Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT₆ receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT₆ receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (K_i < 200 nM) and selectivity towards 5-HT₆R, with respect to 5-HT_2AR, 5-HT₇R, and D₂R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT₆ agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT₆ (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.

Among the serotonin receptors, one of the most recently discovered 5-HT₆ subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT₆ receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT₆ receptor. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT₆ receptor target.

The multitarget-directed ligands demonstrating affinity to histamine H₃ receptor and additional cholinesterase inhibitory potency represent a promising strategy for research into the effective treatment of Alzheimer’s disease. In this study, a novel series of benzophenone derivatives was designed and synthesized. Among these derivatives, we identified compound 6 with a high affinity for H₃R (K_i = 8 nM) and significant inhibitory activity toward BuChE (IC₅₀ = 172 nM and 1.16 µM for eqBuChE and hBuChE, respectively). Further in vitro studies revealed that compound 6 (4-fluorophenyl) (4-((5-(piperidin-1-yl)pentyl)oxy)phenyl)methanone) displays moderate metabolic stability in mouse liver microsomes, good permeability with a permeability coefficient value (P_e) of 6.3 × 10⁻⁶ cm/s, and its safety was confirmed in terms of hepatotoxicity in the HepG2 cell line. Therefore, we investigated the in vivo activity of compound 6 in the Passive Avoidance Test and the Formalin Test. While compound 6 did not show a statistically significant influence on memory and learning, it showed analgesic properties in both acute (ED₅₀ = 20.9 mg/kg) and inflammatory (ED₅₀ = 17.5 mg/kg) pain.

Noting the worldwide rapid increase in the prevalence of overweight and obesity new effective drugs are now being sought to combat these diseases. Histamine H₃ receptor antagonists may represent an effective therapy as they have been shown to modulate histamine synthesis and release and affect a number of other neurotransmitters (norepinephrine, acetylcholine, γ-aminobutyric acid, serotonin, substance P) thus influencing the food intake. Based on the preliminary studies determining affinity, intrinsic activity, and selected pharmacokinetic parameters, two histamine H₃ receptor ligands were selected. Female rats were fed palatable food for 28 days and simultaneously administered the tested compounds intraperitoneally (i.p.) at a dose of 10 or 1 mg/kg b.w./day. Weight was evaluated daily and calorie intake was evaluated once per week. The plasma levels of cholesterol, triglycerides, leptin, adiponectin, ghrelin, corticosterone, CRP and IL-6 were determined at the end of experiment. The glucose tolerance test was also performed. To exclude false positives, the effect of tested compounds on spontaneous activity was monitored during the treatment, as well as the amount of consumed kaolin clay was studied as a reflection of possible gastrointestinal disturbances comparable to nausea. The histamine H₃ receptor antagonists KSK-59 and KSK-73 administered i.p. at a dose of 10 mg/kg b.w. prevented weight gain in a rat model of excessive eating. They reduced adipose tissue deposits and improved glucose tolerance. Both compounds showed satisfying ability to penetrate through biological membranes determined in in vitro studies. Compound KSK-73 also reduced the caloric intake of the experimental animals what indicates its anorectic effect. These results show the pharmacological properties of histamine H₃ receptor antagonists, (4-pyridyl)piperazine derivatives, as the compounds causing not only slower weight gain but also ameliorating some metabolic disorders in rats having the opportunity to overeat.