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Analysis of Benzenoid Substitution Patterns in Small Molecule Active Pharmaceutical Ingredients

submitted on 31.10.2019, 21:12 and posted on 06.11.2019, 22:05 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.


Email Address of Submitting Author


Portland State University


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest


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