Rational Design, Synthesis and Pharmacological Evaluation of Chalcones as Dual-Acting Compounds—Histamine H3 Receptor Ligands and MAO-B Inhibitors
Dorota Łażewska, Agata Doroz-Płonka, Kamil Kuder, Agata Siwek, Waldemar Wagner, Joanna Karnafał-Ziembla, Agnieszka Olejarz-Maciej, Małgorzata Wolak, Monika Głuch-Lutwin, Barbara Mordyl, Oktawia Osiecka, Michał Juszczak, Katarzyna Woźniak, Małgorzata Więcek, Gniewomir Latacz
TL;DR
This paper reports the design and testing of chalcone compounds that act on two brain targets, which could be useful for treating neurodegenerative diseases and brain cancers.
Contribution
The study introduces piperidinyl chalcones as dual-acting ligands for histamine H3 receptor and MAO-B with SPRM analysis of H3R interactions.
Findings
Compound 15 showed nanomolar affinity for H3R and micromolar inhibition of MAO-B.
SPRM was first used to study H3R interactions with ligands like compound 15 and pitolisant.
Compound 15 caused cell cycle arrest and mitochondrial disruption in cancer cells.
Abstract
Chalcone-based derivatives were designed as dual-acting ligands targeting the histamine H3 receptor (H3R) and monoamine oxidase B (MAO-B), based on the lead compound DL76. Three series of compounds (1–18) were synthesised and characterised, including simple chalcones (1–9) and piperidinyl chalcones (10–18). All piperidinyl derivatives exhibited nanomolar affinity for human H3R (hH3R), with compounds 10–12 achieving Ki values ≤ 30 nM. Simple chalcones showed potent human MAO-B (hMAO-B) inhibition (IC50: 0.85–337 nM), especially 3,4-dichloro derivatives. Compound 15 was the most active hybrid, with a Ki of 46.8 nM for hH3R and an IC50 of 212.5 nM for hMAO-B. Molecular docking and 250 ns simulations revealed stabilising interactions at both binding sites and clarified structural features behind dual activity. Preliminary ADMET profiling showed low Caco-2 permeability and rapid microsomal…
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Taxonomy
TopicsMast cells and histamine · Polyamine Metabolism and Applications · Phenothiazines and Benzothiazines Synthesis and Activities