Handzlik J

References (4)

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

Title : Cyanobiphenyls: Novel H(3) receptor ligands with cholinesterase and MAO B inhibitory activity as multitarget compounds for potential treatment of Alzheimer's disease - Godyn_2021_Bioorg.Chem_114_105129
Author(s) : Godyn J , Zareba P , aewska D , Stary D , Reiner-Link D , Frank A , Latacz G , Mogilski S , Kaleta M , Doroz-Plonka A , Lubelska A , Honkisz-Orzechowska E , Olejarz-Maciej A , Handzlik J , Stark H , Kiec-Kononowicz K , Malawska B , Bajda M
Ref : Bioorg Chem , 114 :105129 , 2021
Abstract : Alzheimer's disease (AD) is a complex and incurable illness that requires the urgent approval of new effective drugs. However, since 2003, no new molecules have shown successful results in clinical trials, thereby making the common "one compound - one target" paradigm questionable. Recently, the multitarget-directed ligand (MTDL) approach has gained popularity, as compounds targeting at least two biological targets may be potentially more effective in treating AD. On the basis of these findings, we designed, synthesized, and evaluated through biological assays a series of derivatives of alicyclic amines linked by an alkoxy bridge to an aromatic lipophilic moiety of [1,1'-biphenyl]-4-carbonitrile. The research results revealed promising biological activity of the obtained compounds toward the chosen targets involved in AD pathophysiology; the compounds showed high affinity (mostly low nanomolar range of K(i) values) for human histamine H(3) receptors (hH(3)R) and good nonselective inhibitory potency (micromolar range of IC(50) values) against acetylcholinesterase from electric eel (eeAChE) and equine serum butyrylcholinesterase (eqBuChE). Moreover, micromolar/submicromolar potency against human monoamine oxidase B (hMAO B) was detected for some compounds. The study identified compound 5 as a multiple hH(3)R/eeAChE/eqBuChE/hMAO B ligand (5: hH(3)R K(i) = 9.2 nM; eeAChE IC(50) = 2.63 microM; eqBuChE IC(50) = 1.30 microM; hMAO B IC(50) = 0.60 microM). Further in vitro studies revealed that compound 5 exhibits a mixed type of eeAChE and eqBuChE inhibition, good metabolic stability, and moderate hepatotoxicity effect on HepG2 cells. Finally, compound 5 showed a beneficial effect on scopolamine-induced memory impairments, as assessed by the passive avoidance test, thus revealing the potential of this compound as a promising agent for further optimization for AD treatment.
ESTHER : Godyn_2021_Bioorg.Chem_114_105129
PubMedSearch : Godyn_2021_Bioorg.Chem_114_105129
PubMedID: 34217977

Title : Rational design of new multitarget histamine H(3) receptor ligands as potential candidates for treatment of Alzheimer's disease - Lazewska_2020_Eur.J.Med.Chem_207_112743
Author(s) : Lazewska D , Bajda M , Kaleta M , Zareba P , Doroz-Plonka A , Siwek A , Alachkar A , Mogilski S , Saad A , Kuder K , Olejarz-Maciej A , Godyn J , Stary D , Sudol S , Wiecek M , Latacz G , Walczak M , Handzlik J , Sadek B , Malawska B , Kiec-Kononowicz K
Ref : Eur Journal of Medicinal Chemistry , 207 :112743 , 2020
Abstract : 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 H(3) receptor (H(3)R) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated in vitro for human H(3)R (hH(3)R) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hH(3)R affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC(50) 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 hH(3)R (K(i) = 170 nM and 100 nM respectively) and high inhibitory activity for acetylcholinesterase (IC(50) = 180 nM and 136 nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC(50) = 880 nM and 394 nM respectively) and hMAO B (IC(50) = 775 nM and 897 nM respectively). Furthermore, molecular docking studies were performed for hH(3)R, 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.
ESTHER : Lazewska_2020_Eur.J.Med.Chem_207_112743
PubMedSearch : Lazewska_2020_Eur.J.Med.Chem_207_112743
PubMedID: 32882609