ERT 102 ORGANIC CHEMISTRY
BIOPHARMACEUTICALS AND BIOPRODUCTS
LECTURER:
MISS ROZAINI ABDULLAH
PPK BIOPROSES
UNIVERSITI MALAYSIA PERLIS (UNIMAP)
•
A drug is any absorbed substance that changes or enhances a physical or
psychological function in the body.
•
A proprietary name (trade name or brand name) identifies a commercial
product and distinguishes it from other products.
•
Each drug is also given a generic name that any pharmaceutical company
can use to identify the product.
Antibiotic
2
hormone replacement
therapy
New drugs from old poisons
CH3
O
HO
CH3O
O
O
O
N CH3
O
H
N CH3
N CH3
O
H
H
HO
HO
O
morphine
CH3
codeine
heroin
Examples of Natural Products as Leads & Drugs
Cardiac glycosides, morphine, quinine, salicylic acid, taxol,
camptothecin, penicillin, cyclosporin A, warfarin, artemisine….
O
HO
OH
OH
N
H
H
O
H
H
H
H
N
HO
O
O
O
norethindrone
17-ethynylestradiol
R = H: Morphine
R = Me: Codeine
(pain killer)
OH
HO
HO
RO
OMe
HO
H
O
O
OMe
O
(the "Pill"; contraceptive)
OH
Clarithromycin
(antibacterial)
HO
CO2H
O
O
NH2
H H
CO2H
O
N
N
S
O
OH
Clavulanic acid
-lactamase inhibitor)
Ampicillin
(antibiotic)
OH
O
O
N
O
10
N 11
O
8
N
H
N
N 4
O
O
HN
O
7
O
Augmentin
(antibiotic)
N 2
H
1
O
9
3
N
N
6
N
H
N
5
O
O
Cyclosporine A
Naming Drugs
The most accurate names that define their structures. However, these names
are too long and complicated to appeal to the general public or even to the
physicians.
Example:
Generic Name: Conjugated Estrogens
Brand Name : Premarin®
Use: hormone replacement therapy
Source?
morphine
opium poppy (papaver somniferum)
heroin
cocaine
Coca plant
Lead Compounds
•
The goal of the medicinal chemist is to find compounds that have potent
effects on given diseases, with minimal side effects.
•
A naturally occurring drug can serve as a prototype (lead compound).
•
7
Analogs of the lead compounds are synthesized to improve the therapeutic
properties or side effects.
Molecular Modification Improves the Therapeutic
Properties of Cocaine
Local anesthetic, but also affects
on central nervous system (CNS)
8
Retains the local
anesthetic property
without CNS effects
Anesthetics Obtained by Molecular Modification
9
Replacing the ester linkage of procaine with an amide linkage led to
procainamide hydrochloride:
•
•
•
10
Active as a cardiac depressant
Active as a local anesthetic
Used clinically as an antiarrhythmic
Molecular Modification of Morphine
Morphine is widely used analgesic for severe pain (pain killer)
11
•The shape of the morphine molecule is crucial to its
ability to exactly fit into the active site on the receptor - the
'lock-and-key' mechanism.
•The benzene group of the morphine molecule fits snugly
against a flat section of the receptor protein, whilst the
bent neighbouring group of carbon atoms fits into a
nearby groove.
•This allows the positively charged nitrogen atom to attach
to a negatively-charged group on the receptor, so locking
the two molecules together.
Morphine - replacing the -OH group shown in red with OCH3 produces codeine
Replacing the both the red and blue -OH groups with OCOCH3 produces heroin.
Replacing the hydrogen-bonding -OH groups with -OCOCH3 makes heroin
much less soluble in water than morphine, but more soluble in non-polar
solvents, like oils and fats.
Therefore heroin has to be injected directly into the bloodstream, but once
there it can pass rapidly through the blood-brain barrier which normally
prevents the passage of water-soluble and large molecules.
As a result it is much more potent than morphine, but its effect does not last
as long. Again, once the heroin molecule is absorbed into the body, the acetyl
groups are removed, reforming morphine.
Molecular Modification of Codeine
Dextromethorphan is the major ingredient in most cough medicines.
15
Random Screening
In the development of most drugs, the lead compounds
found by screening thousands of compounds randomly.
A random screen, or a blind screen, is a search for a
pharmacologically active lead compound without any
information about what structures might show activity.
The objective of random screening is to recognize the
Effective compound.
