Professional Documents
Culture Documents
Medicinal Chemistry-I: Dr. Firoj Ahmed Professor Department of Pharmaceutical Chemistry University of Dhaka
Medicinal Chemistry-I: Dr. Firoj Ahmed Professor Department of Pharmaceutical Chemistry University of Dhaka
Chemistry-I
Dr. Firoj Ahmed
Professor
Department of Pharmaceutical
Chemistry
University of Dhaka
Introduction
Medicinal chemistry is a chemistry-based
discipline, involving aspects of biological, medical
and pharmaceutical sciences.
It is concerned with the invention, discovery,
design, identification and preparation of biologically
active compounds, the study of their metabolism,
the interpretation of their mode of action at the
molecular level and the construction of structureactivity relationships (SARs).
In particular, Medicinal chemistry also involves
the discovery of new chemical entities for the
treatment of diseases and the systematic study of
the structure-activity relationships of the active
compounds.
Introduction
Such studies provide the basis for development of
better medicinal agents from lead compounds
found via random screening, systematic
screening and rational design.
Lead compounds
A lead compound is:
A compound from a series of related compounds
that has a desired biological activity.
This molecule can be characterized, and modified
to produce another molecule with a better profile.
A lead compound is a first foothold on the drug
discovery ladder
It takes much more effort to make a lead
compound into a drug candidate
Drug
Drug is any substance presented for treating, curing
or preventing disease in human beings or in animals.
It may also be used for making a medical diagnosis
or for restoring, correcting, or modifying physiological
functions.
Excellent analgesic
Addictive, tolerance
Respiratory depression
Barbiturates
Surgery
Depends on:
Dosage
Almost anything in excess will be toxic
Chronic exposure
Measure of safety of drug = therapeutic
index
Heroin
Diamorphine
One of the best painkillers (hero)
1898: on market
1903: withdrawn (addictive properties)
Today: still used
Therapeutic index
Measure of a drugs beneficial effects at low
dose vs. harmful effects at high dose
Comparison of dose levels which lead to toxic
effects to dose levels which lead to maximum
therapeutic effects
High therapeutic index = large margin of
safety
Marijuana = 1000
Alcohol = 10
Does not take chronic use into account
Classification of drugs
Four main groups (overlap)
1. By Biological Effect
Analgesics, anti-asthmatics, antipsychotics,
etc.
Large and varied assortment of drugs
Many mechanisms of action
2. By Chemical Structure
Penicillins, opiates
Common skeleton
Functions similar or different
Classification of drugs
3. By target system
1. Antihistamines
2. Affect a target system (synthesis, release,
receptor)
3. Variety of structures due to large number of
stages in system
Salix alba
salicin
OH
1. Hydrolysis
2. Oxidation
OH
Salisylic acid
- more effective
- no bitter taste
- gastric bleeding
OH
Ac2O
(1883: Bayer)
Ac
O
Quinine
Cocaine
O
Anesthetic in dentistry
Addiction:
Isolated 1880s
Procaine
O
N
O
NH2
Causative agents of
TB, cholera, and
anthrax.
Nobel Prize-1905
principles of
vaccination,
microbial
fermentation and
pasteurization;
Germ theory of
diseases
by
investigating
Drug Discovery
Morphine
Analgesic
Addiction
Codeine
Antitussiv
e
Addiction
Thebaine
Devoid of
activity
Choosing a Disease
Pharmaceutical
companies
are
commercial
enterprises
Companies will tend to avoid products with a small
market
Companies will also avoid products that would be
consumed by individuals of lower economic status
Most research is carried out on diseases which
afflict
first
world
countries:
(e.g.
cancer,
Drugs
effecting
Agonist/Antagonist
Receptor
Drug
on
receptors
NH2
O side effects
Exploitation of
O
sulphanilamide
H N
2
sulphanilamide
(anantibacterialwiththesideeffectof
loweringglucoselevelsinthebloodandalso
diureticactivity)
(anantibacterialwiththesideeffectof
loweringglucoselevelsinthebloodandalso
diureticactivity)
O
NH
NH
mide
NH2
(anantibacterialwiththesideeffectof
O agent with sideAntibacterial
loweringglucoselevelsinthebloodandalso
S NH2
diureticactivity)
sulphanilamide
effects
of lowering blood
H2N
lowerbloodglucoselevels.Usefulinthetreatment
ofTypeIIdiabetes.)
Cl
NH
S O
H2N
O
Chlorothiazide
NH
tolbutamide
beenoptimizedtoonly
els.Usefulinthetreatment
(acompoundwhichhasbeenoptimizedtoonly
O
H2N
Cl
Cl
NH
S
O
Chlorothiazide
(acompoundwhichhasbeenoptimizedtoonlydisp
N
activity.)
(acompoundwhichhasbeenoptimizedto
activity.)
