oct. 2014 - كلية الصيدلة - جامعة المنصورة -...
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Pharmacists are the Drug Experts
3
Pharmacists are the drug
information specialists. Are we
qualified?
Oct. 20144
Medicinal chemistry is a discipline at the intersection
of chemistry, especially synthetic organic chemistry,
and pharmacology and various other biological specialties,
What is Med Chem?
involved with design, chemical
synthesis and development for
market
of pharmaceutical agents, or
bio-active molecules (drugs).
Oct. 20145
The objectives of the Medicinal Chemistry courses are to enable
the student to gain an understanding of the following general areas
of study:
Drug biotransformation.
Physicochemical properties and drug action.
The chemical structures of different drugs in each class;
their modes of action;
the correlation between chemical structures and biological activities (SAR);
evaluation of the activity of each drug and its selectivity
and the biotransformation.
Different synthetic pathways.
The drug-drug interaction.
Overall Aims of Course
What is Med Chem?
Medicinal Chemistry is the chemistry of Drugs
It deals with the chemical and biological aspects of drugs
It represents a link between chemistry and biology
Oct. 20146
What is important ?
Oct. 2014
The Chemical Structure; Why important?
Mode of action of Drugs. D-R interaction and Forces involved
Structure-Activity Relation (SAR)
Metabolism of drugs
Design of Drugs
Synthesis of Drugs
Analysis of Drugs
Nomenclature of Drugs (3 names)
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Textbooks
Oct. 2014
Wilson and Gisvold’s Textbook of Organic Medicinal and
Pharmaceutical Chemistry
12th edition
by John M. Beale Jr. and John H. Block (Editors)
Lippincott Williams & Wilkins
2010
Foye’s Principles of Medicinal Chemistry
7th edition
T. L. Lemke, D. A. Williams (Editors)
Lippincott Williams & Wilkins
2012
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Oct. 201410
Mid-Term Examination 10
Final-Term Examination 50
Oral Examination 15
Practical Examination(exam, activities, attendance, quizzes, …)
25
Total 100%
Weighting of Assessments
Oct. 201411
Topics Staff member
Drug biotransformation 3Prof. Dr. Said M. Bayomi
(7 x 3 = 21)β-lactam antibiotics and non β-lactam 4
Physicochemical properties and drug action 3
Prof. Dr. Eman R. El-bendary
(6 x 3 = 18)Antiviral 2
Antifungal 1
Sulfonamides 1
Dr. Moh. Abubakr
(7 x 3 = 21)
Antineoplastic agents 3
Antimycobacterial 1
Macrolides &Aminoglycosides 1
Tetracyclines 1
Important Terminology
Oct. 2014
• Pharmacophore
• Prototype (Lead)
• Prodrug
• Isosteric substitution
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What is a drug (D)?
Drug is a chemical compound which is used to
prevent and / or treat diseases
( pharmacologically active compounds)
Sources of drugs
1- Natural source: Drugs obtained through the extraction
of plants such as Aspirin digitalis, quinine, morphine
2- Synthetic source: Drugs obtained through the random
screening of many synthetic chemicals and its
development
NOMENCLATURE OF DRUGS
-A drug is identified by three types of names:
1-Trade, Brand or Proprietary Name
This name is selected and used by the company that manufacturers it.
2- Generic or Non Proprietary Name
This name is chosen by official agencies e.g WHO (world and health organization)
3- Chemical nameThis name describes the exact chemical structure of the drug.Examples:
Generic name: diazepam.Trade names: valium, valpam, …, …., …..Chemical name:
N
N
Cl
O1 2
3
456
7
8
9
CH3
7-Chloro-1-methyl-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one
CLASSIFICATION OF DRUGS:DRUGS CAN BE CLASSIFIED ACCORDING TO:(a) Chemical structure
e.g. penicillins, steroids…….etc.
(b) Pharmacological action
e.g. antihypertensive, analgesics….etc.
(c) Target system
e.g. cholinergic, adrenergic ………….etc.
(d) Mechanism of action at the molecular
level e.g. anticholinesterases, B-blockers……etc.
Where do drugs work?
Receptor (R):
Generally ,it is an integral biological macromolecule embedded in the biological
system. The four main targets (receptors) for drugs are lipids, carbohydrates, proteins and nucleic acids.
Receptor presents on the cell membrane or within the
cytoplasm or cell nucleus that binds to a specific
molecule (a ligand) such as a neurotransmitter or a
hormone or other substance, and initiates the cellular
response to the ligand.
TYPES OF RECEPTORS
a- Enzymes
e.g. Acetylcholeinestrase, carbonic anhydrase, adenylcyclase and monoamine oxidase.
b- Structural and functional component of a cell membrane which consists of lipoprotein.
c- Receptors of nucleic acid
e. g. DNA and RNA.d- Non enzymatic protein receptors
e. g. ( adrenergic receptors)
DRUG-RECEPTOR INTERACTION
Drugs interact with the receptors in a process known as binding forming D-R complexes which are responsible for the biological response.
