Stary D

References (5)

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 : Biphenylalkoxyamine Derivatives-Histamine H(3) Receptor Ligands with Butyrylcholinesterase Inhibitory Activity - Lazewska_2021_Molecules_26_
Author(s) : Lazewska D , Zareba P , Godyn J , Doroz-Plonka A , Frank A , Reiner-Link D , Bajda M , Stary D , Mogilski S , Olejarz-Maciej A , Kaleta M , Stark H , Malawska B , Kiec-Kononowicz K
Ref : Molecules , 26 : , 2021
Abstract : Neurodegenerative diseases, e.g., Alzheimer's disease (AD), are a key health problem in the aging population. The lack of effective therapy and diagnostics does not help to improve this situation. It is thought that ligands influencing multiple but interconnected targets can contribute to a desired pharmacological effect in these complex illnesses. Histamine H(3) receptors (H(3)Rs) play an important role in the brain, influencing the release of important neurotransmitters, such as acetylcholine. Compounds blocking their activity can increase the level of these neurotransmitters. Cholinesterases (acetyl- and butyrylcholinesterase) are responsible for the hydrolysis of acetylcholine and inactivation of the neurotransmitter. Increased activity of these enzymes, especially butyrylcholinesterase (BuChE), is observed in neurodegenerative diseases. Currently, cholinesterase inhibitors: donepezil, rivastigmine and galantamine are used in the symptomatic treatment of AD. Thus, compounds simultaneously blocking H(3)R and inhibiting cholinesterases could be a promising treatment for AD. Herein, we describe the BuChE inhibitory activity of H(3)R ligands. Most of these compounds show high affinity for human H(3)R (K(i) < 150 nM) and submicromolar inhibition of BuChE (IC(50) < 1 microM). Among all the tested compounds, 19 (E153, 1-(5-([1,1'-biphenyl]-4-yloxy)pentyl)azepane) exhibited the most promising in vitro affinity for human H(3)R, with a K(i) value of 33.9 nM, and for equine serum BuChE, with an IC(50) of 590 nM. Moreover, 19 (E153) showed inhibitory activity towards human MAO B with an IC(50) of 243 nM. Furthermore, in vivo studies using the Passive Avoidance Task showed that compound 19 (E153) effectively alleviated memory deficits caused by scopolamine. Taken together, these findings suggest that compound 19 can be a lead structure for developing new anti-AD agents.
ESTHER : Lazewska_2021_Molecules_26_
PubMedSearch : Lazewska_2021_Molecules_26_
PubMedID: 34208297

Title : Biological evaluation and molecular docking of novel 1,3,4-thiadiazole-resorcinol conjugates as multifunctional cholinesterases inhibitors - Skrzypek_2021_Bioorg.Chem_107_104617
Author(s) : Skrzypek A , Matysiak J , Karpinska M , Czarnecka K , Krecisz P , Stary D , Kukulowicz J , Paw B , Bajda M , Szymanski P , Niewiadomy A
Ref : Bioorg Chem , 107 :104617 , 2021
Abstract : Two series of novel 1,3,4-thiadiazole-resorcinol conjugates were efficiently synthesized and evaluated as cholinesterases inhibitors. N-Butyl- and N-chlorophenyl-5-amino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols were identified as the most promising compounds of low nanomolar activity against AChE (IC(50) = 29-76 nM) and moderate activity against BuChE. The inhibition mechanism studies proved that the compounds are mixed type inhibitors. The docking simulations showed great affinity of the compounds for both enzymes. The modelled amine derivatives exhibited a similar arrangement in the catalytic anionic site of AChE similar to that of tacrine. The thiadiazole ring interacted with Trp84 and the phenyl groups created Pi-Pi stacking interactions with the residue - Phe330. The compounds showed better inhibition of the in vitro self-induced Abeta (1-42) aggregation than that compared with curcumin as well as antioxidant properties similar to those of quercetin. They exhibited metal ion chelating properties, acceptable cytotoxicity in vitro and favourable ADMET profile determined in silico.
ESTHER : Skrzypek_2021_Bioorg.Chem_107_104617
PubMedSearch : Skrzypek_2021_Bioorg.Chem_107_104617
PubMedID: 33444983

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