Drugs – Structure and Properties€¦ · Geometric isomerism . 1. Acid-base properties Most drugs...
Transcript of Drugs – Structure and Properties€¦ · Geometric isomerism . 1. Acid-base properties Most drugs...
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Drugs – Structure and Properties
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Learning outcomes
• At the end of this section the student shall be able to:
– differentiate acidic from basic drugs
– predict ionization of a drug at different pH
– estimate acidity/basicity of a drug solution
– predict solubility, absorption and distribution of a drug at different body compartment
– discuss the effect of acidity, size, shape, and stereochemistry of a drug on its activity
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Physicochemical properties of a drug
A drug molecule is a compound that has the ability to bind specifically to a receptor
It should also be absorbed, distributed, metabolized and excreted by the body
This depends on the physicochemical properties of a drug including
1. Acid-base property
2. Water-lipid solubility
3. Size
4. Steric effect
5. Conformational isomerism
6. Optical isomerism
7. Geometric isomerism
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1. Acid-base properties
Most drugs behave as weak acids or bases in solution and might be ionised at physiological pH (pH = 7.4)
Ionization of a compound plays a major role in controlling:
Absorption and transport to site of action
Binding of a compound at its site of action
Elimination of compound
• Biliary and renal excretion
• CYP P450 metabolism
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Acid-base chemistry • Acidity or basicity of a compound is estimated by
measuring its dissociation in water and is expressed using pH
An acidic solution has pH < 7
A basic solution has pH > 7
For pure water pH = 7
• The strength of an acid or bases is expressed using pKa
– The lower the pKa the stronger the acid
• Note: pKa of a basic compounds is the value of its conjugate acid.
– Thus for basic compounds the higher the pKa the stronger the base.
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Acid-base properties of drugs
• For a drug molecule to be an acid or a base depends on the nature of its functional groups.
– A drug molecule with a functional group that can donate hydrogen ion (H+) will be an acid
– A drug molecule with a functional group that can accept hydrogen ion (H+) will be a base
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Common acidic functional groups
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Common basic functional groups
Note: pKa of a drug does not tell if the drug will behave as an acid or a base in a solution. e.g amines (pKa ~ 9) are basic while phenols (pKa ~ 10) are acidic
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Common neutral functional groups
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Acidity and basicity of salts • When a salt is hydrolyzed in water it dissociates
completely to give anion and cation
• The resulting solution can be basic or acidic depending on the constituents of the salts:
Salt Acid/base property Example
strong acid + strong base neutral NaCl
strong acid + weak base acidic NH4Cl
weak acid + strong base basic CH3COO-Na+
weak acid + weak base neutral CH3COO-NH4+
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Henderson-Hasselbalch equation
Henderson-Hasselbalch equation
For a dissociation of a weak acid
In general the degree of dissociation of a weak acid in water can be determined using the Henderson-Hasselbalch equation. Which is derived as follows:
• This equation is also used for a weak base BUT the degree of ionization will be (Recall for a basic compound the pKa refers to its conjugated acid)
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Acidic/base Dissociation • Dissociation of acidic/basic molecule depends on their
strength (i.e. pKa) and is affected by pH of the medium
• pH = pKa compound is approximately 50% ionized
• pH < pKa + 1 compound is approximately fully unionized
• pH > pKa + 1 compound is approximately fully ionized
• Recall: for a basic compounds the pKa is the value of its conjugate acid.
