Sudol-Talaj S

References (2)

Title : Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT(6)R ligands with noticeable action on AChE\/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease - Czarnota-Lydka_2023_Eur.J.Med.Chem_259_115695
Author(s) : Czarnota-Lydka K , Sudol-Talaj S , Kucwaj-Brysz K , Kurczab R , Satala G , de Candia M , Samarelli F , Altomare CD , Carocci A , Barbarossa A , eslawska E , Gluch-Lutwin M , Mordyl B , Kubacka M , Wilczynska-Zawal N , Jastrzebska-Wiesek M , Partyka A , Khan N , Wiecek M , Nitek W , Honkisz-Orzechowska E , Latacz G , Wesolowska A , Carrieri A , Handzlik J
Ref : Eur Journal of Medicinal Chemistry , 259 :115695 , 2023
Abstract : 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.
ESTHER : Czarnota-Lydka_2023_Eur.J.Med.Chem_259_115695
PubMedSearch : Czarnota-Lydka_2023_Eur.J.Med.Chem_259_115695
PubMedID: 37567058

Title : Benzophenone Derivatives with Histamine H(3) Receptor Affinity and Cholinesterase Inhibitory Potency as Multitarget-Directed Ligands for Possible Therapy of Alzheimer's Disease - Godyn_2022_Molecules_28_
Author(s) : Godyn J , Zareba P , Stary D , Kaleta M , Kuder KJ , Latacz G , Mogilski S , Reiner-Link D , Frank A , Doroz-Plonka A , Olejarz-Maciej A , Sudol-Talaj S , Nolte T , Handzlik J , Stark H , Wieckowska A , Malawska B , Kiec-Kononowicz K , Lazewska D , Bajda M
Ref : Molecules , 28 : , 2022
Abstract : The multitarget-directed ligands demonstrating affinity to histamine H(3) 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 H(3)R (K(i) = 8 nM) and significant inhibitory activity toward BuChE (IC(50) = 172 nM and 1.16 microM 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 x 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 (ED(50) = 20.9 mg/kg) and inflammatory (ED(50) = 17.5 mg/kg) pain.
ESTHER : Godyn_2022_Molecules_28_
PubMedSearch : Godyn_2022_Molecules_28_
PubMedID: 36615435