Guanidines: Synthesis of Novel Histamine H3R Antagonists with Additional Breast Anticancer Activity and Cholinesterases Inhibitory Effect

Marek Staszewski; Magdalena Iwan; Tobias Werner; Marek Bajda; Justyna Godyń; Gniewomir Latacz; Agnieszka Korga-Plewko; Joanna Kubik; Natalia Szałaj; Holger Stark; Barbara Malawska; Anna Więckowska; Krzysztof Walczyński

doi:10.3390/ph16050675

Guanidines: Synthesis of Novel Histamine H₃R Antagonists with Additional Breast Anticancer Activity and Cholinesterases Inhibitory Effect

Pharmaceuticals (Basel). 2023 Apr 30;16(5):675. doi: 10.3390/ph16050675.

Authors

Affiliations

¹ Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszyńskiego 1, 90-151 Łódź, Poland.
² Department of Toxicology, Medical University of Lublin, Chodźki 8, 20-093 Lublin, Poland.
³ Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
⁴ Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
⁵ Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
⁶ Independent Medical Biology Unit, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland.

Abstract

This study examines the properties of novel guanidines, designed and synthesized as histamine H₃R antagonists/inverse agonists with additional pharmacological targets. We evaluated their potential against two targets viz., inhibition of MDA-MB-231, and MCF-7 breast cancer cells viability and inhibition of AChE/BuChE. ADS10310 showed micromolar cytotoxicity against breast cancer cells, combined with nanomolar affinity at hH₃R, and may represent a promising target for the development of an alternative method of cancer therapy. Some of the newly synthesized compounds showed moderate inhibition of BuChE in the single-digit micromolar concentration ranges. H₃R antagonist with additional AChE/BuChE inhibitory effect might improve cognitive functions in Alzheimer's disease. For ADS10310, several in vitro ADME-Tox parameters were evaluated and indicated that it is a metabolically stable compound with weak hepatotoxic activity and can be accepted for further studies.

Keywords: antagonist; breast cancer; guanidines; histamine H3 receptor; multi-target directed ligand.

Abstract

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