The Search for Histamine H 4 Receptor Ligands with Anticancer Activity among Novel (Thio)urea Derivatives

Abstract A series of 33 novel (thio)urea‐containing compounds were initially designed and synthesized as potential ligands for the histamine H 4 receptor (H 4 R). However, only 3 compounds showed a statistically significant affinity towards H 4 R ( K i <10 μM). Considering the structural analogy of these thioureas to previously described seleno/thiourea compounds with anticancer and/or reversal multidrug resistance action in cancer cells, selected thioureas were evaluated in in vitro cytotoxicity‐ and cancer multidrug resistance assays. The thiourea derivatives showed a good cytotoxic activity, being the compound 13 d (4‐methyl‐ N‐ (p‐phenylphenyl)‐piperazine‐1‐carbothiamide) the most active (IC 50 = 11.9 μM). They also enhanced the cytotoxicity of the topoisomerase inhibitors topotecan and doxorubicin in a checkerboard combination assay. Compound 13 d showed the strongest synergistic effect on topotecan activity, whereas 13 c (4‐methyl‐ N ‐(p‐tolyl)‐piperazine‐1‐carbothiamide) was the best in combination with doxorubicin. These results can be a good starting point to design more potent and effective (thio)urea derivatives with anticancer activity.