There is usually a specific area of the receptor where this binding takes place and is known as binding site.
D + R D-R Complex
Biological Response
Drug-Receptor Interaction:
Not every drug that binds to a receptor activatesthe receptor.
Drug with good receptor fit, will produce apharmacological response and described as"agonist".
Drug which could deal with the receptor willproduce a reversed pharmacological response, andthe drug described as "antagonist".
Requirements for Drug-Receptor Interaction
1. Binding affinity:
Affinity of a drug to interact with receptor toform drug-receptor complex.
2. Intrinsic activity:
The exact fitness of the drug with the receptor. Itdifferentiates between agonist and antagonist,even both have the affinity towards the receptorbut they produce different responses.
3-Pharmacophoric group:
Is a part of the drug which associate with the receptor and considered as an essential part to produce pharmacological action e.g. Phenothiazine derivatives must have phenothiazine ring as a pharmacophoric group to produce their pharmacological action as tranquilizers.
N
S
Cl
CH2CH2CH2N(CH3)2
Chlorpromazine
STRUCTURE-ACTIVITY RELATIONSHIP (SAR):
Structure-Activity Relationship (SAR) is the relationship between the structure of a particular compound or a group of compounds and its (their) biological activity.
What happens to the drug after its administration?
Liberation
Absorption
Distribution
Metabolism
Excretion
FATE OF DRUG
MAJOR PHASES INVOLVED IN DRUG ACTION
1. The Pharmaceutical Phase
2. The Pharmacokinetic Phase
3. The Pharmacodynamic Phase
PHARMACEUTICAL PHASE
-It involves the time from the administration of the drug till the release of the active principle.
Thus include processes of disintegration and dissolution, now the drug is available for absorption.
The liberation of the drug from the
pharmaceutical dosage form.
PHARMACOKINETIC PHASE
This phase include the time from the release of active principle till the drug reaches its site of action (receptor).
Pharmacokinetics describes how the body affects a specific drug (ADME)? after administration.
Pharmacokinetics includes the study of absorption, distribution, metabolism and excretion process of an administered drug.
PHARMACODYNAMIC PHASE
-It involves the interaction of the drug with the receptor.
The drug will be expected to dissociate from the receptor and re-enter the circulation to be excreted except ?
Physico-Chemical properties
• Disintegration
• Dissolution
• Absorption
• Distribution
• Metabolism
• Excretion
• D-R binding
February 28, 2016M Bakr36
• Solubility
• pKa
• Lipophilicity
• Electronic effects
• Functional groups
• Steric effects
• Stereochemical properties
• …..
some factors affecting pharmaceutical and Pharmacokinetic phases
Disintegration, Dissolution, Absorption, Distribution,
Metabolism, Excretion
1. Solubility
2. Partition coefficient
3. Drug's pKa
4. Electronic and steric parameters
The term solubility refers to
solubilization of the drug in the
different media, polar solvent as water
(hydrophilic character) and non-polar
solvent as lipid (hydrophobic or
lipophilic character).
1- Solubility
A] Water solubility:
The solubility of a drug molecule in watergreatly affects the routes of administration thatare available as well as its absorption,distribution, and elimination
Two key concepts to keep in mind whenconsidering the water (or lipid) solubility of amolecule are:
1-The hydrogen bond.
2-The ionization of functional groups.
1- HYDROGEN BONDS
Each functional group capable ofdonating or accepting a hydrogen bondwill contribute to the overall watersolubility of the compound and increasethe hydrophilic nature of the molecule.
Hydrogen bonds are referred to asdipole-dipole bonds.
Fig. 1: Examples of Hydrogen-Bonding Between water and Hypothetical Drug Molecules.
N
H
H
O
HH
O
H
H
O
HH
O
RR
O
H
H
H
O
H
2- IONIZATION
Another type of bonding interaction plays animportant role in determining water solubility, it isan ion-dipole interaction. Basic drug accept protonand acidic drug loss proton at physiological pH andat the receptor.
Fig. 2: Examples of Ion-dipole Interactions.
N
H
HO
H
H
h
O
O
O H
H
Water and lipid solubility
In a drug structure, hetero-atoms (O, N) and functional groups capable of forming hydrogen bond and ionized bonds with water molecules represent the water solubleor hydrophilic part of the drug molecule.
Carbon skeleton (number of carbon atoms) & halogenatoms as F, Cl, Br or I represents the lipophilic or water insoluble part of the molecular structure since they are incapable to form any bonding with water molecules.
