Download What is the primary objective of medicinal chemistry ? Which

What is the primary objective of medicinal chemistry ?
Which disciplines are involved ?
The primary objective of medicinal chemistry is the design and
discovery of new compounds that are suitable for use as drugs.
This process involves a team of workers from a wide range of
disciplines such as pharmacy, medicine and other related areas
mainly:
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analytical chemistry, organic chemistry, pharmaceutical
chemistry,
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biochemistry, biology, pharmacology, drug metabolism and
toxicology,
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mathematics, and computing,
In our lectures, we will concentrate on the following main titles:
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Research areas of medicinal chemistry
Factors affecting biological activity of drugs
Drug action
Functional groups (their nomenclature, properties, reactions)
Heterocyclics (their nomenclature and properties)
Stability of organic compounds
Metabolism of organic compounds
(aims, good and bad aspects, metabolic phases, in vitro and in vivo experiments,
metabonates)
Pro-drugs
Structure-activity relationships
Clinical drug development processes
Terminology of medicinal chemistry will be given in all of the lectures
Main research areas of medicinal
chemistry
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Drug synthesis
Structure identification
Drug metabolism studies
Chemical basis of drug bioactivation
Pharmacological activity screening
Sources of drugs
Originally drugs and leads were derived from natural
sources. These natural sources are still important sources
of lead compounds and new drugs, however the majority
of lead compounds are now discovered in the laboratory
using a variety of sources, such as local folk remedies
(ethnopharmacology), investigations into the
biochemistry of the pathology of disease states and highthroughput screening of compound collections,
databases and other literature sources of organic
compounds.
FACTORS ACTING ON THE BIOLOGICAL
ACTIVITY OF A DRUG MOLECULE
I- PHYSICO-CHEMICAL PROPERTIES OF DRUGS
-Solubility
-Acid–Base Properties, Ionization,
-pKa, pH, logP (oil/water partition coefficient)
II-CHEMICAL PROPERTIES OF DRUGS
-Chemical bonds
-Functional Groups
-Heterocyclic rings
-Stereoisomerism
Solubility
A degree of lipid solubility is required to pass
through membranes but if it is too high, it is
trapped in the membrane and become
ineffective. For transportation water solubility is
required.
Acid base properties
Functional groups determine and confer acidity
and basicity on a molecule. Human body is 7075% water meaning that we are dealing with a
dilute solution if we have a drug molecule of 200
M.A. and a dose of 20 mg
pH
solution
1 – 3.5
5.3
6.4
7.4
gastric juice
intestine
saliva
blood
We can determine the ionisation and absorption
site.
Chemical properties
Chemical bonds
If covalent bonds occur between drug and receptor,
it is strong and produce irreversible longer
pharmacological effects.
İf ionic bond occur, it is weaker and has reversible
shorter pharmacological effects.
Properties of functional groups determine
activity, solubility etc. These will be shown later
in detail.
Stereochemistry
Three dimensional structures in space may
affect the pharmacological activity. The isomers
may interact with receptors in different ways.
Racemic mixtures (enantiomers) have
asymmetric carbon atoms (chiral center),
different pharmacological effects, metabolism
and toxicity but same chemical properties.
Receptor
In order for drug molecules to exhibit their
pharmacologic activity, they must interact
with a biologic target, typically an enzyme,
nucleic acid, or excitable membrane or other
biopolymer (RECEPTOR). These
interactions occur between the functional
groups found in the drug molecule and those
found within each biologic target.
Lead Compound
A compound of known pharmacological activity, the lead
related compound is called analogue.
Pharmacophor group
The moiety interacting with receptor and responsible
from biological effect.
Bioisosters
Groups having similar pharmacophores to eliminate side
effects. C=S C=O ; SH, OH, NH2 ;
; O
S
N
Some desirable properties of leads and analogues
• Bioavailability (a fraction of the dose of a drug that is found in
general circulation)
• A molecule mass less than 500
• A calculated value of log P less than 5
• less than ten hydrogen bond acceptor groups (eg. –O- and –N- etc.)
• less than five hydrogen bond donor groups (e.g. NH and OH, etc.)
We will now be revieving functional groups used in medicinal chemistry.
Functional groups have rather than C and H in the molecule and they produce a
Chemical, pharmacological, or toxicological effect in the drug formula.
ALCOHOLS
Any hydroxyl (OH) moiety linked to the saturated C atom forms alcohols. These are
generally polar groups. Alcohols can be used as solvents and as mostly synthetic
intermediates (SIM).
Primary alcohols have 2, secondary alcohols 1 and tertiary alcohols have no H atoms.
Alcohols are named with the name of total hydrocarbone name plus -ole ending or
alkyl name plus alcohol ending:
CH3-OH methanol or methyl alcohol ; C2H5-OH ethanol or ethyl alcohol
R
R
OH
OH
R
OH
R
R
primary
secondary
R
tertiary
Primary alcohols can be oxidized to the
corresponding aldehydes and ketones but
tertiary alcohols not.
