Fundamentals of Medicinal Chemistry

The acid chloride based set:

The amine based set:

A^1 + (B^1 ,B^2 ,B^3 ,B^4 ,B^5 ,B^6 ,B^7 ,B^8 ,B^9 ,B^10 )

A^2 + (B^1 ,B^2 ,B^3 ,B^4 ,B^5 ,B^6 ,B^7 ,B^8 ,B^9 ,B^10 )

A^5 + (B^1 ,B^2 ,B^3 ,B^4 ,B^5 ,B^6 ,B^7 ,B^8 ,B^9 ,B^10 )

Etc.

Mixture 1 containing all the possible A^1 −B compounds.

Mixture 6 containing all the possible B^1 −A compounds.

Mixture 15 containing all the possible B^1 −A compounds.

Etc.

RCOCl + R'NH2 RCONHR' + Cl

B^1 + (A^1 ,A^2 ,A^3 ,A^4 ,A^5 ,)

B^10 + (A^1 ,A^2 ,A^3 ,A^4 ,A^5 ,)

Etc. Etc.

Figure 6.14 A schematic representation of the index approach to identifying active compounds

in libraries formed in solution

set of mixtures will identify the amine residue of that amide. Libraries used in

this manner are often referred to as indexed libraries.

This method of identifying the structure of the most active component of

combinatorial libraries of mixtures is known asdeconvolution(see section 6.5). It

depends on both the mixtures containing the active compound giving a positive

result for the assay procedure. It is not possible to identify the active structure if

one of the sets of mixtures gives a negative result. Furthermore, complications

arise if more than one mixture is found to be active. In this case all the possible

structures have to be synthesized and tested separately. However, it is generally

found that the activities of the library mixtures are usually higher than those

exhibited by the individual compounds responsible for activity after they have

been isolated from the mixture.

6.5 Screening and deconvolution

The success of a library depends not only on it containing the right compounds

but also on the efficiency of the screening procedure. Furthermore, it is no use

preparing a combinatorial library if there is not a suitable screening procedure

128 COMBINATORIAL CHEMISTRY