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MEDICINAL CHEMISTRY

INTRODUCTION

Medicinal Chemistry in the Pharmacy curriculum is


emphasis on the Chemical Properties of
Biologically Active Molecules

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DRUG DESIGN: A CONCEPTUAL
APPROACH

1. Basic concepts about drugs, receptors, and drug


receptor interactions
2. Basic concepts about drugreceptor interactions
applied to human disease

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The first phase comprises the essential building
blocks of drug design and may be divided into three
logical steps:

1. Know what properties turn a molecule


into a drug
2. Know what properties turn a macromolecule into
a drug receptor
3. Know how to design and synthesize a
drug to fit into a receptor
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Step 1 involves knowing what properties turn
a molecule into a drug.

All drugs may be molecules, but all molecules are


certainly not drugs. Drug molecules are small
organic molecules (molecular weight usually below
800 g/mol, often below 500).
Penicillin, acetylsalicyclic acid, and morphine are all
small organic molecules.

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Certain properties (geometric, conformational, stereochemical,
electronic) must be controlled if a molecule is going to have what it

takes even to emerge as a drug-like molecule


(DLM).

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Step 2 involves knowing what properties turn
a macromolecule into a receptor.
All receptors may be macromolecules, but all macromolecules are certainly
not receptors. Receptor macromolecules are frequently proteins or
glycoproteins. Certain properties must be present if a
macromolecule is going to have what it takes to be a druggable target. The
receptor macromolecule must be intimately connected with
the disease in question, but not integral to the normal biochemistry of
a wide range of processes.

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I. Physico-Chemical Principles of
Drug Action

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A. Electronic structure and drug action

1. Electronegativity

F>O>N>Cl>S>>>CH
Halogens F>Cl>Br>I

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2. Dipoles and Polarity

F C H

Fluoromethan
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O
H o
109 H
Water
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3. Hydrogen bonding

d d
X H Z X H Z

1) Donating a hydrogen bond


2) Receiving a hydrogen bond
Both X and Z are relatively electronegative

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Examples of Hydrogen Bonds

R O H

H O R
Alcohols

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R
R O H O C
Alcohols and Ketones R'

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R C N R'

O H
Amides
H O

R'' N C R'''
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Example of a Not Possible Hydrogen Bond

C R

C C H O C

C R'

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Dimeric Hydrogen Bonds in Carboxylic Acids

O H O R = R'
R C C R' or
O H O R = R'

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H
O
O
C
OH

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Drug-Receptor Bond Strength

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Covalent bond formation with receptors
Partition coefficients

drug lipid
P
drug water
of drug concentrations (symbolized by the square brackets) in the
two phases. Since partition coefficients are difficult to measure in
living systems, they are usually determined in vitro, using n-octanol
as the lipid phase and a phosphate buffer of pH 7.4 as the aqueous
phase.

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H2 antagonist none of these compounds is
lipid soluble (their average partition
coefficient is only 2), compare with of
coefficients of up to 1000 for typical of H1
antagonist).

They do not produce any sedative CNS action,


since they do not across the blood brain-
barrier.
The Overton-Mayer Hypothesis of
Anesthetic Activity
a. All neutral lipid soluble substance have
depressant properties on neurons.
b. This activity is most pronounced in lipid-rich
cells.
c. The effect increases with increasing partition
coefficient, regardless of structure of the
substance.
Fergusons Role

Pt
a
Ps

Where Pt is the partial vapor pressure of the substance in air and Ps


is the vapor pressure of the substance.

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Fergusons Role

St
a
So
Where St is the molar concentration of the dissolved drug
necessary for biological activity air and So is the molar solubility of
the drug.

Structurally non specific drugs are active at high thermodynamic


activities, between 0,001 and 1; that is, they are active only in high
dose.

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General Anesthetics
Gases Xe Xenon
N2 O Nitrous oxides
Cyclopropan

Volatile liquids
C2O5OC2O5
HCl3
CCl2=CHCl
F3C-CHClBr
Intravenous
anesthetics

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Intravenous Anesthetics

HN C2O5

S
CH CH2CH2CH3
HN
CH3
O
Thiopental

Thiopental, one of the three lactam oxygens of barbituric acid is replaced


by sulfur, and the two alkyl side chains impark a lipophilic character to
the molecule. Thiopental is known as an ultra short acting anesthetic
because the onset of anesthesia and loss of consciousness occur within
seconds of its administration.

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Intravenous Anesthetics

O
H2 H
HN C C CH2

O
CH C C C2H5
N
CH3
CH3 O
Methohexital

Methohexital carries an N methyl group, which prevents its


tautomerization to the lactim form of barbituric acid with the formation of
an enolate ion. This propertiy is increases the lipophilic character
because the enolat ion is hydrophilic and thys capable of forming
hydrogen bonds with water. It also forms soluble sodium salts.
The N methyl group, by maintaning the lipophilic nature of methohexital,
therefore prompts the rapid onset of narcosis. 27
O O O

HN N N

O HO HO

HN N N

O OH O
lactim lactam enolate

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