Download الشريحة 1 - Systematic Approach to Teaching

Systemic Approaches in Teaching
Courses of Pharmaceutical Chemistry
& Pharmaceutical Sciences
By
Mohamed Abdel Hamid Ismail
Prof. Organic & Pharmaceutical Chemistry
&
DEAN
OF FACULTY OF PHARMASCT
AIN SHAMS UNIVERSITY
Department of pharmaceutical
Chemistry
• This department teach :
• 1) Organic Chemistry
•
&
• 2) Pharmaceutical
•
(Medicinal) Chemistry
• Organic Chemistry courses
deals with teaching the
students
•
1) Naming structure
•
2) Predicting method of synthesis
•
•
3) Predicting chemical and Physical
properties of chemical
structures.
• Pharmaceutical Chemistry
courses deals with teaching
the students:
• Predicting Biological Activity of
any molecules (if any)
• Predict chemical and biological
incompatibility of drugs`
combinations.
• Teaching methodologies:
• 1) Linear approach
• 2) Systemic approach
• 3) New E-learning, Self-Learning, … etc.
•
Linear Approach;
•
•
In studying classes of organic chemistry,
if we do the study for each of the function
groups separately without making the
relation between them, this will be the
linear approach of teaching.
•
•
•
•
•
•
Examples:
RH
 -C=C CC
R-X  R-NH2
R-OH  R-O-R`
R-CHO (or R-CO-R`) –> R-COOH
R-COX  R-COOR` 
•
•
Systemic Approach;
It is the reversible relationship of each
concept with other related concepts.
•
Nitrile
Amides
Acids
Acid anhydrides
Esters
Acid Halides
• Organic Chemistry courses
deals with teaching the students
• 1) Naming structure
• 2) Predicting method of synthesis
• 3) Predicting chemical and Physical
properties of chemical structures.
• The best systemic way is through
the reported systemic approach by
clusters of combined information
Systemic Aproach for alkanes (reaction & synthesis)
?
?
? ?
?
?
CH3-CH2-OH
Ethanol
?
CH3-CH2-Br
Ethyl bromide
H2C=CH2
ethylene
? ?
? (1)
? (8)
?(7)
CH3-CH3
ethane
? (6)
HC CH
Acetylene
?
?
?
? (10)
? (5)
? ?
H3C-CHO
Acetaldehyde
?(2)
CH4
? ?
? (4)
H3C-COOH
Acetic acid
CH3-Br
?(9) ? (3)
SYSTEMIC APPROACH FOR STUDYING ALKENES IN RELATION TO ALKANES
OH
H3C C CH3
H
10 ?
??
Isopropanol
H3C
OH
H3C
??
HgOAc
C
H
C
H2
??
Br
C
H2
H
C
9?
CH2
Allyl bromide
H3C C
H2
C
H2
n-Propyl bromide
??
H3C
C
H2
Propane
Isopropyl bromide
13 ?
3?
1? 7?
2?
H3C C CH2
H
5?
6?
14 ?
CH3
H3C
OH
CH2
Propylene glycol
15
H3C
C
H
??
CH 2
Propylene Epoxide
C
H
Br
CH2
Bromohydrine
??
O
C
H2
??
OH
H3C
C
H
Br
vic-Dibromide
11 ?
H3C
??
??
Br
17 ?
OH
C
H
H2
Hydroboration
12 ?
Propene
16 ?
B
C )3
C
H2
( H3C
4?
18 ?
??
Br
H3C C CH3
H
OH
n-propanol
8?
Br
n-Propyl bromide
C C
H2 H
2
• SYNTHESIS & IMPORTANT REACTIONS
• Alkynes: From alkene by halogenation by Cl2, followed by double
dehydrohaogenation with strong base (Na NH2):
• N. B: To convert alkyne into alkene, we make partial hydrogenation of alkyne
using Li /Ethylamine.
• Alkyl halides (R-X):
• Prepared by either halogenation of alkane,
hydrohalogenation of alkene, or substitution of
alcoholic OH by halogens.
R
C
H2
H2
C R
H2 / Ni
R
C
H
Alkene
H
C
Dilute
H2SO4
HI
Cl2 / hu
Cl
+ HCl
R
R
Alc. KOH
( - HCl )
( H2O / H+)
OH
R
H2
C CH
Alcohol
R
Alkyl halides
aqeous
KOH
Conc
H2SO4
H2
C CH
R
Conc. HCl
• SN reactions:
R
R
Alkane
O
`R C O-R
R
Alkyl iodide
R-MgX
K OH
aqeous
R X
Ester
Na C N
Alkyl nitrile
Na NH2
or NH3
NaSR`
R
NH2
Amines
R OH
Na I
K OCOR`
R C N
I
Alcohol
K SH
aqeous
R SH
Thioalcohol
Na OR`
R O-R`
R S-R`
Thio-ether
Ether
(Williamsons Synthesis
of ether)
• Alcohols ( R-OH ) & Amines ( R-NH2 ):
• Alcohols are prepared:From alkene by hydration, 2) From alkyl
halide by SN using aqueous NaOH, 3) From aldehydes or
ketones by reduction using NaBH4 or Li Al H4. & 4) From Acids
or esters by reduction using Li Al H4.
