The indole moiety is a privileged fragment that frequently populates existing bioactive compound collections. The development of an indole‐dearomatization sequence and its application for library expansion of a collection of indole‐containing pseudo‐natural products (NPs) are described. The resulting compounds are topologically distinct from the original compound class. Phenotyping by means of the cell painting assay initially indicates that the dearomatized compounds are morphologically different than the original pseudo‐NP compound class and guiding NPs. However, analysis by means of a new subprofile analysis of the same cell painting assay data indicates that similar morphologies persist throughout the compound classes. Further biological studies support the findings of the subprofile analysis and highlight its potential to more effectively characterize novel compounds. The biological findings suggest that a plethora of indole‐dearomatization reactions can be applied to existing indole‐containing compound collections to rapidly access new biologically relevant scaffolds.