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



R-X



R-COX



-C=C R-NH2



R-COOR`



C



C R-OH



R-O-R` R-CHO (or R-CO-R`) –> R-COOH

• •

Systemic Approach

; It is the reversible relationship of each concept with other related concepts.

Nitrile • Amides Acids Esters Acid anhydrides 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)

CH 3 -CH 2 -OH Ethanol

?

?

?

?

?

?

?

CH 3 -CH 2 -Br Ethyl bromide

?

?

H 2 C=CH 2 ethylene

?

?

H C CH Acetylene

?

?

H 3 C-CHO Acetaldehyde

?

?

H 3 C-COOH Acetic acid ? (1) ?(7) ? (6) ? (5) ? (4)

?

? (8) CH 3 -CH 3 ethane ? (10) CH 3 -Br ?(2) CH 4 ?(9) ? (3)

SYSTEMIC APPROACH FOR STUDYING ALKENES IN RELATION TO ALKANES 10

?

OH H 3 C C H CH Isopropanol 3

??

OH HgOAc H 3 C C H C H 2 n-Propyl bromide

??

Br C H 2 H C Allyl bromide CH 2

9

?

18

?

??

Br H 3 C C H 2 C H 2 n-Propyl bromide

2

?

17

?

??

16

?

H 3 C C H 2 Propane CH 3

??

Br H 3 C C H CH 3 Isopropyl bromide

3

?

1

?

7

?

H 3 C C H Propene CH 2

14

?

OH OH H 3 C C H CH Propylene glycol 2

8

?

4

?

H 3 C C H 2 C H 2 n-propanol OH

13

?

( H 3 C C H 2 C H 2 ) 3 Hydroboration B

12

?

??

Br

5

?

6

?

H 3 C C H C H vic-Dibromide 2 Br

11

?

??

OH Br H 3 C C H CH Bromohydrine 2

??

15 ??

O H 3 C C H CH 2 Propylene Epoxide

??

• • •

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 H 2 / Ni HI R C H Alkene H C R + HCl Alc. KOH ( - HCl ) Cl 2 / hu R H2 C CH Alkyl halides Cl R Conc. HCl Dilute H2SO4

( H 2 O / H + )

Conc H2SO4 R H2 C CH Alcohol aqeous KOH OH R

• SN reactions:

`R O C

Ester

O-R

R

R

Alkane

R-MgX

K OCOR` R

I

Alkyl iodide Na I

R X

K OH aqeous K SH aqeous R

C N Alkyl nitrile

Na C N R Na NH 2 or NH 3

NH2 Amines

NaSR` R

S-R` Thio-ether

Na OR` R

Alcohol

R

O-R` Ether OH

R

SH Thioalcohol

(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 CH 3 CH 2 -X

Ethyl halide

Na NH 2 Conc HX alc. KOH Na OH aqueous H 2 O/H + CH 2 =CH 2

ethene

Conc H 2 SO 4 CH 3 CH 2 -NH 2 Ethyl amine HNO 2 N 2 + H 2 O CH 3 -CH 2 -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 O CH 3 -CH

Acetaldehyde

CH 3 -CH 2 -OH Ethanol Li AlH 4 CrO 3 / py Na BH 4 or LiAlH 4 KMnO4 KMnO4 Li [(But-O) 3 Al H ]

Lithium Tri-tert-butox-aluminium Hydride

CH 3 -COOH

Acetic acid (selective to Reduce acid into aldehyde)

• Acids Synthesis: Mg

CH 3 CH 2 -MgX

Grignard reagent O C O

O

- 40 C carboxylation

CH 3 CH 2 -C-O-MgX

HX

(ASCENDING) CH 3 CH 2 -X

Ethyl halide K C N aqueous

KOH

(SN2)

ASCENDING CH 3 CH 2 -C

Propion-nitrile (Ethyl cyanide)

N

H 2 O H2SO4

CH 3 CH 2 O -C-OH

Propionic acid

CH 3 CH 2 -OH

KMnO 4

( NO ASCENDING ) CH 3 COOH

Acetic acid

• Acids derivatives:

CH 3 CH 2 -C O Conc H 3 PO 4

H 2 O

O CH 3 CH 2 -C-OH Propionic Acid O CH 3 CH 2 -C O Propionic Acid Anhydride R--OH /

