Epigenetic markers of the cellular genome are major controllers of the transcriptional level of various genes in physiological and pathological states. These markers are written and erased by epigenetic factors which have been recently studied as potential therapeutic targets of various disease states. Histone lysine demethylases are an example of these epigenetic factors. The subfamily number 6 of these enzymes (KDM6) are an understudied group of histone demethylases which have been recently connected to cancers and inflammation. In this work, we conducted a rational and computer-aided approach to design and synthesize KDM6 inhibitors. The designed inhibitors are imidazole-based and are functionalized with variable metal-chelating group to be able to chelate the active site ferrous ion. One of the synthesized compounds, compound 6, was able to inhibit KDM6-expressing cancer cell lines by more than 50%. Molecular docking studies suggest that this compound is able to achieve important active site interactions and coordinate the active site metal through a tridentate interaction. Furthermore a correlation was established between the structural features and CLogP of the tested compounds and their activity. These results represent a promising starting point for the future development of novel KDM6 inhibitors with higher potency.