OH
H
R
R
OH
R
O
(O)
(O)
aldehyde
Primary alcohol
R
carboxylic acid
R
(O)
OH
O
R
R
secondary alcohol
R
OH
(O)
no reaction
R
R
tertiary alcohol
O
Esterification of alcohol with carboxylic acid is also important
and produces an ester functional group:
R-OH + R-COOH -> R-COOR + H2O
PHENOLS
Phenols have OH groups linked to aromatic ring.
OH
OH
N
ETHERS The oxygene bridge has two carbon moiety in ethers (symmetrical
or asymmetrical)
R-O-R or R-O-R1
Ether is a very inert and non-polar functional group. Ethers can be used as
solvents. Their anesthetic property is known.
Ring ethers are known as epoxydes and these are generally toxic chemicals.
Ethylene oxide
O
Tetrahydrofurane (THF)
O
Ethers are named as follows:
Groups linked to –O- are alphebetically
indicated:
CH3-O-C2H5
C2H5-O-C2H5
C6H5-O-C2H5
ethylmethylether
diethylether
ethylphenylether
ALDEHYDES and KETONES
Carbonyl gropu at the end of carbon system is aldehyde, if the carbonyl group is in the
middle, it is ketone:
R-CHO (aldehyde)
R-CO-R (ketone)
Aldehydes are more reactive than ketones. Their oxidation produces carboxylic acids
(look at former slides)
Ketones can not be oxidized so they can be somehow inert and used as solvents (ie.
acetone)
One of the most important common reactions of carbonyl group is imine formation
which is rather toxic group:
C=O + H2N-R
->
C=N-R + H2O
(This is a reversible reaction and it goes easily back to the corresponding compounds
by hydrolysis)
Ketones can be named by indicating first the group
linked to carbonyl group alphebetically:
CH3-CO-CH2-CH3
Ethylmethylketone
C2H5-CO-C6H5
ethylphenylketone
CH3-CO-CH3
Dimethylketone (ACETONE)
For naming aldehydes, we should know the
names of carboxylic acids (please refer to
carboxylic acids later).
Aldehydes can not be preferred as sovents
because of their lability against oxidation and
other reactions.
Both aldehydes and ketones are used as SIM
Ring ketones are indicated by -one ending
Their substitent name is oxo
O
cyclohexanone
O
2-oxopentane
CARBOXYLIC ACIDS and THEIR DERIVATIVES
-COOH (carboxyl group = carbonyl + hydroxyl)
This group forms a carboxylic acid moiety and it is a polar and reactive group:
H-COOH metanoic acid (formic acid)
CH3-COOH etanoic acid (acetic acid)
CH3-CH2-COOH propanoic acid (propionic acid)
CH3-CH2-CH2-COOH butananoic acid (butyric acid)
CH3-CH2-CH2-CH2-COOH pentanoic acid (valeric acid)
C6H5-COOH (benzoic acid)
O
OH
N
(pyridine-3-carboxylic acid or 3-carboxypyridine)
Corresponding aldehydes are named by eliminating ic acid and
inserting aldehyde suffixes:
H-CHO (formaldehyde)
CH3-CHO (acetaldehyde)
CH3-CH2-CHO (propionaldehyde)
CH3-CH2-CH2-CHO (butyaldehyde)
CH3-CH2-CH2-CH2-CHO (valeraldehyde)
C6H5-CHO (benzaldehyde)
O
H
N
(pyridine-3-carbaldehyde or 3-formylpyridine)
Important reactions of carboxylic acids:
(from acetic acid)
NaOH
CH3-COOH
1
, acid, R OH
NH3 (R)
CH3-COONa (sodium acetate) - a salt
CH3-COOR1 (R1 acetate) - an ester
CH3-CONH2 (R) (acetamide) - an amide
Why are we preparing carboxylic acid derivatives:
• To purify carboxylic acids (salts)
• To increase and/or decrease the polarity
(salts, amides, esters)
• To prepare prodrugs
(salts, amides, esters)
(Acid group is generally not suitable for oral route)
Ring esters are known as «lactones»:
O
O
Ring amides are known as «lactames»:
NH
O
Diamides from diacides are called «imides»:
O
R
O
O
NH
NH
R
O
Important diacids*:
Oxalic acid
Malonic acid
Succinic acid
Glutaric acid
Adipic acid
Pimelic acid
(n = 0)
(n = 1)
(n = 2)
(n = 3)
(n = 4)
(n = 5)
COOH
CH2
COOH
*these names will be required for the important drug molecules later in pharmaceutical
chemistry
To memorize them bear in mind the following words:
oh my such good apple pie