The hypoxia inducible factor 1 (HIF-1) is an important transcription factor for cell survival in low oxygen concentrations. A variety of methods have been employed to selectively target this HIF pathway toward cancer therapies. A certain benzopyran-based scaffold, of lead compounds KCN1 and 64b, has been further explored to gain insights into the mode of action of those inhibitors. Utilizing established small molecule inhibitors as leads, novel inhibitors have been designed with improved potency and solubility, while only requiring two to five steps for synthesis. Qualitative structure-activity relationships developed in this work have contributed to the scientific development of other, even more therapeutically relevant small molecule inhibitors.