Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

Previous
analyses have revealed that benzenoid rings are prevalent
scaffolds in active pharmaceutical ingredients (APIs). Here, we analyze
the substitution patterns of benzenoid rings in small molecule APIs
approved by the FDA through 2019 and show that only a few substitution
patterns (1-, 1,2-, 1,4-, and 1,2,4-) prevail, and the distribution
has remained relatively constant over time. We postulate the connection
between available synthetic methods and the occurrence of a few benzenoid
substitution patterns by providing an overview of synthetic methods
that elaborate existing substitution patterns and those that create
new substitution patterns, including those of the former that are
favored by medicinal chemists. Finally, we calculated medicinal chemistry
properties of benzenoid containing APIs that are often used by practitioners
as design elements, including “druglikeness”, shape,
complexity, and similarity/diversity and discuss these properties
in the context of synthesis.