1. Combinatorial chemistry
Guided by : Mr. R.T.Lohiya
Presented by : Mr. Bhaskar H. Borkar
Department of pharmaceutical chemistry ,S.K.B. college of pharmacy ,
New – Kamptee .

2. CONTENTs
Introduction
Background
Basic concepts
Combinatorial synthesis
Combinatorial synthesis & Traditional synthesis
Techniques
Isolation/Detection/Purification /Analysis
Chemical Diversity & Liabrary Design
Application & limitation
Recent & Future Prospect
References

3. history Continuous improvement in various field
In 1992 Bunin & Ellman demonstrate the
synthesis of 1,4-Benzodiazepine
Introduce the method of generating small
Non-peptide molecule i.e.Peptoid
First combinatorial chemistry experiment
were applied to the study of Epitope
In 1982 Hungarian Patent Literature
published
Arpad Furka ,extend the Merrifield ‘s concept
In 1984 Merrifield got Nobel prize
In 1963 Merrifield introduce the concept

4. What is combinatorial chemistry ?
 Parallel generation of all possible combination of
substituent's or components in a synthetic experiments.

5. Role of combinatorial chemistry

6. Difference Between Traditional
Synthesis & Combinatorial Synthesis :
1 Reaction Many a times simpler Not so simple
2 Extreme condition i.e. at Avoid May possible to use
extreme temp./ pressure
3 Use of highly Caustic Generally avoid Possible to use
reagent
4 Use of Inert atmosphere Avoid May use
5 Multistep Reaction Avoid Possible
6 Yield of compound Gives chemical library Gives single
compound

7. Techniques used in the combinatorial
synthesis :
 solid phase Technique
 Solid Support Method
 Parallel Synthesis
 Manual method
 Automated
 Mixed combinatorial Synthesis
 Mixed & split Combinatorial Synthesis
 Solution phase Technique

8. Solid phase technique :
 The solid support
e.g. Cross-linked
polystyrene Bead
 The anchor / linker
e.g. Polystyrene resin ,
Tentagel resin ,
Polyacrylamide resin,
Glass & ceramic beads .

9.  Mixed combinatorial synthesis :
Gly Ser
Ala Val Phe
Combine
Phe Ala
Val
Gly
Ser
Gly
Ser Gly
Val Gly
Phe Phe
Ala Gly
Gly
Gly Gly

10.  Split & Mix Synthesis :

11.  Parallel synthesis
What is the basic idea behind parallel synthesis ?
The process where
a single reaction
product is
produced in
each reaction
vessel.
Approach
 Houghton's Tea bag Procedure
 Automated Parallel Synthesis

12. Solution phase combinatorial
chemistry
 It is the modified reaction to accommodate a solid
support .
 Solution phase combinatorial chemistry often lead
to a formation of Mixture of product .
 May helpful for development of Amazing-Mixture
Problems : # difficulty of removing unwanted material
# purification at each step is necessary
# other practical problem

13. Comparison between solid phase & solution
phase chemistry :

14. Comparison between solid phase & solution
phase technique :
Sr. No. Parameter Solid Phase Solution phase
technique Technique
1 Reagent Excess Optimum
(unless purification
done)
2 Purification Easy Can be difficult
3 Automation Easy Difficult
4 Reaction Suitable for few Suitable for any organic
substance reaction
5 Scale-up Expensive Easy & inexpensive
6 Dependence of Mainly on - Time
reaction development - support
- Linkers

15. Detection / Purification / Analysis
 Quantities of analyzed are very small
 Nondestructive / Allow recovery
 Rapid / Parallel analysis
 Use hyphenated analytical technique e.g. HPLC-MS
 Chromatography
 Use IR / FTIR (computerized method)
 Use NMR / 2D-NMR / HPLC-NMR / CE-NMR
 MS / EI / MALDI-TOF / SIMS
 Use HPLC
 Supercritical Fluid Chromatography

16.  Isolation i.e. Deconvlution
- micromanipulation
- recursive deconvolution
- sequential release
 Structural determination of the active compd.
- Tagging
- Encoded sheets
- Photolithography

17. Chemical diversity & Libraries :
It has been suggested that effectiveness of
combinatorial chemistry could be improved by
enhancing the chemical diversity of screening
libraries .
Two more important features :
- Chirality
- Rigidity

18. Limitation of combinatorial chemistry
 How many beads will be required for
combinatorial synthesis ?
 Probability of finding sample ………….?
 Requirement of practical details of weight &
volume.

19. Example of combinatorial chemistry
 Early work carried on peptides
 Next work done on peptoid
 Now researcher get concentrated on the
heterocyclic combinatorial libraries
e.g.- 1,4-Benzodiazepine
 All common reaction ,moisture sensitive &
organometallic reactions
e.g. Aldol reaction ,Dibal Reduction, Wittig
reaction etc.

20. Example of lead compounds obtained by
combinatorial chemistry
Sr. No. Source Target Mechanism
1 Merck HIV-1 Integrase Block viral
integration
2 Smith-Kline Beecham Human 5-HT 6 Antagonist,
Serotonin cognitive
Receptor disorders
3 Pfizer Farnesyl Inhibition
transferase
4 Park Davis KDO-8-P Inhibition,
Synthetase Antibacterial .

21. Miniaturization
Dynamic combinatorial
chemistry
chemoinformatics
Use of advanced
Targeted & diversified software & robotics
libraries
Agro-Chemical
Computational
sector QSPR
chemistry
Advances in
solution phase &
Solid phase
organic synthesis QSAR

22. References
 Douglas R Henry ; Wilson & Gisvold‘s Textbook of Organic
Medicinal chemistry ; 11th edition ;Lippincott William &
Wilkins Publication ; 2004 ;Page No. 43-63 .
Grahm L. Patrick ; Introduction To Medicinal Chemistry ;
2nd Edition ; Oxford publication ; 2003 ;Page No. 289-318
Gareth Thomas ; Medicinal Chemistry –An Introduction ;
Willey publication ; 2000 ; Page No. 69-90 .
 R.B.Silverman ; Organic chemistry of drug design & Drug
Action ; 2nd Edition ;Elsevier publication ;2004 ; Page
No.35-43 .
www.netsci.org/science/Combichem/feature02.html
 www.biotech.nature.com ; NATURE BIOTECHNOLOGY ;
Vol 18 ; Supplement 2000.