Combinatorial chemistry is to prepare libraries of very large number compounds then identify the useful compounds of the libraries.

1. Presented by:
S.Afreen
18M71S0101
M.Pharm
Pharmacology.
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2.  It is a chemical synthetic method that make
possible to prepare a large number of
compound in a single process.
Definition:
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The basic principle of combinatorial chemistry is
to prepare libraries of very large number
compounds then identify the useful compounds of
the libraries.

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Therapeutic target
Lead discovery
Lead optimization
Development candidates
Drug
Combinatorial
chemistry

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APPROACH:
The combinatorial chemistry approach has two
phases:
1. Making a library.
2. Finding the active compound.

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Conventional synthesis Combinatorial synthesis
Only one compound is synthesized
at a time
A range of compounds are
synthesized at a time
Require more time Require less time
More expensive Less expensive
Slower lead generation Faster lead generation
Strategies:

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• The creation of large libraries of molecules in a short time .
• Medicinal chemistry can be synthesized using combinatorial
techniques
• More opportunities to generate lead compounds.
• Speeds up drug discovery
Advantages:
Disadvantages:
 solve all the problems associated with drug discovery, one
still needs to synthesize the right compound.
 There is a limit to the chemistry you can do when using solid
phase synthesis.

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TECHNIQUES :
• solid phase Technique
 Solid Support Method
 Parallel Synthesis
Manual method
Automated
 Mixed combinatorial Synthesis
 Mixed & split Combinatorial Synthesis
• Solution phase Technique

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Solid phase technique:
•In solid phase combinatorial chemistry, the starting
compound is attached to an insoluble resin bead,
reagents are added to the solution in excess, and the
resulting products can be isolated by simple filtration,
which traps the beads while the excess reagent is
washed away.
•Synthesis of peptides and most of the easily carried
out on combinatorial synthesis was performed on
peptides.

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The solid supports are usually composed of two
parts:
The core and The linker.
Core--------Linker--------Start compound
Three major components that are required for
solid phase synthesis are:
 The solid support
 The anchor/ linker
 Protection and Deprotection method

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Types of solid phase used:
* Polystyrene resins
* Poly acrylamide resins
* Tenta Gel resins

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Linker and Anchor used in solid phase:
It is a molecular unit covalently attached to the
solid support via the linker.
 Linker is a bifunctional molecule.
 The linker is bound the resin is called anchor.
Resin + Linker ----------> Resin----Anchor
Ex: Merrifield resin
Tritylchloride resin
Wang resin
Hydroxymethyl resin

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Protecting groups:
A protecting group is reversibly attached to the functional
group to convert it to a less reactive form.
When the protection is no longer needed, the protecting
group is cleaved and the original functionality is restored.
A large number of protecting groups were developed for
use in peptide synthesis since the amino acids are
multifunctional compounds.
Ex: Boc
Fmoc/ t-Bustrategy

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Parallel synthesis:
• Starting material is reacted
with each building block
separately .
• After each reaction step the
product is split into ‘n’ portions
before it is reacted with n new
building blocks.
• The identity of each structure
is known.

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• Each tea bag contains beads and is labelled
• Separate reactions are carried out on each tea bag.
• Combine tea bags for common reactions or work up
procedures.
• A single product is synthesised within each tea bag.
• Different products are formed in different tea bags.
• Cheap and possible for any lab
• Manual procedure and is not suitable for producing
large.
Teabag method :

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• Automated synthesisers are available with 42, 96 or
144 reaction vessels or wells.
• Use beads or pins for solid phase support
• Reactions and work ups are carried out
automatically.
• Same synthetic route used for each vessel, but
different reagents.
• Different product obtained per vessel.
Automated parellel synthesis:

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Mixed Combinatorial Synthesis
• To use a standard synthetic route to produce a large variety
of different analogues where each reaction vessel or tube
contains a mixture of products.
• The identities of the structures in each vessel are not known
with certainty.
• Useful for finding a lead compound
• Capable of synthesizing large numbers of compounds
quickly.
• Each mixture is tested for activity as the mixture.
• Inactive mixtures are stored in combinatorial libraries.
• Active mixtures are studied further to identify active
component.

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Mix and Split Method
•In this technique, the starting
material is split in ‘n’ portions,
reacted with ‘n’ building blocks,
and recombined in one flask.
•For the second step, this
procedure is repeated.

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Solution phase Technique:
• It is the modified reaction to accommodate a solid
support .
•The solution phase synthesis involves conducting
chemical reaction simultaneously, preferably in well-
ordered sets (arrays) of reaction vessels in solution.
• Solution phase combinatorial chemistry often lead to
a formation of Mixture of product .
• May helpful for development of Amazing Mixture

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Problems :
1. difficulty of removing unwanted material
2. purification at each step is necessary
3. other practical problem.

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