– Thus in the intestine (pH = 7-8) weak acids will be ionized while weak bases will be neutral
– Hence: weakly acidic oral drugs will have reduced absorption
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2. Water-Lipid solubility
A successful drug must exhibit solubility to some extent in both water and lipid environments
Because:
– extremely water-soluble drugs may be unable to cross lipid barriers
– very lipophilic drugs will be trapped in lipid and will not be able to reach their target quickly
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Predicting solubility • A drug molecule will be soluble in water or in
nonaqueous lipid solvent
• A molecule that dissolves in water is hydrophilic (lipophobic)
• A molecule that dissolves in lipid solvent is lipophilic (hydrophobic)
• Solubility in water or lipid depends on functional groups and occurs via intermolecular bonds including
– van der Waals forces – dipole-dipole bonding – ionic interaction – ion-dipole bonding
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Predicting solubility Bond Description Energy
kcal/mol Solubility
(Water/lipid) Functional group
Comments
van der Waals forces electrostatic interaction due to distortion of covalent bonds
0.5 – 1.0 lipid
Hydrocarbons distance temperature-dependent
Dipole-dipole occurs between permanent dipoles (e.g Hydrogen bond)
1 – 10 water Polar groups (e.g. alcohol, ketone, thiols, acid, ethers, amines)
distance temperature-dependent
Ionic interaction attraction between a negative and a positive charged atom
5 water Acid, bases, salts
least affected by distance and temperature
Ion-dipole when an ion pair attract a dipole or induce a dipole in a neighboring nonpolar molecule
1 – 7 water Polar groups (e.g. alcohol, ketone, thiols, acid, amines)
insensitive to temperature or distance
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Intermolecular bonds
van der Waals also called induced dipole-induced dipole interaction
Dipole-dipole Ionic interaction
Ion-dipole R4N
+------NR3
ion-induced dipole K-I -------I-I
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Predicting solubility
• Many drugs are poly-functional and can make all types of intermolecular interactions
• Water/lipid solubility can be predicted by weighing the contribution of each functional group in the compound
• There are two approaches for that: 1. Empirical: based on carbon solubilizing
potential of functional groups
2. Quantitative: calculating logP (log of partition coefficient)
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Predicting water solubility – Empirical approach
• A molecule is water soluble if the solubilizing potential of FG exceed the total number of carbon atoms present.
• Note: ionized functional group has solubilizing potential of 20 to 30 carbon atoms.
Water solubilizing potential of organic functional
groups in mono- or polyfunctional molecules
No of carbon atoms in a
molecule
Functional group Monofuntional Polyfunctional
Alcohol 5 – 6 3 – 4
Phenol 6 – 7 3 – 4
Ether 4 – 5 2
Aldehyde 4 – 5 2
Ketone 5 – 6 2
Amine 6 – 7 3
Carboxylic acid 5 – 6 3
Ester 6 3
Amide 6 2 – 3
Urea, carbonate,
carbamate
2
Water solubility is defined as >1% solubility
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Predicting water solubility – Quantitative approach
In this approach water/lipid solubility is estimated by measuring partition coefficient (P)
Partition coefficient (P) is the ratio of concentrations that a substance partition itself between two immiscible liquids
𝑃 = [Drug]org
[Drug]aq
It is usually expressed as LogP
If LogP < +0.5 a compound is water soluble
If LogP > +0.5 a compound is water insoluble
If a compound ionizes during experiment the partition coefficient will be apparent
𝑃𝑎𝑝𝑝
= 𝑃 × 𝑓𝑢𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑
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Determination of LogP
• LogP can be determined by two methods:
1. Experimental method using chromatography
or the shake-flask method
– Experimentally measured logP are referred as MlogP
2. Summation of hydrophobic-hydrophilic
constants (π) assigned to different functional groups
– Calculated LogP are referred as ClogP
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Calculating logP using π values
• LogP are calculated using the equation
logP = π (π values are the contribution of each functional group)
FG Symbol πaromatic πaliphatic
floro F 0.13 -0.17
chloro Cl 0.76 0.39
bromo Br 0.94 0.60
iodo I 1.15 1.00
