Topliss tree

FIGURE 12.6 A portion of the Topliss tree for aromatic substitution... 

Steinbaugh, B.A., Hamilton, H.W., Vara Prasad, J.V.N., Para, K.S., Tummino, P.J., Fergusson, D., Lunney, E.A., and Blankley, C.J. 1996. A topliss tree analysis of the HlV-protease inhibitory activity of 6-phenyl-4-hydroxy-pyran-2-ones. Bioorganic and Medicinal Chemistry letters, 6(10) 1099-104. 

Topliss tree The Topliss tree is an empirical decision scheme for a stepwise aromatic substituent selection and lead optimization that is guided by the supposed influence on potency due to the hydrophobic, electronic, and steric effects of the substituents. 

Topliss tree and Craig plot Factorial, central composite and D-optimal designs Principal properties of substituents Drug-like properties Combinatorial libraries Virtual screens IV Determining relationships between chemical and biological data A Overview... 

In the pyranenamine series, choice among the "next" appropriate derivatives had been made difficult by experimental uncertainty surrounding the relative potency values, and as a result Table I contains information about most of the nodes In the "Topliss tree", not merely an individual branch. In fact, the A-OH derivative, the most potent of the nineteen, can be reached via the tree only by taking the apparent "wrong turn" at two of three nodes. Strict adherence to the decision model would have produced nothing but derivatives less active than the starting unsubstituted compound. 

FIGURE 8.2 A Topliss Tree for aliphatic side chain substitutions. The Topliss schemes were constructed by consideration of hydrophobic and electronic factors and are designed such that the optimum substituent maybe found as efficiently as possible. It is assumed that the methyl substituted compound has been made, tested, and compared to the unsubstituted compound. There are three possibilities the analogs will have less (L), equal (E), or more (M) activity and this determines which branch of the tree should be followed next. 

Fig. 2.7. Illustration of the Topliss tree process for compound selection L, E, and M represent less, equal, and more active respectively (after Topliss and Martin 1975, with permission of Academic Press).

---