Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT(6) 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-HT(6) 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-HT(6)R, with respect to 5-HT(2A)R, 5-HT(7)R, and D(2)R, 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-HT(6) 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-HT(6) (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.
The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT6 receptors and beta-amyloid aggregation. Structure-activity relationship analyses supported by crystallography and docking studies led to the identification of a fused-type multifunctional ligand 50, with remarkable and balanced potencies against BuChE (IC50 = 90 nM) and 5-HT6R (Ki = 4.8 nM), and inhibitory activity against Abeta aggregation (53% at 10 microM). In in vitro ADME-Tox and in vivo pharmacokinetic studies compound 50 showed good stability in the mouse liver microsomes, favourable safety profile and brain permeability with the brain to plasma ratio of 6.79 after p.o. administration in mice, thus being a promising candidate for in vivo pharmacology studies and a solid foundation for further research on effective anti-AD therapies.
New tritarget small molecules combining Ca(2+) channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca(2+) channels blockade activity (IC50 = 21 +/- 1 muM), potent affinity against hH3R (Ki = 565 +/- 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 +/- 0.10 muM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.