Lecture 1

MEDICINAL CHEMISTRY

1
Topic Online in Medicinal Chemistry for S1 Student presented by
Drs. H. Zulharmita. MS Apt through the Stifarm (School of High
Pharmacy) at September - October 2020 in Padang.

GENERAL ONLINE

I. Introduction
Overview of lecture, quizzes and examinations, textbook.
Discussion of assumed prerequisites
Review and discussion of important background principles
 
II. Physico-Chemical Principles of Drug Action
Solvation and the structure of water
Solubility
Partition coefficients
Surface activity and drug effects
Streochemical aspects of drug action
Electronic structure and drug action
Chemical bonding and biological activity
Quantitative structure activity relationships (QSAR) 2
III Drugs Acting on Neurotransmitters and Their Receptors
Review of neuroanatomy and neurophysiology
Acetylcholine and the cholinergic receptors
Norepinephrine and the adrenergic receptors
Dopamin and the dopaminergic receptor
Serotonin and the serotonic receptors
Histamine and the histaminergic receptors
Amino acid neurotrasmitters and related drug effects

IV Non-Messenger Targets for Drugs Action

Enzym

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 TEXT BOOK and REFERENCE MATERIALS
Text for Special Lecture
Thomas Nogrady, “Medicinal Chemistry: A Biochemical Approach”, 1985,
Oxford University Press
Thomas Nogrady and Donald F. Weaver “Medicinal Chemistry: A
Molecular and Biochemical Approach”, 3 rd ed. 2005, Oxford University
Press
Supplemental Texts
•William O. Foye, Editor, “Principles of Medicinal Chemistry”, 2 nd Edition,
1981, Philadelphia, Lea and Febiger
•R. Ganellin and S.M. Roberts Editor. Medicinal Chemistry, The Role of
Organic Chemistry in Drug Research. Academic Press, London. 1993
•Abraham-Burger’s Medicinal Chemistry Drug Discovery Sixth Edition Vol

1- 6, 1998. A John Wiley and Sons, Inc., Publication

Reference Materials
•“Annual Repors of Medicinal Chemistry”’ New York, Academic Press,
Selected articles
•Journal of Medicinal Chemistry, Washington, D.C., American Chemical
Society, selected articles
•Biochemistry, Washington, D.C., American Chemical Society, selected
article
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 INTRODUCTION

Medicinal Chemistry in the Pharmacy curriculum is

emphasis on the Chemical Properties of
Biologically Active Molecules

5
 CHAPTER I
Physico-Chemical Principles of Drug Action

A. Electronic structure and drug action

1. Electronegativity

F>O>N>Cl>S>>>C≥H
Halogens F>Cl>Br>I

6
2.Dipoles and Polarity

F C H

Fluoromethan
7
 O
H 109 o
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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 Chemical bonding and biological Activity

• Drug-Reseptor Interaction

k1 k3
D + R DR E
k2

Where D = Drug, R = receptor, DR = drug receptor complex, E = biological

effect and k1, k2, and k3 = rate constants
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.

19
• 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.
Biochemical Building Blocks

Amino Acids
COOH COOH
*
H2N C H H C NH2

R R
General Structure General Structure
in Fisher Projection in Fisher Projection
L-Configuration shown D-Configuration shown
S-Configuration shown R-Configuration shown

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Nomenclature

Amino Acids
R = H-, Glycine (Gly) H3C
H2
R = CH3-, Alanine (Ala) R= CH C , Leucine (Leu)
H3C

H2
R= C , Phenylalanine (Phe)

H3C
R= CH , Valine (Val)
H3C

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 H2
H3C C
R= CH , Isoleucine (Ile)
H3C

R= HO C , Serine (Ser)
H2

R= HS C , Cystein (Cys)
H2

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 H2
C
R= Tryptophan (Trp)
N
H

H2
C
R= , Histidine (His)
N NH

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Heterocyclic Bases
O O NH2

HN CH3 HN
HN

O N O N
O N H H
H
Thymine Cytosine
Uracyl
NH2 O
N N
N HN

N N H2N N N
H H
Adenine Guanine

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Nucleosides
NH2
O O
N
HN HN CH3
O N
O N O N HO

