Recent structure-activity relationship (SAR) studies identified multiple Hsp90/Aha1 small molecule disruptors that manifest moderately improved potencies and physiochemical properties. Among these molecules, a 1,5-bisubstituted-1,2,3-triazole containing molecule (Triazole A), demonstrated the importance of a cis-amide bond. Consequently, this work aimed to optimize Triazole A via a nitrogen scan and Topliss tree approach. The potency was determined against cell lysates and co-Immunoprecipitation (co-IP) experiments. The most efficacious molecules were evaluated for physiochemical properties that include aqueous solubility, human liver microsome half-life, and MDCK-MDR1 permeability. New molecules emerged from this study that manifest nanomolar potency and improved activity in cell-based co-IP experiments. These new molecules represent a significant improvement over prior Hsp90/Aha1 disruptors and provide chemical tools to investigate the significance of Hsp90/Aha1 complexes.