alkane C 0.50 0.50
phenyl C6H5 2.13 2.13
acid COOH -0.32 -1.26
1o amide CONH2 -1.49 -1.71
amide NHCOR -0.97 -0.97
ketone COCH3 -0.55 -0.71
nitrile CN -0.57 -0.84
alcohol OH -0.67 -1.12
ether OCH3 -0.02 -0.47
ester COOCH3 -0.64 -0.91
1o amine NH2 -1.23 -1.19
2o amine NHR 0.47 -0.67
3o amine N(CH3)2 -0.18 -0.32
nitro NO2 -0.28 -0.85
IMHB IMHB 0.65 0.65
The π values are obtained as: π = logPx – logPH
where, logPx is value for derivative, logPH is value for parent compound
Note: π is +ve for lipophilic group π is -ve for hydrophilic group
Note: LogP also depends on other factors such as the capacity of a group to form intramolecular hydrogen bond (IMHB)
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logP Values for salicylic and p-Hydroxybenzoic acid
Salicylic acid p-Hydroxybenzoic acid
Fragment Value Fragment Value
Phenyl +2.13 Phenyl +2.13
OH -0.67 OH -0.67
COOH -0.32 COOH -0.32
IMHB +0.65
LogP +1.79 +1.14
Prediction Water insoluble Prediction Water insoluble
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Importance of LogP Lipophilicity (LogP) is used to predict: Solubility, Absorption,
Membrane penetration, Plasma protein binding, Distribution, Target recognition, CYP450 interactions etc.
logP Binding to target
Aqueous solubility
Binding to metabolising enzymes
Absorption through membrane
Binding to blood proteins
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Solubility of salts
• Solubility of organic salt in water depends on the degree of its dissociation
– Salt of strong acid/strong base > strong acid/weak base > weak acid/weak base
• Also on molecular weight, high molecular weight salts are less soluble in water
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Water solubilities of different salt forms of some drugs
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0
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Molecular Weight
fre
qu
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cy %
3. Molecular size Molecular size is one of the most important
factors affecting biological activity
Most of the oral drugs have molecular weight < 500
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4. Steric Effects
Bulky substituent appended close to pharmacophore may impede the geometry of interaction between a drug and its receptor
Steric effect is estimated by The Taft steric parameter (Es)
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5. Conformational isomerism Conformational flexible drugs are able to bind to different
subtypes of a receptor.
For example, acetylcholine exhibits both muscarinic and nicotinic activity.
Flexible molecules have increased likelihood of drug toxicity due to their ability to interact with undesirable receptor sites
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6. Optical isomerism Only one of the
enantiomers will have the maximum affinity to the receptor.
– The better fitting enantiomer is called the eutomer,
– the lower affinity is called the distomer.
– eudismic index: The ratio of activity of the eutomer and distomer is expressed as:
A
B
C
D
Drug
Biomolecular target
Desired responce
D
B
C
A
No desired resonceSide effects??
EI = log affinityEu – log affinityDist
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Stereoisomers and Pharmacological Activity Pharmacological activity Example
Both show same type and
potency The R and S isomers of chloroquine
Show activity of same
type but one is weaker
Oestrogenic activity of E –diethylstilbestrol is only 7%
that of Z-isomer
Show activity of a
different type
S-Ketamine is an anaesthetic but R-Ketamine is a
psychotic
One active the other
inactive S--Methyldopa is a hypertensive but R is inactive
Same activity but different
side effects
Thalidomide: both R & S isomers are sedative but S is
also teratogenic
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7. Geometric isomerism
the Cis/Trans (E/Z) isomers of a drug will have different binding affinity to the same receptors
For examples: – the Z isomers of antipsychotic drugs, thiothanxenes
are several times more active than their E isomers
– cis-diethylstilbestrol has only 7% of the oestrogenic activity of trans- diethylstilbestrol
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Lipinski’s rule of five
Druggable molecule should possess these characteristics:
– A molecular weight of less than 500
– A logP value of less than 5
– Few than 5 H-bonding donors (Sum of NH and OH)
– Less than 10 H-bonding acceptors (Sum of N and O)