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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 .

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


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



Hungarian Patent Literature published

Arpad Furka ,extend the Merrifield s concept In

1984 Merrifield got Nobel prize


1963 Merrifield introduce the concept

What is combinatorial chemistry ?

Parallel generation of all possible combination of substituent's or components in a synthetic experiments.

Role of combinatorial chemistry

Difference Between Traditional Synthesis & Combinatorial Synthesis :

1 Reaction Many a times simpler Not so simple

Extreme condition i.e. at extreme temp./ pressure

Use of highly Caustic reagent Use of Inert atmosphere


May possible to use

3 4

Generally avoid Avoid

Possible to use May use

5 6

Multistep Reaction Yield of compound



Gives chemical library Gives single compound

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

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 .

Mixed combinatorial synthesis :

Gly Ala Val Combine Ala Gly Ser Phe



Ser Val Ala Gly Gly Phe Gly Gly

Gly Phe


Split & Mix Synthesis :

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

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

Comparison between solid phase & solution phase chemistry :

Comparison between solid phase & solution phase technique :

Sr. No. Parameter Solid Phase technique Solution phase Technique



Optimum (unless purification done)

Can be difficult Difficult Suitable for any organic reaction Easy & inexpensive Time

2 3 4 5 6

Purification Automation Reaction Scale-up Dependence of reaction development

Easy Easy Suitable for few substance Expensive Mainly on - support - Linkers

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

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

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

Limitation of combinatorial chemistry

How many beads will be required for combinatorial synthesis ?

Probability of finding sample .?

Requirement of practical details of weight & volume.

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.

Example of lead compounds obtained by combinatorial chemistry

Sr. No. Source 1 Merck Target Mechanism

HIV-1 Integrase Block viral integration Human 5-HT 6 Serotonin Receptor Farnesyl transferase KDO-8-P Synthetase Antagonist, cognitive disorders Inhibition Inhibition, Antibacterial .

Smith-Kline Beecham

3 4

Pfizer Park Davis

Miniaturization Dynamic combinatorial chemistry chemoinformatics

Targeted & diversified libraries

Use of advanced software & robotics

Agro-Chemical sector Advances in solution phase & Solid phase organic synthesis

Computational chemistry



Douglas R Henry ; Wilson & Gisvolds 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 . ; NATURE BIOTECHNOLOGY ; Vol 18 ; Supplement 2000.