4-tert-Pentylphenoxyalkyl derivatives – Histamine H3 receptor ligands and monoamine oxidase B inhibitors. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Łażewska, Dorota; Olejarz-Maciej, Agnieszka; Kaleta, Maria; Bajda, Marek; Siwek, Agata; Karcz, Tadeusz; Doroz-Płonka, Agata; Cichoń, Urszula; Kuder, Kamil; Kieć-Kononowicz, Katarzyna
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 23/24(2018)
• Page Start: 3596
• Page End: 3600
• Publication Date: 2018-12-15
• Subjects: 4-tert-Pentylphenoxy derivatives -- Histamine H3 receptor -- Monoamine oxidase B -- Small molecule inhibitors -- Kinetic studies; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.10.048
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A series of 4-tertpentylphenoxy alkyl derivatives was synthesized and biologically evaluated. Compounds tested in vitro showed human histamine H3 receptor affinity and human monoamine oxidase B inhibitory activity. Compound5 displayed affinity for hH3 R with a Ki of 63 nM and inhibited hMAO B activity with an IC50 value of 4.5 nM. Non-competitive inhibition of hMAO B for compound5 in the enzyme kinetic study was determined. For the most potent compounds investigation of the reversibility of hMAO B inhibition was performed. Abstract: The synthesis and biological activity of 4- tert -pentylphenoxypropyl derivatives are described in this manuscript. All compounds (except one) showed human histamine H3 receptor affinity with Ki values below 760 nM. The inhibitory activity toward human monoamine oxidase B (hMAO B) was evaluated using a fluorometric Amplex-Red assay, and most of the compounds were effective in the submicromolar range. Among them, 1-(3-(4- tert -pPentylphenoxy)propyl)pyrrolidine (5 ) exhibited hMAO B inhibitory activity with an IC50 value of 4.5 nM. In addition, hMAO B inhibition by5 was shown to be non-competitive and reversible. Further, recently described potent histamine H3 receptor ligands – 4- tert -pentylphenoxyalkyl derivatives (with a 4–8 carbon spacer) – were evaluated for hMAO B inhibitory activity, and some of them displayed activity in the submicromolar range. Selected compounds were also tested for human MAO A (hMAO A) inhibitory potencies and exhibited no activity. Moreover, molecular modeling studies were carried out for tested compounds to explain their molecular mechanism of hMAO B inhibition and the selectivity of compounds for hMAO B over hMAO A.