Download Medicinal Chemistry - Millennium Organization

Lecture 1
Medicinal Chemistry 1
PC 509
Prof. Dr/ Ghaneya Sayed Hassan
[email protected]
1
Weighting of Assessments
2
Final-term Examination
Oral Examination
Two Practical Examinations
Tutorials
50 Marks
15 Marks
30 Marks
5 Marks
Total
(100 Marks)
Subject
Lecturer name
hours
Introduction
β- lactame Antibiotics
Non β-lactame Antibiotics
Sulfonamides
Prof.Dr. Ghaneya
8
Metabolism
Prof. Dr. Hassanein
5
Physicochemical parameters
Anticancer
Antiviral
Antifungal
Dr. Riham
6
Antiprotozoal
Antimycobacterial
Antimalarial
Antiinfective
Dr. Essam
5
Total
3
Course Coordinator
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4
Section
No.
Date
1
10/10
Determination of LogP
2
17/10
Determination of pKa
3
24/10
Calculation of π and σ constants + Revision
4
31/10
Exam 1
5
7/11
Hydrogen Peroxide + Nalidixic acid
6
14/11
I.N.H + Resorcinol
7
21/11
Chlorobuanol + Zinc in Prisoline
8
28/11
Tincture Iodi + Busulfan
9
5/12
Sulfamethoxazole and Trimethoprim + Povidone
Iodine
10
12/12
Ampicillin + Cyclophosphamide + Revision
11
19/12
Exam 2
Content
Distribution of Students in Labs
Course Code: 509
(2015 -2016)
Building
C
J
5
Lab
8-10
10-12
‫أ السابع‬
C/721
1-25
171-195
‫ب السابع‬
C/719
26-50
196-220
‫ج السابع‬
C/712
51-75
221-245
‫د السابع‬
C/710
76-100
246-270
‫أ فوق‬
J/101
101-135
271-305
‫ب فوق‬
J/102
136-170
306-340
Introduction
to medicinal
chemistry
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Medicinal chemistry and pharmaceutical chemistry are disciplines at
the intersection of chemistry ,especially synthetic organic chemistry,
and pharmacology and various other biological specialties, where
they are involved with design ,chemical synthesis and development for
market of pharmaceutical agents, or bio-active molecules )drugs)
Medicinal Chemistry
Pharmaceutical Chemistry
Medicinal Chemistry is more related
to the molecular interactions of drugs
and e.g. receptors and the
development of new drugs including
the extensive field of computational
chemistry.
Pharmaceutical Chemistry is not "limited to the
discovery of new pharmaceutical agents."
Pharm.Chem. also includes the synthesis and
analysis of existing drugs and all kinds of
properties (chemical, physicochemical) and
effects (pharmacological, toxicological, ...) of
drugs - a very broad field.
Medicinal Chemistry is the science of Pharmaceutical Chemistry is the same plus the
design and chemical synthesis
science of pharmaceutical and biomedical
focusing mainly on small organic
analysis to the synthesized agents.
molecules and their development of
pharmaceutical agents, or bio-active
7molecules (drugs).
Medicinal chemistry involves the application of a
number of specialized disciplinary approaches all
focused on the ultimate goal of drug discovery .
The techniques and approaches are applied by medicinal
chemists towards drug discovery:
chemical biology, synthetic organic chemistry,
combinatorial (bio)chemistry, mechanistic enzymology,
computational chemistry, chemical genomics, and highthroughput screening
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Medicinal chemistry is integrated with pharmacology to
present a coherent picture of the principles of drug
action. Pharmacology mainly deals with drug action at
the cellular, tissue/organ and organism levels.
Medicinal chemistry focuses on the molecular aspects of
drug action:
1) interactions with the drug targets from both the drug
and the target point of view.
2) the relationship of drug chemical structure to drug
action (SAR).
3) the effects of metabolism on the drug structure and
hence its action.
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Medicinal Chemistry is the science, which deals with the discovery and design
of new and better therapeutic chemicals and development of these chemicals
into new medicines and drugs.
Design and synthesis of new drugs which aimed to be
1- more active, 2- more selective, 3- with low toxicity.