Water and lipid solubility
Ionizable and polar functional groups
increase water solubility e.g. OR,
NH2, COOH, C=O, -O-, O-C=O, OCH3, ..............etc.
• Halogens (F, Cl, Br & I), alkyl groups (CH3, CH3-CH2-, CH3-CH2-CH2-, ), cycloalkyl
(cyclopentanyl, cyclohexanyl, ), aryl gps(phenyl) and others, in addition to sulfur are
water insoluble.
PRODRUG APPROACH TO ALTER THE DRUG SOLUBILITY
Prodrugs are compounds that are inactive in their native form, but are easily metabolized to the active agent .
Example : Methylprednisolone
Methylprednisolone
Solu-Medrol
Water soluble
parenteral formula
HO
O
OH
O
O
O
O
O.Na
CH3
Methylprednisolone sodium succinate
HO
O
OH
O
O
O
CH3
Methylprednisolone acetate
February 28, 2016 M Bakr 46
Depo-Medrol
Lipid soluble
long-acting
In side the body, the ester linkage will be cleaved by the effect of esterase enzyme giving the active drug.
ON THE OTHER HAND SUCCINATE ESTER MAKES IT MORE SOLUBLE MAKING INTRAVENOUS FORMULATION
MORE EFFECTIVE
The active drug
HO
O
OH
O
O
O
O
O.Na
CH3
Methylprednisolone sodium succinate
esterase
B] LIPID SOLUBILITY AND ABSORPTION
OF DRUGS
Some drugs, even they are in the un-ionized
form, they are poorly absorbed by passive
diffusion from GIT, this is because of their low
lipid solubility.
A guide for the lipid solubility or the lipophilic
nature of a drug is known as partition
coefficient (p.c.).
[drug] lipid [drug] octanol
P.C. = =
[drug] water [drug] water
For simplicity log P.C. is used instead of P.C.
Hydrophobic (lipophilic) compounds will
have a high log P and achieve good
absorption from GIT.
[drug]octanollog P.C. log
[drug]water
The hydrophobicity constant (π)
Practical estimation
π = logPx – logPlogP is the log partition coefficient of unsubstituted compound e.g. benzene.
logPx is the log partition coefficient of substituted compound e.g chlorobenzene.
logP calculated of a drug of known chemical structure = Σπ
If The hydrophobicity constant of a particular
group ,π (fragment constants) is negative
value , (like COOH, CN, NO2, SO2CH3),
(hydrophilic). It means that the substituent
increases water solubilityof a parent
compound.
•If The hydrophobicity constant,π (fragment
constants) is positive value, (like CH3, C3H7, C4H9,
Cl), ( lipophilic). it means that the substituent
increases liposolubility of a drug.
Significance of π
3. DISSOCIATION CONSTANT (pKa ):
Henderson-hassalbach equation can be used to calculate the
percentage ionization of a compound at a given pH.
[conj. base]pH = pKa + log
[acid]
Because pKa is a constant for any given molecule, the ratio of
acid to base will determine the pH of the solution. Conversely,
a given pH determines the ratio of acid to base.
Drug's Ionization State (Drug's pKa):
• Most drugs are either weak acids that donate proton and form conjugated base or weak bases that accept proton and form conjugated acid.
-[A ] [ionized acid]pH=pKa+log =pka+log
[HA] [undissociated acid]
HA + H2O H3O+ + A-
weak acidunionized form
conjugated baseionized form
B + H2O BH+ + OH-
weak baseunionized form
conjugated acidionized form
B+H + H2O H3O++ Bprotonated acidionized form
conjugated baseunionized form
Model to understand how the environment can shift
the pKa of a functional group
pH=0 pH=14
-COOH -COO-
-NH3+ -NH2
pK = 4.76
pK = 10.66
PKa of strong acid < 2
PKa of weak acid 4-6
PKa of weak base 8-10
PKa of strong base >12
The stomach has a pH of 1-3,
in the duodenum pH from 5 to 7 and increase gradually till reaching pH 8 in the colon.
MANY DIFFERENT ORGANIC FUNCTIONAL
GROUPS BEHAVE AS ACIDS OR BASES
Organic functional groups that cannot give up
or accept a proton are considered to be "neutral"
or non-electrolyte with respect to their acid-base
properties.
AMPHOTERIC DRUG: THAT IS, ACT AS AN ACID OR
A BASE, DEPENDING ON THE CONDITION (PH OF THE MEDIUM).
Example: Ciprofloxacin, a fluroquinolone
antibiotic contains:
A secondary alkyl amine
Two tertiary arylamines
A carboxylic acid.
N
O
N
COOHF
HN20 amine
(basic)
Carboxylic
acid
(acidic)
30 arylamine
(weak base)
Fig. 1: Chemical Structure of Ciprofloxacin Showing the Various Organic Functional Groups.