Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

2019-11-06T22:05:19Z (GMT) by Aleksandra Nilova David Stuart
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 (SEAr), 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.