are enols, N-hydroxyl
amines, and N-hydroxyl amides.
- Carboxy: Aryl acids prefer conjugation with glycine but could be
glucuronated.
- N- glucuronation:
- Occur occasionally with aromatic amines, amides and sulphonamide.
Considered minor pathway compared to N-acetylation, or oxidative process.
- Some compounds form quaternary ammonium glucuronide metabolite.
- S-glucuronation:
- With the thiol group.
- C- glucuronation:
- Novel form of conjugation occur in little examples (Phenylbutazone).
- Bile excretion of glucuronated endogenous compounds occur for

compounds more than 300Da, which may be hydrolyzed by β-
glucuronidase.
- In neonates and children, glucuronidation is not fully mature, so

some drugs and bilirubin could be accumulated and cause serious
toxicity (gray baby syndrome).
Phase II: Sulphate conjugation
- Occur mainly with phenols, and to less extent alcohols, aromatic
amines, and N-hydroxy compounds.
- There is limited amount of sulphate, so it is limited reaction.
- used extensively by the body to excrete endogenous compounds

such as steroids, heparin, catecholamines.
- The process involve formation of PAPS and then transfer process by

sulfontransferase.
- Lead to water soluble and inactive metabolite, but some O-sulfate

and N-hydroxy compounds give toxic metabolites.
- Low level of glucuronyltransferase or undeveloped enzyme may cause

acetaminophen to be mainly excreted as sulfate conjugate in
neonates rather than glucuronyl derivative as both process are
competitive.
Phase II: Sulphate conjugation
- O-sulfate ester conjugates and N-hydroxy compounds are important
as they could cause reactive toxic intermediates.
- Carcinogenic species such as 2-acetylaminofluorene mediate toxicity

thorough O-sulfate esters that generate electrophilic niternium
species.
- Phenacetin: is metabolized by N-hydroxylphenacetin and then

conjugated with sulfate which in turn binds to bind covalently to
microsomal protein causing hepato and nephrotoxcity.
Phase II: Aminoacids conjugation
- Glycine and glutamine used to conjugate (COOH) aromatic acids and
arylalkyl acids.
- This process is limited due to competition with glucuronic acid and
limited supply of amino acids.
- The process of conjugation is as follows:
- Activation of the carboxylic acid containing compound to form Acyl-CoA.
- Acylation of glycine or glutamate by N-acyltransferase which occur in
mitochondria of liver and kidney.
- Glutamine conjugation occur mainly for arylacetic acids such as
phenylacetic acid and 3-indolylacetic acid.
Phase II: GSH (mercapturic acid conjugates)
- Important pathway for detoxifying chemically reactive
electrophilic compounds.
- sulfhydryl group is considered the important group that interact

with electrophilic positions in the toxic compounds.
- GSH is a tripeptide (γ-glutamyl-cysteinyl glycine) that found in

many tissues which will be further biotransformed to form S-
substituted N-acetylcysteine called mercapturic acid.
- The enzyme involved in the GSH conjugation is called glutathione

S-transferase, and the degradation step is performed by renal
and hepatic microsomal enzymes.
- No need to form activated coenzyme or substrate.
- Compounds that react with GSH do this by two mechanisms:

- Nucleophilic displacement at an electron deficient carbon or
heteroatom.
- Nucleophilic addition to an electron deficient double bond.
- Nucleophilic displacement at an electron deficient carbon or
heteroatom.
- Aliphatic and aryl alkyl halides, sulphates (OSO3-), sulphonates (OSO2R),
and nitrates (NO2) possess electron deficient carbon atoms that react
with GSH to form GSH conjugates.
H2C X GS CH2 HX
GSH
R R
X: Br, Cl, OSO3, OSO2R, OPO(OR)2
- It is facilitated when the carbon atom is benzylic or allylic or when X is a

