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New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

Łażewska, Dorota ; Więcek, Małgorzata ; Satała, Grzegorz ; [et al.]

MDPI AG ; 2023

In: Molecules Vol. 28, No. 3 ( 2023-01-22), p. 1108-

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In: Molecules, MDPI AG, Vol. 28, No. 3 ( 2023-01-22), p. 1108-

Abstract: Since the number of people with Alzheimer’s disease (AD) continues to rise, new and effective drugs are urgently needed to not only slow down the progression of the disease, but to stop or even prevent its development. Serotonin 5-HT6 receptor (5-HT6R) ligands are still a promising therapeutic target for the treatment of AD. 1,3,5-Triazine derivatives, as novel structures lacking an indole or a sulfone moiety, have proven to be potent ligands for this receptor. In present work, new derivatives of the compound MST4 (4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine), the potent 5-HT6R antagonist (Ki = 11 nM) with promising ADMET and in vivo properties, were designed. The synthesized compounds were tested for their affinity towards 5-HT6R and other receptor (off)targets (serotonin 5-HT2A, 5-HT7 and dopamine D2). Based on the new results, 4-(2-tert-butylphenoxy)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) was selected for extended in vitro studies as a potent and selective 5-HT6R ligand (Ki = 13 nM). Its ability to permeate the blood–brain barrier (BBB) and its hepatotoxicity were evaluated. In addition, X-ray crystallography and solubility studies were also performed. The results obtained confirm that 6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine derivatives, especially compound 3, are promising structures for further pharmacological studies as 5-HT6R ligands.

Type of Medium: Online Resource

ISSN: 1420-3049

URL: Article

DOI: 10.3390/molecules28031108

Language: English

Publisher: MDPI AG

Publication Date: 2023

detail.hit.zdb_id: 2008644-1

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Crystallographic studies of piperazine derivatives of 3-methyl-5-spirofluorenehydantoin in search of structural features of P-gp inhibitors

Żesławska, Ewa ; Szymańska, Ewa ; Nitek, Wojciech ; [et al.]

International Union of Crystallography (IUCr) ; 2021

In: Acta Crystallographica Section C Structural Chemistry Vol. 77, No. 8 ( 2021-08-01), p. 467-478

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In: Acta Crystallographica Section C Structural Chemistry, International Union of Crystallography (IUCr), Vol. 77, No. 8 ( 2021-08-01), p. 467-478

Abstract: 5-Spirofluorenehydantoin derivatives show efflux modulating, cytotoxic and antiproliferative effects in sensitive and resistant mouse T-lymphoma cells. In order to extend the knowledge available about the pharmacophoric features responsible for the glycoprotein P (P-gp) inhibitory properties of arylpiperazine derivatives of 3-methyl-5-spirofluorenehydantoin, we have performed crystal structure analyses for 1-[3-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)propyl] -4-phenylpiperazine-1,4-diium dichloride monohydrate, C 29 H 32 N 4 O 2 2+ ·2Cl − ·H 2 O ( 1 ), 3′-methyl-1′-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}spiro[fluorene-9,5′-imidazolidine] -2′,4′-dione, C 29 H 29 N 5 O 4 ·H 2 O ( 2 ), 3′-methyl-1′-{5-[4-(4-nitrophenyl)piperazin-1-yl]pentyl}spiro[fluorene-9,5′-imidazolidine] -2′,4′-dione, C 31 H 33 N 5 O 4 ( 3 ), and 1-benzyl-4-[5-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)pentyl] piperazine-1,4-diium dichloride 0.613-hydrate, C 32 H 38 N 4 O 2 2+ ·2Cl − ·0.613H 2 O ( 4 ). Structure 3 is anhydrous but the other three structures crystallize with water present. The investigated compounds crystallize in the monoclinic crystal system, with the space group P 2 1 / n for 1 and 3 , and P 2 1 / c for 2 and 4 . The cations of salts 1 and 4 are doubly protonated, with the protons located on the N atoms of the piperazine rings. The packing of 1 and 4 in the crystals is dominated by intermolecular N—H...Cl and O—H...Cl hydrogen bonds. In the crystal structure of 2 , the intermolecular interactions are dominated by O—H...O and O—H...N hydrogen bonds, while in 3 , which is lacking in classic hydrogen-bond donors, it is C—H...O contacts that dominate. Additionally, we have performed induced-fit docking studies for the investigated compounds docked to the P-gp human homology model.

Type of Medium: Online Resource

ISSN: 2053-2296

URL: Article

DOI: 10.1107/S2053229621006756

DOI: 10.1107/S2053229621006756/ky3205sup1.cif

DOI: 10.1107/S2053229621006756/ky32051sup2.hkl

DOI: 10.1107/S2053229621006756/ky32052sup3.hkl

DOI: 10.1107/S2053229621006756/ky32053sup4.hkl

DOI: 10.1107/S2053229621006756/ky32054sup5.hkl

Language: Unknown

Publisher: International Union of Crystallography (IUCr)

Publication Date: 2021

detail.hit.zdb_id: 2025703-X

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An insight into the structure of 5-spiro aromatic derivatives of imidazolidine-2,4-dione, a new group of very potent inhibitors of tumor multidrug resistance in T-lymphoma cells

Żesławska, Ewa ; Kucwaj-Brysz, Katarzyna ; Kincses, Annamária ; [et al.]