HO HO O
O O
OH R

OH OH R = OH, Cytidine
R = H, Deoxy Cytidine
Uridine Thymidine

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 NH2 O

N N
N N

H2N N N
N N

HO HO

O O

OH OH R
R
R = OH, Adenosine R = OH, Guanosine

R = H, Deoxy Adenosine R = H, Deoxy Guanosine

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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.
Ferguson’s 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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Ferguson’s 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
N2O Nitrous oxides
∆ Cyclopropan

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

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Intravenous Anesthetics
O

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

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. 33
 O O O

HN N N

O HO HO

HN N N

O OH O
lactim lactam enolate

34
  
Quantitative Structure–Activity
Relationship (QSAR) Studies

INTRODUCTION

The relationship between chemical structure and

biological activity has always been at the center
of drug research. All of the electronic properties
of a drug are determined by the atomic composition,
shape and size of the drug molecule, in other words,
by its chemical structure.
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1. Hansch Approach

• The substituent hydrophobicity constant, based on partition

coefficients-analogous to Hammet constants:

 x  log Px  log PH
• Where x is the substituent in question and P is the n-
octanol-water partition coefficient. Positif π value indicated
increased liphophilicity of the substituent. Since these
values are additive, P values measured on standard
molecules permit prediction of the hydrophobicity of novel
molecules.

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 H
R C N S
CH3
O
CH3
N
O COOH

H2
benzyl penisiline C

H
ampicilline C

NH2

amoxiciline H
HO C

NH2

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π values
P1 = CH3 – (CH2 ) – OH
P2 = CH3-OH
------------------------------
P2 – P1 = π for -CH2-
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 Quantifying Drug Molecule Electronic Properties:
The Hammet Correlations

There have been many attempts to quantify the

electronic properties of drug molecules. Hammet
correlations were among the first to be used and
represent the classical way of quantifying electronic
properties. The Hammet correlations (Hammet,
1970) express quantitatively the relationship
between chemical reactivity and the electron-
donating or electron-accepting nature of a
substituent.

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The Hammet constituent constant (σ)
was originally defined for the purpose of
quantifying the effect of a substituent on
the dissociation constant of benzoic acid.

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 2. The Hammet Correlations

O O
O O
C C
C C
O O
O O

N N
O O O O H O H
O

Fig. Resonance and field effects of the electron acceptor nitro group and the
electron donor hydroxyl group on the stability (and pKa) of the benzoate ion.
Electron acceptors stabilize the anion while electron donors have the opposite
effect, increasing the electron density in the vicinity of the carboxylate ion and
creating on unfavorable ion-dipole interaction.
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 KX
log 
KH
Where Kx is the dissociation
constant of benzoic acid carrying
substituent X; KH is the dissociation
constant of unsubstituted benzoic
acid. 42
Electron attracting substituent

O
such as C , NO2 , NR3
OH

have a positive σ value.

while electron donating substituent ( -OH, -OCH3,

NH2, -CH3) have a negative σ.
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  
 
CF3
COOH Cl Br

0,4 0,8 1,2 1,6

OH
NH2 CH3

 
 
Two-dimensional Craig plot of sigma(σ)substituent constants versus
pi (π) for aromatic substituents. 44
3. Taft steric parameter (Es)

This parameter was defined as the logarithm of the relative rate of the
acid-catalyzed hydrolysis of a carboxymethyl-substituted compound,
using the rate of hydrolysis of methyl acetate as standard:

Esx = log KXCOOCH3 – log KCH3COOCH3

Where X is the molecule in question. With some correction suggested

by other authors, Es has proven to be useful in quite a few structure-
activity correlations.

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The linear correlation (A) show the dose of substituted penicillins curing 50% of
mice infected by Staphyloccoccus aureus, versus the sum of π values of the
substituents

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The parabolic curve (B) is the bactericidal concentration of alifatic
fatty acids versus the partition coffecients
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