Topliss tree

Before computers were everywhere, a chemist still needed a smart way to choose which few compounds to make next out of a vast number of options. The Topliss tree is a simple paper decision chart, proposed by John Topliss in the 1970s, that guides you toward the best aromatic or aliphatic substituents in as few synthesized compounds as possible.

The scheme works by branching on results. You start from an unsubstituted lead and make a defined first analog, such as a 4-chloro derivative on an aromatic ring. Depending on whether the new compound is more potent, equipotent, or less potent than the parent, the chart sends you down a branch — toward more lipophilic and electron-withdrawing groups, toward different electronics, or toward less lipophilic groups — each step chosen to test the most informative substituent next. The logic is built on Hansch lipophilic (pi) and Hammett electronic (sigma) parameters, so the tree is essentially a manual, stepwise QSAR.

The Topliss tree was elegant and influential as an efficient, intuition-saving way to traverse substituent space by hand. Its modern role is mostly historical and educational: it assumes activity is driven mainly by lipophilicity and electronics, ignores steric subtleties and multi-parameter goals like ADMET, and has largely been superseded by parallel synthesis and computational design that can survey far more substituents at once.