Medicinal Chemistry 2

Drug Structure and Solubility

Dr. Friardi, Apt
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 TOPIK
• INTRODUCTION
• CARDIOVASKULAR DRUGS
• HORMON
• S A R Steroidal Hormone

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 Drug Design:
Functional groups / Pharmacological Activity

Structure - Mechanism of action

(Interaction with target)

Structure - Physiochemical properties (Bioavailability etc)

• Acid / base properties
• Water solubility
• Partition coefficient
ADME
• (Crystal structure)
• Stereochemistry

Absorbtion. Distribution, Metabolism, Excretion

(ADMET, ADMEtox)

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 1- Acidity and Basicity
Acidic and/or basic properties of OMAs are important in both:
1- Pharmaceutical phase (dosage formulation, etc.) and
2- Pharmacological phases (disposition, structure at target site, etc.).

The three aspects of acid-base chemistry:

(1) Definitions
(2) Recognition of acidic or basic organic functional groups and
(3) An estimation of the relative acid/base strength of these groups.

Definitions:
Acid: An organic compound containing a functional group that can donate a proton
(H+)
Base: An organic compound that contains a functional group that can accept a H+ 8
Structure - Physiochemical properties

• Acid / base properties

Human body: ca 75% water
pH blood ca 7.4 (physiolog. pH)
pH stomach 1 - 3.5
pH duodenum ca. 4
pH urine ca. 6

Identification of acidic / basic functional groups

pKa determines degree of ionization different places in the body

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 2- Recognition of acidic or basic organic functional
groups
1- Common acidic organic functional groups
◙Carboxylic acid (-COOH)
◙Phenol (Ar-OH)
◙Sulfonamide (R-SO2NH2)
◙Imide (R-CO-NH-CO-R)
◙-Carbonyl group (-CO-CHR-CO-)
O +
O
+ H3O
+
R SO2 NH2 + H2O R SO2 NH- + H3O
+ H2O R C
R C -
O
O H Sulfonamide
Carboxylic acid
O O
O O- R
H R -
R + H2O R + H3O
+
N H + H2O
N + H3O+
R R
O O
Phenol
Imide
+ NH2
NH3
+
R + H2O R + H3O

Anilinium cation

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 2-Recognition of acidic or basic organic functional
groups(cont)

2- Common basic organic functional groups

◙Aliphatic 1º (R-NH2), 2º (R2NH) and 3º (R3N)-amines

◙Heterocyclic amines
◙Aromatic amines (Ar-NH2)
R NH2 NH3 +
R
R N + H3O+ R N+ H+ H2O + H3O+ + H2O
R R
Aliphatic amines Aromatic amines

+ H3O+ + H2O
N NH
N N+
N N
Heteroaromatic amines R Pyridine H Imidazole
Piperidine

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Estimation of the Relative Acid/Base Strength

The following chart is comparing acid/base strengths:

INCREASEING ACIDITY
+
ACIDS H2SO 4, HCl, HNO 3, H3O , RCO 2H, ArOH, RSO 2NH2, CONHCO , H2O, ArNH2, RNH2, NaOH/KOH BASES

INCREASING BASICITY

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Acidic and Basic Functional Group - Salt
Formation
Salt: is the combination of an acid and a base
All salts are strong electrolytes (with few exceptions: mercuric and cadmium
halides and lead acetate)
The salt form of the drug is more soluble than its parent molecule
Drug salts can be divided into two classes:
1)Inorganic salts: are made by combining drug molecules with inorganic
acids and bases, such HCl, H2SO4, KOH and NaOH. Inorganic salts are
generally used to increase the aqueous solubility of a compound
2)Organic salts: are made by combining two drug molecules, one acidic
and one basic. The salt formed by this combination has increased lipid
solubility and generally is used to make depot injections (e.g. procaine
penicillin).
Sodium salt formation from carboxylic acid:
- +
RCOOH + NaOH RCOO Na + H2O

+ -
R3 N + HCl R3NH Cl
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Hydrochloric salt formation from an aliphatic amine

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2- SOLUBILITY OF ORGANIC MEDICINAL AGENTS
Importance of solubility:

(1) Formulation of the drug in an appropriate dosage

form and
(2) Bio-disposition: Disposition of OMAs in the living
system after administration (absorption, distribution,
metabolism, and excretion).
The solubility expression: in terms of its affinity/philicity or
repulsion/phobicity for either an aqueous (hydro) or lipid (lipo)
solvent.

