ert 102 organic chemistry biopharmaceuticals and bioproducts lecturer: miss rozaini abdullah ppk...
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ERT 102 ORGANIC CHEMISTRY
BIOPHARMACEUTICALS AND BIOPRODUCTS
LECTURER:MISS ROZAINI ABDULLAH
PPK BIOPROSESUNIVERSITI MALAYSIA PERLIS (UNIMAP)
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• 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 hormone replacementtherapy
New drugs from old poisons
O
HO
HN
HO
CH3
O
O
HN
O
CH3
O CH3
O
CH3
O
CH3O
HN
HO
CH3
codeineheroin
morphine
Examples of Natural Products as Leads & Drugs
Cardiac glycosides, morphine, quinine, salicylic acid, taxol, camptothecin, penicillin, cyclosporin A, warfarin, artemisine….
O
HO
RO
N
R = H: MorphineR = Me: Codeine
(pain killer)
HOH H
OH
H
HOH H
OH
HH
17-ethynylestradiol norethindrone
(the "Pill"; contraceptive)
Clarithromycin(antibacterial)
O
O
O
OHOMeHO
O
O
O
OMe
OH
OHO
N
HOO N
S
O
NH2
CO2H
HH
Ampicillin(antibiotic)
N
O
O
OH
CO2H
Clavulanic acid-lactamase inhibitor)
Augmentin(antibiotic)
NN
O
O
O
N
HN
NNH
HN
N
O
O
O
OO
O
N
O
OH
N
ONH
Cyclosporine A
1 2
3
4
567
89
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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
cocaine
heroinopium poppy (papaver somniferum)
Coca plant
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• 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).
• Analogs of the lead compounds are synthesized to improve the therapeutic properties or side effects.
Lead Compounds
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Molecular Modification Improves the Therapeutic Properties of Cocaine
Local anesthetic, but also affects on central nervous system (CNS)
Retains the localanesthetic
property without CNS effects
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Anesthetics Obtained by Molecular Modification
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Replacing the ester linkage of procaine with an amide linkage led to procainamide hydrochloride:
• Active as a cardiac depressant• Active as a local anesthetic• Used clinically as an antiarrhythmic
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Molecular Modification of Morphine
Morphine is widely used analgesic for severe pain (pain killer)
•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.
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Molecular Modification of Codeine
Dextromethorphan is the major ingredient in most cough medicines.
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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.
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.
No active compounds were found, so the project was abandoned
2.4
NO
N
R2
R1
X
Y
2.5
+-N
N R1
O
R2
X
Y
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
N CH2Cl
OClN
HN NHCH3
OCl
CH2Cl
CH3NH2
NCH2
NNHCH3
Cl
Cl
OH
N
N CH2NHCH3
OCl
..
-+
-+
-+
..
2.6
CH3NH2
N
N
Cl
NHCH3. HCl
O
chlordiazepoxide HCl2.3
+-
Librium
methylamide
An addition reaction occured
An addition reaction occured
A substitution reaction did not occur
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Structural modification of Librium led to the generation of other tranquilizers:
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• 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.
Receptors
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Excess histamine in the body causes the symptoms associated with the common cold and allergic responses:
Protonated ethylamino group anchoring molecule to a negatively charge portion of the histamine receptor.
Drugs
Interfere with natural action of histamine called antihistamine
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Antihistamines alleviate the action of histamine by binding to the histamine receptor:
Example :
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Acetylcholine is a neurotransmitter that enhances peristalsis, wakefulness, and memory:
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.
Binding acetylcholine-cholinergic receptor contribute the characteristic loss of memory in Alzheimer’s disease.
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4-Methylhistamine was used as a lead compound to develop antiulcer drugs:
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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
a drug withhypoglycemic activity
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Molecular modification of promethazine led to the discovery of the tricyclic antipsychotic drugs:
What is Penicillin?Treatment of bacterial diseases (not viral!)Prescribed against Gram- positive bacteriaMostly healing of respiratory tract infections
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Drugs as Enzyme Inhibitors
Penicillin destroys bacteria by inhibiting the enzyme that synthesizes bacterial cell walls:
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.
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Bacteria develop resistance to penicillin by secreting penicillinase, which destroys penicillin:
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Chemists have developed drugs that inhibit penicillinase:
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.
Peroxyacid
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Mechanism of Penicillinase Inhibition by Sulfone
•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 thanThe 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