• * Amines are prepared from alkyl halides using NH3 or NaNH2.
• * Amines could be converted to alcohols by nitrous acid (HNO2)
+ HX
CH3-CH2-X
alc. KOH
Ethyl halide
Na NH2
CH3-CH2-NH2
Ethyl amine
CH2=CH2
Conc
HX
Na OH
aqueous
HNO 2
N2 + H2O
ethene
Conc
H2SO4
H2O/H+
CH3-CH2-OH
Ethanol
Aldehyde (R-CHO) , Ketones (R-CO-R: •
•
•
Aldehydes are prepared by oxidation of 1ry alcohol using selective weak
oxidizing agent; (Cr2O3 in the presence of pyridine (Cr2O3 / Py).
* Aldehydes can undergo further oxidization by KMnO4 into Carboxylic acid.
* The reverse pass ways is by lithium tritertbutoxyaluminium hydride
CH3-CH2-OH
CrO3 / py
O
CH3-CH
Acetaldehyde
Na BH4 or
LiAlH4
Ethanol
Li AlH4
KMnO4
KMnO4
Li [(But-O)3Al H]
Lithium Tri-tert-butox-aluminium Hydride
(selective to Reduce acid into aldehyde)
CH3-COOH
Acetic acid
• Acids Synthesis:
O
C
CH3-CH2-MgX
Grignard
reagent
Mg
O
O
- 40 C
carboxylation
CH3-CH2-C-O-MgX
HX
(ASCENDING)
CH3-CH2-X
KC N
Ethyl halide
ASCENDING
aqueous
KOH
(SN2)
CH3-CH2-OH
O
CH3-CH2-C
N
Propion-nitrile
(Ethyl cyanide)
KMnO 4
( NO
ASCENDING )
H2O
H2SO4
CH3-CH2-C-OH
Propionic acid
CH3-COOH
Acetic acid
• Acids derivatives:
O
CH3-CH2-C
O
Conc H3PO4
H2O
CH3-CH2-C
R-OH
O
O
CH3-CH2-C-OH
Propionic Acid
H2O
NH3
Propionic Acid Anhydride
O
R--OH / H SO
2
4
H2O / dil H2SO4
CH3-CH2-C-O-R
NH3
Alkyl propionate ester
R-OH
PCl5
or
SOCl2
O
CH3-CH2-C-NH2
Propionaamide
NH3
+
H2O/H
O
CH3-CH2-C-Cl
Acid Chloride
H2O/H+
• Best wishes from Dr Mohamed. A. H. Ismail
Systemic Approach in Aromatic Chemistry
• Pharmaceutical Chemistry
courses deals with teaching the
students:
• Predicting Biological Activity of any molecules (if
any)
• Predict chemical and biological incompatibility of
drugs combinations.
• The best systemic way is through
• Structure Activity Relation-ship
• (SAR)
Summary of SAR for NALIDIXIC ACID &
other quinolones as anti-infective
TOPOISOMERASE ENZYME INHIBITION
4-One
armomatic with or without
N isoster at 5,6,7,or 8
O
5
Substitution by
Florine
6
7
Ring fusion
Substitution by
alkyl, piperazines
or bicyclic amines
COOH
3-Carboxylic acid
4
1,4-dihydro
8
1
N
Ring fusion
Z
(CH, or N)
Alkyl Substitution by methyl,
ethyl or cyclopropyl
5) OFLOXACIN (Tarivid)
&
6) Levofloxacin (Tavanic)
• Tarivid is racemic
Tavanic is levo
O
COOH
F
N
N
H3C
N
O
CH3
H
Other recently introduced quinolones
(novel ME-TOO DRUGS):
• SPARFLOXACIN (Zagam), MOXIFLOXACIN
(Avelox) &
GATIFLOXACIN (Tequin)
NH2 O
NH2 O
COOH
F
H3C
HN
F
COOH
F
N
N
N
HN
OCH3
Moxifloxacin
(Avelox)
COOH
F
N
H3C
Sparfloxacin
(Zegam)
NH2 O
N
N
HN
OCH3
H3C
Gatifloxacin
(Tequin)
Chemical Incompatabilities to
quinolones
• The quinolones chelate with heavy metals
like (Ca2+, Mg2+, Al+, and Fe2+ to form
less water-soluble complexes and thereby
lose considerable potency.
• So, these drugs are contra-indicated with
Ca, Mg, Fe nutitions
• The Metal Chelates
M
O
O
F
O
N
R1
N
N
M = Ca, Mg, Al, Fe,
R2
Metal Complex with Quinolones
SARs for the substituted barbiturates
CNS depressants
• 1) At C-5 : both hydrogen must be substituted
• 2) Introduction of polar groups (like OH, NH2, CO, COOH,
SO3H, …etc., at the alkyl substituents destroy potency.