NH2
N(CH3)2
HO
H3C
N
H
N
H
ydroxytryptamine(5HT)
nin(anaturalneurotransmitter
5Hydroxytryptamine(5HT)
edincertainneuronsintheCNS)
Serotonin(anaturalneurotransmitter
synthesizedincertainneuronsintheCNS)
H
N
H3C
S
O
H
N
S
O
Sumatriptan(Imitrex)
Sumatriptan(Im
Usedtotreatmigrainheadaches
knowntobea5HTUsedtotreatmigrain
1agonist
knowntobea5HT
O
N
N
NH
S
O
Viagra
viagra
Structure-Activity-Relationships
(SARs)
Structure-Activity-Relationships
(SARs)
Pharmacophore
The pharmacophore is the precise section of the
molecule that is responsible for biological activity
Pharmacophore
This may enable one to prepare a more active
molecule
This may allow the elimination of excessive
functionality, thus reducing the toxicity and cost of
production of the active material
This can be done through synthetic modifications
Example: R-OH can be converted to R-OCH3 to see if
O-H is involved in an important interaction
Example: R-NH2 can be converted to R-NH-COR to
see if interaction with positive charge on
protonated amine is an important interaction
Metabolism of Drugs
The body regards drugs as foreign substances, not
produced naturally.
Sometimes such substances are referred to as
xenobiotics
Body has goal of removing such xenobiotics from
system by excretion in the urine
The kidney is set up to allow polar substances to
escape in the urine, so the body tries to chemically
transform the drugs into more polar structures.
Random Screening
The lead compound for the development of most drugs
is found by screening thousands of compounds randomly
an antibiotic
a drug with
hypoglycemic activity
penicillinase
penicillinase
penicillinase
Bioisosteric replacements
Bioisosteric groups (bioisosteres) are substituents or
functional groups with related physical (or chemical)
properties that give rise to similar biological
properties in a compound.
The purpose of making an isosteric replacement is
to find enhanced biological (i.e. greater potency,
less toxicity etc.) and / or physical properties in a
compound, but without making significant changes
to the chemical structure. Isosteric replacements
may modulate molecular size, conformation, Hbonding, pKa, solubility and stability etc.
Bioisosteric replacements
Bioisosteres - examples
Making isosteric replacements were key steps in the
development of the H3-(histamine) receptor antagonist
cimetidine (7) from the initial starting point of
burimamide (1).
Analogues
Analogue design is an alternative to high-throughput
screening (and the other methods discussed) for
discovering a new lead, especially against a known
drug target.
Analogues can be compounds that either:
A. exhibit chemical and pharmacological
similarities, and these may be referred to as direct
analogues;
B. have chemical similarity, but which show
unexpected pharmacological profiles - structural
analogues;
C. exhibit pharmacological similarity but have distinct
chemical structures - functional analogues.
For structural
analogues
compounds are of no
use unless they have
an
alternative biological
activity. For example:
Functional Analogues
How can functional analogues be designed (discovered
in a nonrandom fashion)? The central core of a drug
molecule, the scaffold, may be modified quite
drastically to produce a functional analogue if the
essential activity-determining groups of the drug are
retained.
Identification of a pharmacophore
We have defined a lead compound as a compound
from a series of related compounds.... The question
is therefore posed what are the essential structural
elements for biological activity?
Prodrugs
A prodrug is drug which is given (taken) in an inactive form. Once
administered,the prodrug is metabolized by the body into the
biologically active compound. Prodrug strategies are used to
overcome a variety of problems by:
1. altering solubility
Making a compound either more or less soluble may assist in
achieving the
desired formulation
2. improving membrane permeability
Absorption into a cell means crossing a hydrophobic cell
membrane. If a drug is too polar drugs it may not pass the
membrane, but too non-polar and it may not come back out!
3. Slow release of the active agent
If a drug is eliminated from the body quickly then an effective
dosage cannot be sustained. Slow release of the active agent by
controlled release from a prodrug allows a more controlled dosage
of the active being released into the body.
4. Masking drug toxicity or side effects
Many anticancer agents are cytotoxic, but it is the cancerous cells
only which we want to kill. Masking toxicity can be achieved by
Prodrugs - examples
1. The antibiotic chloramphenicol is very bitter, but the
palmitate ester does not get absorbed by the tongue so
much when taken orally and so is more palatable. The
succinate ester on the other hand makes it more soluble
making IV formulation more effective. Once absorbed the
esters are quickly hydrolysed.
Drug-receptor Interaction
The ability of a drug to get bound to a receptor is termed as the affinity of the drug for the receptor.
The receptors are also dynamic in nature and have a special chemical
affinity and structural requirements for the drug. Thus, affinity
represents kinetic constants that relate to the drug and the receptor.
The drug elicits a pharmacological response after its interaction with
the receptor.
A given drug may act on more than one receptor differing both in
function and in binding characteristics (non-selective drugs).
There are also many factors effect changes in receptor concentration
and/or affinity.
A drug, which initiates a pharmacological action after combining with
the receptor, is termed agonist.
Drugs which binds to the receptors but are not capable of eliciting a
pharmacological response produce receptor blockage, these
compounds are termed antagonists.
84
86
CH3
H
OH
CH3
H
CH3
OH
2-Hydroxybutane enantiomers (mirror images can not superimposed)
HO
OH
Cis-die thylstilbestrol
HO
Trans -die thylstilbestrol
88
(CH3) 3
H
H
OAc
Trans
N
H
(CH3) 3
H
OAc
H
Gauche
Conformations of acetylcholine
89
N= N+ O) ;
CH3
CH2 CH3
CHO CH2 CH2
CH3
CH2 CH3
Compound A has twice the activity of C, and many times greater than B
91