H Y (A)ClClClClClY (B)LMEY(C)LMCF 3 Y(F) (E) (D)O 2 N Y YEKey :
Y = the structure of the rest
of the lead compound.Figure 4.8 A hypothetical example of the use of the Topliss decision tree. The compounds are
synthesized in the order A, B, C,... etc. It should be realized that only some of the compounds
synthesized will be more potent than the original lead A
S. aureusand activity of this compound and its analogues can be readily
assessed by a biological method. The first step in the Topliss approach is to
synthesize the 4-chloro derivative (B) of A. Suppose the activity of B is greater
than that of A, then following the M branch the Topliss tree (Figure 4.8)
indicates that the next analogue to produce is the 3,4-dichloro derivative (C)
of A. Once again suppose that the biological assay of C was less than that of B.
In this case, the Topliss tree shows that the next most promising analogue is the
4-trifluromethyl derivative of (D) of A. At this point one would also synthesize
and biologically test the 2,4-dichloro (E) and the 4-nitro analogues (F) of A. It is
emphasized that the decision tree is not a synthetic pathway for the production
of each of the analogues. It simply suggests which of the substituents would be
likely to yield a more potent analogue. The synthetic route for producing each of
the suggested analogues would vary for each analogue and would use the most
appropriate starting materials.
The Topliss decision tree does not give all the possible analogues but it
is likely that a number of the most active analogues will be found by this
method.
THE TOPLISS DECISION TREE 91