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PHARMACEUTICAL ORGANIC CHEMISTRY RESEARCH

Combinatorial Chemistry

INTRODUCTION :
Combinatorial chemistry is one of the important new methodologies developed by
academics and researchers in the pharmaceutical, agrochemical, and biotechnology
industries to reduce the time and costs associated with producing effective, marketable,
and competitive new drugs. Simply put, scientists use combinatorial chemistry to create
large populations of molecules, or libraries, that can be screened efficientlyen masse. By
producing larger, more diverse compound libraries, companies increase the probability that
they will find novel compounds of significant therapeutic and commercial value. The field
represents a convergence of chemistry and biology, made possible by fundamental
advances in miniaturization, robotics, and receptor development. And not surprisingly, it
has also captured the attention of every major player in the pharmaceutical, biotechnology,
and agrochemical arena.
While combinatorial chemistry can be explained simply, its application can take a variety of
forms, each requiring a complex interplay of classical organic synthesis techniques, rational
drug design strategies, robotics, and scientific information management. This article will
provide a basic overview of existing approaches to combinatorial chemistry, and will outline
some of the unique information management problems that it generates.

DEFINITION :
Combinatorial chemistry is a technique by which large numbers of structurally distinct molecules
may be synthesised in a time and submitted for pharmacological assay. The key of
combinatorial chemistry is that a large range of analogues is synthesised using the same
reaction conditions, the same reaction vessels. In this way, the chemist can synthesise many
hundreds or thousands of compounds in one time instead of preparing only a few by simple
methodology.
In the past, chemists have traditionally made one compound at a time. For example compound
A would have been reacted with compound B to give product AB, which would have been
isolated after reaction work up and purification through crystallisation, distillation, or
chromatography.

In contrast to this approach, combinatorial chemistry offers the potential to make every
combination of compound A1 to An with compound B1 to Bn.

The range of combinatorial techniques is highly diverse, and these products could be made
individually in a parallel or in mixtures, using either solution or solid phase techniques.
Whatever the technique used the common denominator is that productivity has been amplified
beyond the levels that have been routine for the last hundred years.

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Application of Combinatorial Chemistry :
Applications of combinatorial chemistry are very wide. For example in pharmaceutical
companies for drug designs. For illustrate this, one a practical example:
Transition-state analog HIV protease inhibitors.
Extensive efforts toward the rational design of aspartyl protease inhibitors such as renin and
HIV have led to the discovery of several transition-states analog mimics. These templates
can serve as the central unit around which molecular diversity can be generated by
application of appropriate chemistries. Recently, solid phase synthesis of hydroxyethylamine
and 1,2-diol transition-state pharmacophore units and their utility for synthesis of HIV
protease inhibitors have been reported by two different groups.
The first instance, bifunctional linker are used by Wang to serve the dual purpose of
protecting the hydroxyl group of these BBs and providing point for attachment on solid
support.

Thus, one linker possesses a vinyl ether group at one end and a free carboxylate group at
the other. The vinyl ether moiety is reacted with diamino alcohol BB 1 under acid-catalysed
conditions to form an acetal protecting group and the carboxylic acid group is used for
ester-type linkage to the solid support. The other linker possesses a methyl ketone and
carboxylic groups at the two ends, with the ketone group forming a ketal with diol 3.
Resulting intermediates 2 and 4 are now well suited for a bi-directional solid phase

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synthesis strategy for preparing C2 symmetric HIV protease inhibitors. The two terminal
amino groups of 2 and 4 are deprotected and reacted with a variety of carboxylic acid,
sulfonyl chlorides, isocyanates, and chloroformates to extend the core unit in both directions
and generate a wide variety of aspartyl protease inhibitors. The authors claim that a library
of 300 discrete analogs was prepared and screened against HIV protease to identify several
potent inhibitors.

ADVANTAGES AND DISADVANTAGES :

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REFRENCES :

1- http://www.combichemistry.com/combichem_applications.html
2- http://en.wikipedia.org/wiki/Combinatorial_chemistry
3- http://www.wiziq.com/tutorial/2967-Combinatorial-Chemistry-and-Library-Design
4- http://www.netsci.org/Science/Combichem/feature02.html
5- http://www.chem.msu.su/rus/books/patrick/part1.pdf

MADE BY SECTION(2) :

1- Jehan Essam Mahmoud (112) .
2- Aya Ahmed Saber Yossiff (86).
3- Eman Mohammed Mostafa Sherra (83).
4- Eman Ahmed Alaa Elshamy .
5- Aya Samir .

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Pharmaceutical organic chemistry research

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