Design and development of multitarget-directed
ligands (MTDLs) has become a very important approach in the search of new
therapies for
Alzheimer's disease (AD). In our present research, a number of
xanthone derivatives were first designed using a pharmacophore model for
histamine H3 receptor (H3R) antagonists/inverse agonists, and virtual docking was then performed for the
enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human H3R (hH3R) affinity and inhibitory activity on
cholinesterases. Most of the target compounds showed hH3R affinities in nanomolar range and exhibited
cholinesterase inhibitory activity with IC50 values in submicromolar range. Furthermore, the inhibitory effects of monoamine
oxidases (
MAO) A and B were investigated. The results showed low micromolar and selective human
MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hH3R (Ki = 170 nM and 100 nM respectively) and high inhibitory activity for
acetylcholinesterase (IC50 = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for
butyrylcholinesterase (IC50 = 880 nM and 394 nM respectively) and hMAO B (IC50 = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hH3R, human
cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for in vivo studies. The results showed significant memory-enhancing effect of compound 23 in
dizocilpine-induced
amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable
analgesic effects of compound 23 were observed in
neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.