Given that the scaffold has three aromatic rings and contains several heteroatoms that could partake in both intramolecular and intermolecular hydrogen-bonds we posited that perhaps the low solubility of the scaffold may be a function of planarity and high-crystal packing energy. It has previously been observed that introducing contiguous rotatable bonds may reduce crystal packing and improve solubility of molecules in aqueous media. Thus, analogs 35 and 36 were designed to insert a methylene between the amide carbonyl and the pendent phenyl to explore both AC1 potency and solubility. Unfortunately, the modification was detrimental to AC potency as each analog was at least 10-fold less potent compared to their nearest neighbor analogs without the extra methylene. However, qualitatively these analogs were more soluble in aqueous media compared to the matched molecular pairs, although exact measurements were not obtained because the molecules were inferior in AC1 activity. Nonetheless, for future analog design the strategy of reducing planarity of the scaffold may prove useful. Finally, when combinations of substitutions were made there was not an improvement in activity versus AC1 that was desired. Regardless, the combined modifications in 38 did project to yield a CNS active analog according to QikProp projections. Thus, this molecule, along with three analogs in 16, 20, and 39 that exhibited better potency with inferior projected BBB permeability were prioritized for further evaluation in downstream assays.