Generally Medicinal Chemists can:
• Make new compounds
• Determine their effect on biological processes.
• Alter the structure of the compound for optimum effect and minimum side
effects.
• Study uptake (absorption), distribution, metabolism and excretion of drugs
(ADME profile).
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Design and synthesis of new drugs
aimed to
be
more
active
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more
selective
low
toxicity
Pharmacokinetic (ADME) properties
to study what the body affect to drug
It must be for medicinal chemist to study drug absorption,
distribution, metabolism, elimination at an early stage.
Pharmacodynamic properties
to study what the drug affect to the body
The study of the physiological response, mechanism of drug
action and dose response curve.
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What are drugs and why do we
need new ones?
• Drugs are defined as chemical substances (natural,
semi-synthetic or synthetic) that are used to prevent
or cure diseases in humans, animals and plants.
• Drugs act by interfering with biological processes, so
no drug is completely safe.
• Drug resistance or tolerance (tachyphylaxis) occurs
when a drug is no longer effective in controlling a
medical condition.
• The development of an enzyme that metabolises the
drug is a relatively common reason for drug
resistance.
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Drug Classification
Pure organic compounds are the chief source of agents for the cure,
mitigation or the prevention of disease.
These remedial agents could be classified according to their origin:
• Natural compounds: materials obtained from both plant and
animal, e.g. vitamins, hormones, amino acids, antibiotics, alkaloids,
glycosides…. etc.).
• Synthesis compounds: either pure synthesis or synthesis naturally
occurring compounds (e.g. atropine, steroids and chloramphenicol) to
reduce their cost.
• Semi-synthesis compounds: Some compounds either can not be
purely synthesized or can not be isolated from natural sources in low
cost. Therefore, the natural intermediate of such drugs could be used
for the synthesis of a desired product (e.g. semi synthetic penicillins).
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Drug Classification
Drugs can treat different types of diseases:
1-Infectious diseases: Born (transmitted) from person to
person by outside agents, bacteria (pneumonia, salmonella),
viruses (common cold, AIDS), fungi (thrush, athletes foot),
parasites (malaria)
2-Non-infectious diseases: disorders of the human body
caused by genetic malfunction, environmental factors, stress,
old age etc. (e.g. diabetes, heart disease, cancer. Haemophilia,
asthma, mental illness, stomach ulcers, arthritis).
3-Non-diseases: alleviation of pain (analgesic), prevention of
pregnancy (contraception) , anesthesia.
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Drug Classification
Since there is no certain relation between chemical structure and
pharmacological activity therefore, it would be unwise to arrange all
drugs on the basis of their structures or origin.
Thus, it is better to arrange the drugs according to their medicinal
use.
Drugs can be classified according to their medicinal uses into
two main classes:
I-Pharmacodynamic agents: Drugs that act on the various
physiological functions of the body (e.g. general anaesthetic, hypnotic
and sedatives, analgesic etc.).
II-Chemotherapeutic agents: Those drugs which are used to fight
pathogenic (e.g. sulphonamides, antibiotics, antimalarial agents,
antiviral, anticancer etc.).
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Chemotherapeutic Agents
• Definition:
Chemicals used for treatment or control of diseases
caused by pathogenic invading organisms or cells.
• Paul Ehrlich [father of chemotherapy] definition:
Use of drugs to injury invading organism without injury host
[MAGIC BULLET].
Selective Toxicity is the main requirement for chemotherapeutic
agents:
It's expressed by Therapeutic Index [T.I] → measure of Drug Safety
[increase T.I. = increase safety]:
T.I. = LD50 / ED50
where:
LD50 = Lethal Dose that kill 50 % of test animals.
ED50 = Effective Dose that give therapeutic response to 50 % of test
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animals.
It's expressed by Therapeutic Index [T.I] → measure of Drug Safety
[increase T.I. = increase safety]
T.I. = LD50 / ED50
Example:
You have two drugs, A and B, both of them have ED50 = 2 mg/ Kg.
body weight. Compound A has LD50 = 10 mg/kg. b wt,
while compound B has LD50 = 4 mg/ kg. b. wt.
