The hypoxia inducible factor (HIF) pathway is an attractive target for cancer, as it controls tumor adaptation to growth under hypoxia and mediates chemotherapy and radiation resistance. We previously discovered 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N- phenylbenzenesulfonamide as a novel, small-molecule HIF-1 pathway inhibitor in a high-throughput cell-based assay, but its in vivo delivery is hampered by poor aqueous solubility (0.009 μM in water; log P 7.4 = 3.7). Here we describe the synthesis of 12 N-alkyl-N-[(8-R-2,2-dimethyl-2H-chromen-6-yl) methyl]heteroarylsulfonamides, which were designed to possess optimal lipophilicities and aqueous solubilities by in silico calculations. Experimental log P 7.4 values of 8 of the 12 new analogs ranged from 1.2-3.1. Aqueous solubilities of three analogs were measured, among which the most soluble N-[(8-methoxy-2,2-dimethyl-2H-chromen-6-yl)methyl]-N-(propan-2-yl) pyridine-2-sulfonamide had an aqueous solubility of 80 μM, e.g., a solubility improvement of ∼9000-fold. The pharmacological optimization had limited impact on drug efficacy as the compounds retained IC 50 values at or below 5 μM in our HIF-dependent reporter assay. © 2012 American Chemical Society.