The combination of natural product fragments to design new scaffolds of unprecedented bioactivity is a powerful strategy for the discovery of tool compounds and potential therapeutics. However, the choice of fragments to couple and the biological screens to employ remain open questions in the field. By choosing a primary fragment comprising the A/B ring system of estradiol and fusing it to nine different secondary fragments, we were able to identify compounds that modulated four different phenotypes, including inhibition of autophagy and osteoblast differentiation, as well as potassium channel and tubulin modulation. The latter two were uncovered by using unbiased morphological profiling with the cell painting assay. The number of hits and variety in bioactivity discovered validates the use of natural product fragment recombination coupled to phenotypic screening for the rapid identification of biologically diverse compounds.