good leaving group.
- Examples are benzyl chloride, methyl-iodide, allyl-chloride,
methylparathion.
- Aromatic substitution occur when the ring is attached
to strong electron withdrawing group.
- Azathioprine
- Arene and aliphatic epoxides are detoxifies by GSH.
- GSH conjugation involving substitution at heteroatoms such as O,

found in organic nitrates. (nitroglycerine, isosorbiddinitrate). The
final product is glutathion disulfide and alcohol.
- Nucleophilic addition to an electron deficient double bond.
- Occur mainly on α,β-unsaturated systems (but not all) that are

electron deficient by being within resonance or conjugated with
carbonyl group.
- GSH adduct is formed by Michael addition reactions.
- Oxidation reaction could produce α,β-unsaturated systems as in

acetaminophen and 2-hydroxy estrogen.
- Some examples have showed that GSH could cause toxicity, as the
GSH conjugates are themselves are electrophilic.
- 1,2 dichloroethane, react with GSH to produce S-(2-

chloroethyl)glutathion, then the S will displace one of the chlorine
atoms to produce episulfonium ion.
Phase II: Acetylation
- Important pathway for drugs containing primary amino groups
(ArNH2, H2NC6H4SO2NHR, hydrazines (-NHNH2), hydrazides
(CONHNH2), and primary aliphatic amines).
- The end product will be amides that are expected to be nontoxic

and inactive.
- No enhancement of water solubility, so it is expected to terminate

activity or detoxification process (not always).
- The source of acetyl group is acetyl-CoA, and then transferred by

the enzyme N-acetyltransferase.
- Examples of aromatic primary amines; procainamide, dapsone, Nitro

derivatives; clonazepam, sulphonamides; sulphamethoxazole,
sulfanilamide (crystallurea), hydrazine; hydralazine, hydrazide;
INH, aliphatic amines (minor compared to oxidative deamination);
histamine and mescaline
.
- Acetylation polymorphism: bimodal character in human relate to drug
acetylation process and classified as rapid or slow acetylator.
- The variation is related to genetic characters that is associated with

N-acetyltransferase activity related to ethnic groups.
- Eskimos and Asians are rapid acetylators, while Egyptians and some
western European countries are slow acetylators, while other groups
are intermediate between the two.
- Rapid acetylators will not show the expected results of the given
dose, while the slow are expected to develop side effects.
- INH is one example; in rapid acetylators the t1/2 is 45-80 min, while in
slow acetylators is 140-200 min.
Phase II: Methylation
- Used for biosynthesis of endogenous compounds (ephedrine and
melatonine).
- Used also for inactivation of endogenous compounds (dopamine,

seratonine).
- Minor pathway for xenobiotic compounds.
- Reduces water solubility except the case of creation quaternary

ammonium compound.
- S-adenosylmethionine (SAM) is the coenzyme and then there is

transferase enzymes that deliver this group.
- Methyltransferase enzymes are important such as catechol-O-

methyltransferase (COMT), phenol-O-methyltransferase.
- COMT is important in performing O-methylation for

neurotransmitters norepinephrine and dopamine.
Phase II: Methylation
- Catecholes are metabolized by COMT, methyldopa and
isoproterenol to mono methylated (only C3 OH), terbutaline is not
O-methylated.
- Little case where phenols were O-methylated (minor); Morphine to

codeine.
- N-methylation of xenobiotic compounds is very low such as

amantadine.
- N-methylation present at heteroatom such as nicotine and nicotinic

acid to give quaternary ammonium products.
- S-methylation for drugs contain thiols (6-mercaprtopurine,

propylthiouracil)
Enzyme Induction
- The process by which the activity of the metabolizing enzymes is
increased, which is related mainly to increased amount of newly
synthesized enzyme.
- Could lead to reduction of activity of some drugs as they will be

metabolized faster.
- Could cause Drug-Drug interaction (Phenobarbital-warfarin) and

(Contraceptives with [rifampin or phenobarbital]).
- Drug-Side effects such as osteomalacia when treatment with

phenobarbital and phenytoin (vitamin D mertabolism).
- By inducing glucuronyl transferase to conjugate bilirubin with

glucuronic acid, so it may be used to treat hyperbilirubinemia.
- Benzo[α] pyrene a smoking byproduct is a strong enzyme inducer, so

affect other drugs such as theophylline, phenacetin.
- Exposure to pesticides and insecticides stimulates drug metabolism.