Elsevier BV ; 2021

In: Bioorganic Chemistry Vol. 109 ( 2021-04), p. 104735-

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In: Bioorganic Chemistry, Elsevier BV, Vol. 109 ( 2021-04), p. 104735-

Type of Medium: Online Resource

ISSN: 0045-2068

URL: Article

DOI: 10.1016/j.bioorg.2021.104735

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 1462232-4

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Knowledge Base component of Intelligent ALMM System based on the ontology approach

Gomolka, Zbigniew ; Twarog, Boguslaw ; Zeslawska, Ewa ; [et al.]

Elsevier BV ; 2022

In: Expert Systems with Applications Vol. 199 ( 2022-08), p. 116975-

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In: Expert Systems with Applications, Elsevier BV, Vol. 199 ( 2022-08), p. 116975-

Type of Medium: Online Resource

ISSN: 0957-4174

URL: Article

DOI: 10.1016/j.eswa.2022.116975

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 1041179-3

detail.hit.zdb_id: 2017237-0

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Architecture of the rings of 5-arylidenerhodanine derivatives versus P-gp inhibition

Nitek, Wojciech ; Szymańska, Ewa ; Tejchman, Waldemar ; [et al.]

International Union of Crystallography (IUCr) ; 2023

In: Acta Crystallographica Section C Structural Chemistry Vol. 79, No. 9 ( 2023-09-01), p. 334-343

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In: Acta Crystallographica Section C Structural Chemistry, International Union of Crystallography (IUCr), Vol. 79, No. 9 ( 2023-09-01), p. 334-343

Abstract: 5-Arylidene derivatives of rhodanine show various biological activities. The new crystal structures of five derivatives investigated towards ABCB1 efflux pump modulation are reported, namely, 2-[5-([1,1′-biphenyl]-4-ylmethylidene] -4-oxo-2-thioxothiazolidin-3-yl)acetic acid dimethyl sulfoxide monosolvate, C 18 H 13 NO 3 S 2 ·C 2 H 6 OS ( 1 ), 4-[5-([1,1′-biphenyl]-4-ylmethylidene] -4-oxo-2-thioxothiazolidin-3-yl)butanoic acid, C 20 H 17 NO 3 S 2 ( 2 ), 5-[4-(benzyloxy)benzylidene]-2-thioxothiazolidin-4-one, C 17 H 13 NO 2 S 2 ( 3 ), 4-{5-[4-(benzyloxy)benzylidene]-4-oxo-2-thioxothiazolidin-3-yl}butanoic acid, C 21 H 19 NO 4 S 2 ( 4 ), and 5-[4-(diphenylamino)benzylidene]-2-thioxothiazolidin-4-one, C 22 H 16 N 2 OS 2 ( 5 ). Compounds 1 and 3 – 5 crystallize in the triclinic space group P -1, while 2 crystallizes in the monoclinic space group P 2 1 / n , where the biphenyl moiety is observed in two positions ( A and B ). Two molecules are present in the asymmetric unit of 5 and, for the other four compounds, there is only one molecule; moreover, 1 crystallizes with one dimethyl sulfoxide molecule. The packing of the molecules containing a carboxyl group ( 1 , 2 and 4 ) is determined by O—H...O hydrogen bonds, while in the other two compounds ( 3 and 5 ), the packing is determined by N—H...O hydrogen bonds. Additionally, induced-fit docking studies have been performed for the active compounds to investigate their putative binding mode inside the human glycoprotein P (P-gp) binding pocket.

Type of Medium: Online Resource

ISSN: 2053-2296

URL: Article

DOI: 10.1107/S2053229623006502

DOI: 10.1107/S2053229623006502/yp3230sup1.cif

DOI: 10.1107/S2053229623006502/yp32301sup2.hkl

DOI: 10.1107/S2053229623006502/yp32301sup7.cml

DOI: 10.1107/S2053229623006502/yp32302sup3.hkl

DOI: 10.1107/S2053229623006502/yp32302sup8.cml

DOI: 10.1107/S2053229623006502/yp32303sup4.hkl

DOI: 10.1107/S2053229623006502/yp32303sup9.cml

DOI: 10.1107/S2053229623006502/yp32304sup10.cml

DOI: 10.1107/S2053229623006502/yp32304sup5.hkl

DOI: 10.1107/S2053229623006502/yp32305sup11.cml

DOI: 10.1107/S2053229623006502/yp32305sup6.hkl

Language: Unknown

Publisher: International Union of Crystallography (IUCr)

Publication Date: 2023

detail.hit.zdb_id: 2025703-X

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Generalization of ALMM Based Learning Method for Planning and Scheduling

