Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

An analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients (APIs) approved by the FDA reveals a preference for 1,4-substituted ( para ), 1-substituted ( mono ), 1,2,4-substituted, and 1,2-substituted ( ortho ) arenes. Notably, these substitution patterns are widely commercially available and readily accessible by electrophilic aromatic substitution (S E Ar), but more highly substituted and contra-electronic substitution patterns are severely underrepresented in drug substances. Finally, structural variation decreases with increasing substitution and there is a strong reliance on natural product scaffolds in drugs with more highly substituted benzenoid rings.