Enzyme Inhibition
- Reduced metabolism cause accumulation of certain drugs so
increase the duration of action and side effects.
- This process occur by: substrate competition, interfere with

protein synthesis, inactivate drug-metabolizing enzymes and
hepatotoxicity.
- Chloramphenicol and disulfuram and INH reduce the metabolism of

phenytoin.
- Grapefruit contain furanocumarines and bioflavonoids such as

naringin is weak CYP inhibitor.
THE END
GOOD LUCK IN THE FINAL EXAM

Medicinal Chemistry 1 - Full Version

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Medicinal Chemistry 1 - Full Version

Uploaded by

Copyright:

Available Formats

Absorption, Distribution, Metabolism and

An Introduction to the Principles

Dr. Qosay Al-Balas

- Absorption: process by which the drug is transported into the

- Distribution: process by which a drug is transported from

- Metabolism: chemical modification of the drug at different

- Elimination: process by which the drug or modified drug is

1- Reach to site of action: Governed by absorption and

2- Interact with the site of action: Governed by the chemical

Physicochemical properties: measurable characters by which the

Pharmacokinetics – what the body does to the drug

What are the concepts?

Which barriers to cross? Can fast metabolism

Pool of non-available Pool of available

•Pharmacokinetics – what the body does to the drug

•Pharmacodynamics – what the drug does to the body

Factors affecting the absorption:

1- pH: affect mainly the ionizability and chemical stability

2- Surface Area [SA]: intestine has villi and microvilli that

3- Enzymes: might degrade the drugs before being absorbed

4- Biomembranes: Lipid bilayer composed of phospholipids,

-Passive Diffusion: movement of drugs from the area of high concentration

-Passive Diffusion: depends mainly on lipophilicity (partitioning) and the

-Active Transport: used to transport endogenous compounds such as amino

-Active transport: is characterized by consuming energy and being a

Drug Drug Drug Drug

Membranes have lipid character and act as barriers

Functional groups will determine whether a drug will

- Water Solubility: drug should have some water solubility

1- Should be soluble in the gastric fluids

- Hydrophobic nature of membranes imposes some lipid

z log P > 2: highly lipophilic

-F -0.38 0.37 C6H4 1.67 1.67

- The unionized/uncharged forms (free acids or bases) tend

- Drugs can therefore have both water soluble and fat

IONISED UNIONISED IONISED

We cannot change the ratio of the ionized to unionized species by

Aspirin is undissociated Aspirin is dissociated

Drugs move between these compartments, so we need

-The DISSOCIATION constant for the acid, HA, is given by Ka.

- In other words, acids are proton donors and their conjugate

- The ASSOCIATION constant for the base (B) is referred to as

You can’t tell from the pKa value whether the

To apply these rules, you must be able to recognise

Do not confuse pKa with pH – pH is simply a

Remember what pKa is – a dissociation constant

For acids: a high pka means the species is predominantly

a low pka means the species is predominantly ionised,

For bases: a high pka means the species is predominantly

a low pka means the species is predominantly

- ONLY THE UNIONISED FORM OF A DRUG

- [required for drug absorption into the body]

- THE IONISED FORM TENDS TO BE MORE

• The equilibrium in the aqueous layer is

RCOOH RCOOH Drug Absorption

• If the pH shifts the balance towards the

• If the pH shifts the balance towards the ionized/dissociated

• Assume the pH of the stomach is 2.0 and the pH of the small

Now consider a drug that is basic, with a pKa of 7.0

H + RNH2 RNH2 Drug Absorption

• Where is the likely site of absorption?

• We therefore have to account for the partitioning properties of our