Phenolic Metabolites as Therapeutics for Chronic Diseases: One Researcher’s PAINS Is Another’s Translatable Polypharmacology

Abstract Phenols, natural and semisynthetic compounds in which a hydroxylated or oxygenated aromatic scaffold is a defining structural feature, occupy a paradoxical position in drug discovery. On the one hand, these compounds are frequently scrutinized for triggering Pan-Assay INterference compoundS (PAINS) structural alerts; on the other, their reported wide-ranging bioactivities support continued evaluation as potential therapeutics, particularly given that several phenolic compounds and mixtures have attained FDA approval for treating diseases ranging from cancers to viral infections. Accordingly, this perspective contrasts concerns raised by PAINS structural alerts with reported broad pharmacological activity and proposes a framework for the rational evaluation as well as the synthetic development of phenolic scaffolds.