Next, while the analogs made to this point have exhibited mid-nanomolar levels of potency in the cellular assays we observed that aqueous solubility may be a liability for the series despite the molecules possessing favorable predicted physicochemical properties from QikProp (Schrödinger, LLC; average molecular weight = 354 g/mol and QPLogPo/w = 2.55, full QikProp data set provided in a spreadsheet in supporting information). In the interest of improving aqueous solubility, we evaluated the SAR for polar substituents on the phenyl ring. The 3-OMe ( ) and 4-OMe ( ) displayed AC1 IC50s around 1 µM versus AC1 activity accompanied with much reduced AC8 inhibition (5% and 0%, respectively). Replacement of the 3-methoxy group for the 3thiomethyl substituent in analog 30 produced a two-fold improvement in AC1 activity but displayed reduced selectivity versus AC8. Compounds containing bulkier polar substituents began to display reduced AC1 potency. For example, the 3-ethoxy derivative 31 possessed an AC1 IC50 value of 0.90 µM while the 4-methoxymethoxyl (32, AC1 IC50 = 4.3 µM) and 4-dimethylamino (34, 2.3 µM) substituents all showed reduced AC1 potency. The 4-hydroxy derivative 33 is noteworthy as it is the only phenyl-substituted analog in this series that showed no activity at concentrations up to 60 µM. This suggests an intolerance of a hydrogen-bond donor at the 4position as other polar para-substitutions such as the 4-methoxy ( ), 4-methoxymethoxyl (32), and 4-dimethylamino (34) still maintained AC1 IC50 < 5 µM. Nonetheless, polar functional groups led to reduced AC1 potency across the entire series.