COMBINATORIAL CHEMISTRY

NITHYASRI.R
1ST YEAR PG DEPT.OF PHARMACOLOGY
DEFINITION

Combinatorial chemistry is a technique by which

large number of different but structurally similar
molecules are produced rapidly and submitted for
pharmacological assay
SYNOPSIS
History and Introduction
Principle and Objectives
Approaches of combinatorial chemistry
Types of chemical library
Methods of Combinatorial chemistry
Techniques of Combinatorial chemistry
Merits and Demerits
HISTORY
• The concept of combinatorial chemistry was developed in the mid 1980’s with
Geysen’s multi-pin technology and Houghten’s tea-bag technology to synthesize
hundreds of thousands of peptides.
• Bunin & Ellman reported the first example of a small-molecule combinatorial
library

Jonathan A Ellman Barry Bunin

INTRODUCTION
• By accelerating the process of chemical synthesis, this method is having a
profound effect on all branches of chemistry, especially drug discovery
• Focus mainly on the preparation of chemical libraries for generation of new lead
for drug discovery
• It reduces “time and cost” associated with producing effective and competitive
new drugs
BASIC PRINCIPLE AND OBJECTIVES
PRINCIPLE :
Prepare large number of similar compounds at the same time instead of synthesizing
a compound conventional one at -a- time manner.

OBJECTIVE:
Build a large library of compounds from a starting “Scafolld” to interact with
specific biological targets
Orthodox synthesis
In orthodox synthesis, there is a stepwise-directed synthesis of one
specific product using basic fundamentals of organic chemistry

A+B AB

One reactant (A) reacts with another reactant (B) to yield one product
AB
Combinatorial synthesis

In combinatorial chemistry, we synthesize directly large number of compounds

through preparing many single compounds in parallel or many compounds
simultaneously in mixtures

A1-n + B1-n A1-nB1-n

Different building blocks of type A react combinatorially with different

building blocks of type B to yield a combinatorial library
APPROACHES OF COMBINATORIAL CHEMISTRY

1. Making a library
2. Finding the Active compound
Chemical Libraries
TYPES OF CHEMICAL LIBRARIES

Scaffold-
based library

Backbone -
based library
SCAFFOLD BASED LIBRARIES:
Core structure is retained in all compounds in the library and only variations are in
additional or modified functional groups

EXAMPLE:
Amino acid and Amino Benzophenone
BACK BONE BASED LIBRARIES:
Back bone-based where certain building blocks are used

EXAMPLE: Peptides
METHODS OF COMBINATORIAL CHEMISTRY

Combinatorial chemistry can be applied to:

1. Solid phase synthesis

2. Solution phase synthesis.
Solid phase synthesis
The starting compound attached to an
insoluble Resin Bead

The reagent are added to the solution in

excess

Resulting Product Isolated by Simple

Filtration

The Excess Reagent is washed away

Solid phase combinatorial chemistry
Solution phase synthesis

Reaction proceeds in Solution

Can be used to produce libraries that consist of

single compound or a mixtures

Purification is Required at each step

Standard Protocols can be used to characterize

products between each reaction step
Solution phase combinatorial chemistry
Solid phase synthesis Solution phase synthesis

Fast Time consuming

Large excess reagent used Optimum reagents used

Purification at the end Purification after each step

Expensive Cost effective

TECHNIQUES OF COMBINATORIAL CHEMISTRY

Two distinct mechanisms for elaborating molecular diversity may be

are:

1. Parallel Synthesis
2. Split and Mix synthesis
Parallel Synthesis Method

In separate vessel different compounds are synthesized

(without remixing)

Simultaneous addition of reactants in different reaction

vessel and parallel handling of each library sample

It requires a solid support

Advantages

No deconvolution is required.

No risk of synergistic effects leading to false positive results
during screening.
Easier biological evaluation
Split and Mix synthesis

Starting material is split in n portions

Reacted with n building blocks, and recombined in one

flask for the second step

Procedure is repeated

This method is particularly employed for solid phase

synthesis
Advantages:
Large libraries are readily available
Less reaction vessel required

Limitations:
Complex mixtures are formed.
Deconvolution or tagging is required.
Synergistic effect may be observed during screening, leading to false
positive
MERITS OF COMBINATORIAL CHEMISTRY
FAST
Combinatorial approach give rise to million of compounds at same time
ECONOMICAL
A negative result of mixture save the determine of synthesis,
purification and identification of each compound
EASY
Isolation, purification and identification of active molecule from
combinatorial library is relatively easy
PERFORM FEWER REACTION

Perform fewer reaction and fewer test to identify the biological activity
of winning molecule

LARGE LIBRARY OF MOLECULE

Creates large library of molecule in a short time

DEMERITS

Efficiency is highly affected by compound size, solubility and

functional group

Compound produced tend to be a Achiral of Racemic.

SUMMARY
REFERENCES

• Indian Journal of Chemistry-Combinatorial chemistry -Vol. 44B

• Combinatorial chemistry synthesis and application
• Combinatorial chemistry and its application - a modern synthetic approach
Konda Ravi Kumar and B. Sai Keerthana
• World Journal of Advance Healthcare Research (WJAHR)
• Journal of Medicinal chemistry-Combinatorial chemistry Design and
Evaluation -Vol.45