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

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.

4-Oxypiperidine Ethers as Multiple Targeting Ligands at Histamine H3 Receptors and Cholinesterases

“…Previously, our laboratory has described piperazine, 40 guanidine, 41 and 4-hydroxpiperidine-based H 3 R antagonists. 42,43 The structure−activity relationship (SAR) of the 4- 2).…”

“…Previously, our laboratory has described piperazine, guanidine, and 4-hydroxpiperidine-based H 3 R antagonists. , The structure–activity relationship (SAR) of the 4-hydroxpiperidine series found the most potent compounds to be 5-((1-(benzofuran-2-ylmethyl)­piperidin-4-yl)­oxy)- N -methyl- N -propylpentan-1-amine ( ADS003 ) (pA 2 = 8.47, for reference: thioperamide pA 2 = 8.67) and 5-((1-benzylpiperidin-4-yl)­oxy)- N -methyl- N -propylpentan-1-amine ( ADS009 ) (pA 2 = 7.79) (Figure ). , Further in vivo evaluation of the impact of ADS003 on brain neurotransmitter systems showed its ability to cross the blood–brain barrier and potency at H 3 R similar to the reference compound, ciproxifan …”