• 3) Replacement of one oxygen by sulfur increases lipid
solubility and increase rate of reaching to the brain
O
6
R1
N
2
5
R2
R3
1
4
O
3
NH
O
1,5,5-trisubstituted Barbiturate
THE VITAMIN Ks
Naphtho-quinones;
The term vitamin K (Koagulation-Vitamin)
O
O
3
O
phytonadione
(Vitamin K1)
O
n, =1-12
O
Menaquinone
(Vitamin K2)
O
Menadione
(Vitamin K3)
SAR for Antihemorrhagic activity of Vitamin
Ks
• .
:
R= OH, CO, OCH3, OC2H5, OAc,
R`=CH3
R
R`
Ring A= aromatic
or dihydro aromatic
A
B
R``=H, SO3H, NMe2, alkyl gp
containing 10 Carbon, with unasturation
at beta or gama position
R``
Ring B= aromatic
or dihydro aromatic
R```
R```= H, OH, NH2, CO, OCH3, OC2CH5,
OAc
NICOTINAMID
• .
O
NH2
Nicotinamide (Niacinamide)
• Biologically, nicotinamide is present in the
building block of the coenzyme II (called:
Nicotinamide-Adenine DinucleotidePhosphate (NADP) which is responsible
for biological REDOX system.
• NADP / NADPH system
H2N
CONH 2
N
O
N
N
N
P
O
HO
1)When R= H:
O
O
OR
O
O
P
N
O
O
O
HO
OH
[ Nucleotide Adenine Dinucleotide (NAD+)]
2) When R= PO3- [Nucleotide Adenine Dinucleotidephosphate (NADP+)]
• Biological REDOX reactions.
c
a
H
CON H2
CON H2
H
O
C
+
+
N
N
O-H
b
Substrate
•
H
NADP
H
Ribose
Conenzym e I
(NAD+)
Oxidized
Product
Ribose
Reduc ed Coenzym e I
(NADH+)
NADPH
Nicotinic acid, ( Vitamine B3)
O
• 3-pyridine carboxylic acid
OH
N
Nicotinic acid
• Serious deficiency of niacin or tryptophan may
lead to pellagra (from the Italian, pelle agra, for
rough skin).
6) Pyridoxine Hydrochloride
vitamin B6
• .
OH
HO
H3C
OH
N
Pyridoxine
O
NH2
HO
H3C
OH
N
Pyridoxamine
H
HO
H3C
OH
N
Pyridoxal
RIBOFLAVIN (VITAMIN B2)
OH
HO
• .
HO
HO
H
N
N
O
NH
N
Riboflavin
O
• It Accelerate REDOX reactions of NAD/NADH
R
N
R
N
O
N
H
N
O
NAD+
NADH+
N
Oxidized form O
NH
N
H
O
Reduced form
NH
+
ANTIOXIDANTS
Highly conjugated
double bonds,
Electron rich
molecules
Anti-oxidants are those molecules which
can quench free radical in the body and
thus
stop AGING
Mechanism of quenching Free
Radicals by conjugated
systems:
R
+
Conjugated drugs
RO
Reactive Free Radical
R
R
OR
Stable Free Radical by resonance and so it is inert
and cannot attack protein,DNA or Lipids
OR
etc..
•
•
•
•
Electron rich molecules like:
1) Phenols,
2) Amines,
3) Alcohols or 4) Thiols
They can trap and detoxify the free
radicals by supplying electrons and
forming stable radicals.
O
OH
O
O
+ ROH
+ RO
R
Reactive
Free Radical
R
R
R
R
R
Stable unreactive Free radical
R
R
IMPORTANT EXAMPLES OF
ANTIOXIDANT THERAPIES
Vitamine E
O
HO
Tocopherol
OH
O
HO
HO
O
OH
Vitamine C
1
6
HS
8
COOH
2
SH
Lipoic Acid
OH
Vitamine A
Carotein
Lycopene
(Derieved from tomatoes)
OH
O
O
O
CO-ENZYME Q 10
• Computer Aided Drug
Design
•&
• Molecular Modeling
• As a systemic method
of drug discovery
Hypothesis Generation of the binding sites of
Receptors
and use for compare fit with data base
molecules to predict their activity
Comparison of the hypothesis with the following Data Base spreadsheet :
Results of COMPARE / FIT searching of the
hypothesis of methotrexate with the data base.
Displaying the fitting
Compare fitting of data base compounds with methotrexate hypothesis
If the features of a Molecule
could fit part of the cavity of
these meshes (hypothesis),
it will be considered as a
biologically
ACTIVE HIT molecule
for drug discovery.
Binding site
Then Draw the New molecule inside the cavity
based on complementarily
• Systemic Approach
• Between other
•PHARMACEUTICAL
SCIENCES
•For drug discovery
Drug Discovery Team-work:
Synthesis
Isolation of
Natural Products
Molecular Modeling
Bio-Technology
Analysis &
Quality control
Pharmacology & Toxicology
X-Ray
Clinical Studies
Crystallography
Stages
Pharmaceutics &
Technology
To the Market
THANK YOU
For Your Interest
Best wishes from
Mohamed Abdel Hamid Ismail
[16/4/2008]