H 2 SO 4

H2O / dil H2SO4

R-OH

O CH 3 CH 2 -C-O-R Alkyl propionate ester

NH 3 NH 3

O CH 3 CH 2 -C-NH 2 Propionaamide H 2 O PCl 5 or SOCl 2 O CH 3 CH 2 -C-Cl Acid Chloride

R-OH H 2 O/H + NH 3 H 2 O/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 4 COOH 3-Carboxylic acid 1,4-dihydro Ring fusion 7 8 1 N Z (CH, or N) Substitution by alkyl, piperazines or bicyclic amines Ring fusion Alkyl Substitution by methyl, ethyl or cyclopropyl

5) OFLOXACIN (Tarivid) & 6) Levofloxacin (Tavanic )

• Tarivid is racemic Tavanic is levo O F COOH H 3 C N N O N H CH 3

Other recently introduced quinolones (novel

ME-TOO

DRUGS): •

SPARFLOXACIN (

Zagam

), MOXIFLOXACIN

(Avelox) &

GATIFLOXACIN

(Tequin) NH 2 O F H 3 C HN H 3 C N F N Sparfloxacin (Zegam) COOH HN N F NH 2 OCH Moxifloxacin (Avelox) 3 O N COOH F NH 2 O N HN OCH 3 H 3 C Gatifloxacin (Tequin) N COOH

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

R 1 N M O O F O N N R 2 M = Ca, Mg, Al, Fe, 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

R 1 O 6 1 N R 3 5 2 O R 2 4 3 NH O 1,5,5-trisubstituted Barbiturate

THE VITAMIN Ks

Naphtho-quinones; The term

vitamin K (K

oagulation-Vitamin

)

O O O phytonadione (Vitamin K1) 3 O Menaquinone (Vitamin K2) O n, =1-12 O Menadione (Vitamin K3)

• .

SAR for Antihemorrhagic activity of Vitamin Ks

: R= OH, CO, OCH 3 , OC 2 H 5 , 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`` R``` Ring B= aromatic or dihydro aromatic R```= H, OH, NH2, CO, OCH3, OC2CH5, OAc

• .

NICOTINAMID

O NH 2 Nicotinamide (Niacinamide) • Biologically, nicotinamide is present in the building block of the

coenzyme II

( called:

N

icotinamide-

A

denine

D

inucleotide-

P

hosphate (NADP) which is responsible for biological REDOX system.

• NADP / NADPH system H 2 N N N N N O O O O P O O P O O O N HO OR HO OH 1)When R= H: [ Nucleotide Adenine Dinucleotide (NAD+)] 2) When R= PO3- [Nucleotide Adenine Dinucleotidephosphate (NADP+)] CONH 2

• Biological REDOX reactions.

• a H C + O-H Substrate b CON H 2 N Ribose Conenzym e I (NAD+) c H H CON H 2 Oxidized Product O + N Ribose H Reduc ed Coenzym e I (NADH+) NADP NADPH

Nicotinic acid, ( Vitamine B3)

•

3-

pyridine carboxylic acid O OH N

Nicotinic acid

• Serious deficiency of niacin or tryptophan may lead to

pellagra

rough skin). (from the Italian,

pelle agra, for

HO • .

6) Pyridoxine Hydrochloride vitamin B6

OH NH 2 O H OH HO OH HO H 3 C N Pyridoxine H 3 C N Pyridoxamine H 3 C N Pyridoxal OH

• .

RIBOFLAVIN (VITAMIN B2)

OH HO HO HO H N N O Riboflavin NH N • O

It Accelerate REDOX reactions of NAD/NADH

R N N O R N H N O NADH+ NAD+ 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 R Conjugated drugs + RO Reactive Free Radical R OR Stable Free Radical by resonance and so it is inert and cannot attack protein,DNA or Lipids OR etc..

R • 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 . OH O O O R + RO Reactive Free Radical R R R R Stable unreactive Free radical R R + ROH

IMPORTANT EXAMPLES OF ANTIOXIDANT THERAPIES

Vitamine E O HO Tocopherol

HO OH O O HS 8 HO OH Vitamine C 6 SH 2 Lipoic Acid 1 COOH

Carotein Vitamine A OH

Lycopene (Derieved from tomatoes) O OH 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 Crystallography Clinical Studies Stages Pharmaceutics & Technology To the Market

THANK YOU

For Your Interest

Best wishes from Mohamed Abdel Hamid Ismail [16/4/2008 ]