Rational design of new multitarget histamine H₃ receptor ligands as potential candidates for treatment of Alzheimer's disease

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 (K_i = 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.