♣hydrophilic....................water loving
♣lipophobic.....................lipid hating
♣lipophilic.......................lipid loving
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♣hydrophobic..................water hating
2- SOLUBILITY OF ORGANIC MEDICINAL AGENTS

Majority of OMAs possess balanced solubility (have

some degree of solubility in both aqueous and lipid
media).

Because there is a need for OMAs to move through

both aqueous (plasma, extracellular fluid, cytoplasm,
etc.) and lipid media (biologic membranes) in the
biological system.

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 Structure - Physiochemical properties
• Acid / base properties
• Water solubility Ionisation -permanent charge
-acid / base properties

Hydrogen bonds

Ion - dipole bonds Intramoleculare interact. reduce water sol.

+ +
H H
+ O -
O
- O H H
H H + H
O
R N H
CO2
H R O
R Strong intramolec interact.
Acidic form of amines Basic form of carboxylic acid NH3
(carboxylate)

O
H H

Salts between weak organic acids and weak organic bases does not dissolve well in water

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The more H-bonds possible - the more water sol.

H H
O O H H
H O
H

Alchohol O 3 H-Bonds H H
R H
Primary amine R N H O
3 H-Bonds
O H
H H
H H
O
H H
O O
H H

Aldehyde / ketone O 2 H-Bonds

R' H
R R' Secondary amine R N H O
2 H-Bonds
H

H H H H
O O O
H H
R'
Ester O 3 H-Bonds 1 H-Bonds
Secondary amine R N R''
R
R O
H H
H H O
O

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 Structural features of drugs and their
pharmacological activity

Stereochemistry: Space arrangement of the atoms or three-

dimensional structure of the molecule.

Stereochemistry plays a major role in the pharmacological properties

because:

(1) Any change in stereospecificity of the drug will affect its

pharmacological activity
(2) The isomeric pairs have different physical properties (partition
coefficient, pka, etc.) and thus differ in pharmacological activity.

The following steric factors influence pharmacological activity:

● Optical and geometric isomerism
● Conformational isomerism
● Isosterism and bioisosterism 20
 Structural features of drugs and their
pharmacological activity

I-Optical and geometric isomerism and pharmacological

activity

Optical isomers are compounds that contain at least one chiral

carbon atom or are compounds that differ only in their ability
to rotate the pollarized light.

The (+) or dextrorotatory: isomer rotates light to the right

(clockwise). The (-) or levorotatory: isomer rotates light to the
left (counterclockwise).

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 I-Optical and geometric isomerism
and pharmacological activity

CH3 CH3
H H CH3
H3C
OH
OH
2-Hydroxybutane enantiomers (mirror images can not superimposed)

Enantiomers (optical isomers) can have large differences in potency,

receptor fit, biological activity, transport and metabolism.
For example, levo-phenol has narcotic, analgesic, and antitussive
properties, whereas its mirror image, dextro-phenol, has only
antitussive activity.

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I-Optical and geometric isomerism and pharmaco-
logical activity
Geometric isomerism (cis-trans isomerisms).
Occur as a result of restricted rotation about a chemical bond, owing to
double bonds or rigid ring system in the molecule.
They are not mirror images and have different physicochemical properties
and pharmacological activity. Because different distances separate the
functional groups of these isomers.
They generally do not fit to the same receptor equally well and if these
functional groups are pharmacophores the isomers will differ in biologic
activity.
For example, cis-diethylstilbestrol has only 7% of the oestrogenic activity of
trans- diethylstilbestrol
OH

HO OH HO 23

Cis-diethylstilbestrol Trans -diethylstilbestrol

 II- Conformational isomersim and
pharmacological activity
Conformational isomersim is the non-identical space arrangement of atoms
in a molecule, resulting from rotation about one or more single bonds.
Almost every drug can exist in more than one conformation and thus the drug
might bind to more than one receptor but a specific receptor site may bind
only to one of many conformations of a drug molecule.
For example, the trans conformation of acetylcholine binds to the
muscarinic receptor, where as the gauche conformation binds to the
nicotinic receptor.

+ +
N (CH3) 3 N (CH3) 3

H H H H
H H
H OAc
OAc H
Trans Gauche
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Conformations of acetylcholine