The Search for Histamine H4 Receptor Ligands with Anticancer Activity among Novel (Thio)urea Derivatives

Enrique Domínguez-Álvarez, Dorota Łażewska, Zsanett Szabó, Stefanie Hagenow, David Reiner, Márió Gajdács, Gabriella Spengler, Holger Stark, Jadwiga Handzlik, Katarzyna Kieć-Kononowicz

Research output: Contribution to journalArticle


A series of 33 novel (thio)urea-containing compounds were initially designed and synthesized as potential ligands for the histamine H4 receptor (H4R). However, only 3 compounds showed a statistically significant affinity towards H4R (Ki<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 (IC50= 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.

Original languageEnglish
Pages (from-to)10943-10952
Number of pages10
Issue number36
Publication statusPublished - Sep 30 2019



  • Cytotoxicity
  • Drug design
  • Multidrug resistance
  • Neurotransmitters
  • Ureas, Thioureas

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Domínguez-Álvarez, E., Łażewska, D., Szabó, Z., Hagenow, S., Reiner, D., Gajdács, M., Spengler, G., Stark, H., Handzlik, J., & Kieć-Kononowicz, K. (2019). The Search for Histamine H4 Receptor Ligands with Anticancer Activity among Novel (Thio)urea Derivatives. ChemistrySelect, 4(36), 10943-10952.