Calculate Therapeutic Index for drugs A and B. Comment for their
safety.
Solution:
‫اإلجابة‬
T.I. = LD50 / ED50
T.I for drug (A) = 10/2 = 5
T.I for drug (B) = 4/2 = 2
[increase T.I. = increase safety]
Drug (A) is more safe than drug (B)
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It's mainly due to :
[I] Biochemical Differences.
[II] Cytological Differences. [III] Distribution Differences.
[I] Biochemical Differences
(i) Enzyme present in parasite or invading cell & absent in host:
Examples:
NH2
* Pyruvate Ferrodoxin
Oxidoreductase enzyme [P.F.O]:
Present in protozoa & anaerobic
bacteria NOT in mammalian cell
N
O2N
N
CH3
CH2
CH2 OH
Metronidazole
N
SO2
NH
N
Sulfadiazine
** Dihydropteroate synthetase:
Used in synthesis of dihydropteroic acid from dihydropteridine base +
PABA [in synthesis of folic acid]
This occur in bacteria only [mammalian take folic acid from diet & not
synthesize it].
Sulphonamides: inhibit this enzyme [So, toxic to bacteria NOT to
21mammalian cells].
(ii) Enzyme present in host not in parasite or invading cell
Example: asparaginase is used for the treatment of
acute lymphoblastic leukemia
Asparagine
L-Asparaginase
Aspartic acid + Ammonia
Asparginase enzyme → hydrolyzes blood aspargine to aspartic
acid and ammonia. This deprives the leukemic cell of circulating
asparagine, which leads to cell death.
L-asparagine synthetase enzyme:
Present in normal cells [used for synthesis of asparagines from
aspartic acid & ammonia]
ALL leukemic cells and some other suspected tumor cells are unable
to synthesize asparagine (non essential amino acid) whereas normal
cells are able to make their own asparagine
Asparagine Synthetase
Aspartic acid + Ammonia
Asparagine
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(iii) Enzyme present in both BUT with different affinity
[Differ from human than parasite cell]
O
CH3
H2N
H2C
O
N
Trimethoprim
O
CH3
NH
N
N
CH3
Cl
NH
C
NH
NH
N
C
CH3
NH CH
CH3
Proguanil
Dihydrofolate Reductase enzyme [convert DHF →THF which is the
active form of folic acid ] → Trimethoprim [ anti-bacterial ] &
Proguanil [ anti-malarial ] bind tightly to bacterial & malarial enzyme
>> human.
(iv) Activation of drug is done by enzyme present only in target cell
Acyclovir by thymidine kinase, induced by infective
O
cell  mono-  triphosphate which is active form of the HN
N
drug [inhibit herpes simplex DNA polymerase].
N
N
This is because acyclovir is guanosine analogue & so, H2N
compete for natural enzyme substrate [deoxyguanosine
Acyclovir
triphosphate].
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O
OH
[II] Cytological Differences
Examples:
(1) Penicillins & Cephalosporins  inhibit C.W.
synthesis [C.W. not present in mammalian cells ]
(2) Anti-fungal as polyene antibiotics [Amphotericin B ],
imidazoles & allyl naphthyl amines act on Ergosterol
[which is present in fungal cell membrane NOT in
mammalian cells ]
(3) Choramphenicol, Tetracycline & Streptomycin  act
on 30 S & 50 S rRNA subunits in bacterial cells [in
mammalian cells  40 S & 60 S rRNA units].
CH2
O
H2C
C
HN
S
N
O
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Penicillin G
HC
CH3
CH3
COOH
C
HN
NH2
S
O
N
CH2 O
O
Cephaloglycine
COOH
C
CH3
[III] Distribution Differences
(1) Tetracycline  preferentially absorbed in bacteria >>
mammalian cells.
(2) Grisefulvin  concentrate in keratinized cells of skin, hair &
nails which are infected by fungi.
(3) Methotrexate  anti-metabolite act on folic acid
which is present in  concentration in leukemic
cells [Invading cells with hyperactive
OCH3
transport system   concentration
of substrate inside them].
O OCH3
O
O
H3CO
Cl
H3C
Griseofulvin
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