16
Serendipitous Discovery of Librium without a
Lead
In 1955 Roche set out to prepare a series of
benzheptoxdiazines as potential new tranquilizer drugs, but the
actual structure was found to be that of a quinazoline 3-oxide.
N
R1
O
N
X
Y
R2
2. 4
N
R1
N+ O
X
R2
Y
2.5
No active compounds were found, so the project was
abandoned
In 1957, during a lab cleanup, a vial containing what was thought to be
the latter compound (X = 7-Cl, R1 = CH2NHCH3, R2 = C6H5) was sent for
testing, and it was highly active.
Further analysis showed that the actual structure of the compound was the
benzodiazepine 4-oxide, Librium, presumably produced in an unexpected
reaction of the corresponding chloromethyl quinazoline 3-oxide with
methylamine.
N
CH 2Cl
N+ O
Cl
H
N
..
CH 3NH2
methylamide
Cl
NHCH 3
CH 2Cl
N + O
An addition
reaction occured
2.6
CH 3NH2
N
Cl
CH 2NHCH 3
N+ O
N
Cl
A substitution
reaction did not
occur
N
NHCH 3
.. CH 2 Cl
N
OH
Cl
NHCH 3. HCl
N+
O-
chlordiazepoxide HCl
2.3
Librium
Structural modification of Librium led to the generation of other tranquilizers:
19
Receptors
•
Many drugs exert their physiological effects by binding to a specific
cellular binding site, called a receptor.
•
A drug interacts with its receptor by hydrogen bonding, electrostatic
attractions, and hydrophobic (van der Waals) interactions.
•
The most important factor in the interaction between a drug and a
receptor is a snug fit.
20
Excess histamine in the body causes the symptoms associated with the
common cold and allergic responses:
Drugs
Interfere with
natural action
of histamine
called
antihistamine
Protonated ethylamino group anchoring molecule to a negatively charge
portion of the histamine receptor.
21
Antihistamines alleviate the action of histamine by binding to the histamine
receptor:
Example :
22
Acetylcholine is a neurotransmitter that enhances peristalsis, wakefulness,
and memory:
Binding acetylcholine-cholinergic
receptor
contribute
the
characteristic loss of memory in
Alzheimer’s disease.
The binding sites of cholinergic
receptors are structurally similar to
the binding sites of histamine
receptors.
The antihistamine diphenhydramine has been used to treat insomnia and
motion sickness.
23
4-Methylhistamine was used as a lead compound to develop antiulcer drugs:
24
When modified compounds are screened, it is possible to find a compound
whose pharmacological activity is completely different from that of the lead
compound:
an antibiotic
25
a drug with
hypoglycemic activity
Molecular modification of promethazine led to the discovery of the tricyclic
antipsychotic drugs:
26
What is Penicillin?
Treatment of bacterial diseases (not viral!)
Prescribed against Gram- positive bacteria
Mostly healing of respiratory tract infections
Drugs as Enzyme Inhibitors
Penicillin destroys bacteria by inhibiting the enzyme that synthesizes bacterial
cell walls:
30
The nitrogen get obtain a proton from an acidic group at the
active site of the enzyme, and the nucleophilic serine residue
will give up a proton.
Bacteria develop resistance to penicillin by secreting penicillinase, which destroys
penicillin:
31
Chemists have developed drugs that inhibit penicillinase:
Peroxyacid
These drugs is given to a patient along with penicillin, the antibiotic is not
destroyed.
The drug that inhibits penicillinase has no therapeutic effect itself, but act s by
protecting a therapeutic drug.
32
Mechanism of Penicillinase Inhibition by
Sulfone
33
•The oxygen atom of the OH group of the peroxyacid is electron deficient and is
therefore an electrophile.
•It accept a pair of electrons from the π bond of the alkene, which causes the week
O-O bond to break.
•The electron from the O-O bond are delocalized.
•The electrons left behind as the O-H bond breaks add to the other sp2 carbon
of the alkene.
Why does sulfone is an effective inhibitor?
Because the reactive amine group does not appear until after the sulfone has
been bound to the enzyme that is to be inactiveted.
When two drugs are given simultaneously to a patient, what happen?
The two drugs used in combination can be equal to, less than, or greater than
The sum of the effect obtained when the drugs are administered individually.
Example:
The sulfone inhibits the penicillinase, so penicillin will not be destroyed and
will be able to inhibit the enzyme that synthesizes bacterial cell walls.
Thank you