Gomolka, Zbigniew ; Dudek-Dyduch, Ewa ; Zeslawska, Ewa

MDPI AG ; 2022

In: Applied Sciences Vol. 12, No. 24 ( 2022-12-12), p. 12766-

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In: Applied Sciences, MDPI AG, Vol. 12, No. 24 ( 2022-12-12), p. 12766-

Abstract: This paper refers to a machine learning method for solving NP-hard discrete optimization problems, especially planning and scheduling. The method utilizes a special multistage decision process modeling paradigm referred to as the Algebraic Logical Metamodel based learning methods of Multistage Decision Processes (ALMM). Hence, the name of the presented method is the ALMM Based Learning method. This learning method utilizes a specifically built local multicriterion optimization problem that is solved by means of scalarization. This paper describes both the development of such local optimization problems and the concept of the learning process with the fractional derivative mechanism itself. It includes proofs of theorems showing that the ALMM Based Learning method can be defined for a much broader problem class than initially assumed. This significantly extends the range of the prime learning method applications. New generalizations for the prime ALMM Based Learning method, as well as some essential comments on a comparison of Reinforcement Learning with the ALMM Based Learning, are also presented.

Type of Medium: Online Resource

ISSN: 2076-3417

URL: Article

DOI: 10.3390/app122412766

Language: English

Publisher: MDPI AG

Publication Date: 2022

detail.hit.zdb_id: 2704225-X

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5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells

Żesławska, Ewa ; Tejchman, Waldemar ; Kincses, Annamária ; [et al.]

MDPI AG ; 2022

In: International Journal of Molecular Sciences Vol. 23, No. 18 ( 2022-09-16), p. 10812-

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In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 18 ( 2022-09-16), p. 10812-

Abstract: Multidrug resistance (MDR) is considered one of the major mechanisms responsible for the failure of numerous anticancer and antiviral chemotherapies. Various strategies to overcome the MDR phenomenon have been developed, and one of the most attractive research directions is focused on the inhibition of MDR transporters, membrane proteins that extrude cytotoxic drugs from living cells. Here, we report the results of our studies on a series newly synthesized of 5-arylidenerhodanines and their ability to inhibit the ABCB1 efflux pump in mouse T-lymphoma cancer cells. In the series, compounds possessing a triphenylamine moiety and the carboxyl group in their structure were of particular interest. These amphiphilic compounds showed over 17-fold stronger efflux pump inhibitory effects than verapamil. The cytotoxic and antiproliferative effects of target rhodanines on T-lymphoma cells were also investigated. A putative binding mode for 11, one of the most potent P-gp inhibitors tested here, was predicted by molecular docking studies and discussed with regard to the binding mode of verapamil.

Type of Medium: Online Resource

ISSN: 1422-0067

URL: Article

DOI: 10.3390/ijms231810812

Language: English

Publisher: MDPI AG

Publication Date: 2022

detail.hit.zdb_id: 2019364-6

SSG: 12

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Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma

Ali, Wesam ; Garbo, Sabrina ; Kincses, Annamária ; [et al.]

Elsevier BV ; 2022

In: European Journal of Medicinal Chemistry Vol. 243 ( 2022-12), p. 114761-

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In: European Journal of Medicinal Chemistry, Elsevier BV, Vol. 243 ( 2022-12), p. 114761-

Type of Medium: Online Resource

ISSN: 0223-5234

URL: Article

DOI: 10.1016/j.ejmech.2022.114761

Language: English

Publisher: Elsevier BV

Publication Date: 2022

detail.hit.zdb_id: 2005170-0

SSG: 15,3

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Intelligent ALMM System - implementation assumptions for its Knowledge Base

Dudek-Dyduch, Ewa ; Gomolka, Zbigniew ; Twarog, Boguslaw ; [et al.]

EDP Sciences ; 2018

In: ITM Web of Conferences Vol. 21 ( 2018), p. 00002-

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In: ITM Web of Conferences, EDP Sciences, Vol. 21 ( 2018), p. 00002-

Abstract: The paper introduces the concept of implementation assumptions about the Knowledge Base (KB) system cooperating with intelligent information system for the discrete optimization of problem solving, named Intelligent ALMM System. This system utilizes a modeling paradigm named Algebraic Logical Meta Model of Multistage Decision Processes (ALMM) and its theory, both developed by Dudek-Dyduch E. The system solves combinatorial and discrete optimization problems including NP-hard problems with possible user assistance. The models of problems are stored in a Problem Model Library. In this paper the idea of KB for the storage of the properties of problems is presented. The concept of the KB on problems presented in previous works has been extended by introducing an additional module pertaining to the properties of a problems library. A discussion was presented in the context of the selection of tools that enable the construction of such a library as well as its architecture. In the adopted strategy of storing the properties of problems, the interface for exchanging information is compatible with the library of problems using polymorphic and component properties of object-oriented programming. Considerations are explained by means of a sample UML diagram and interface prototypes.

Type of Medium: Online Resource

ISSN: 2271-2097

URL: Article

DOI: 10.1051/itmconf/20182100002

Language: English

Publisher: EDP Sciences

Publication Date: 2018

detail.hit.zdb_id: 2755683-9

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A new approach to spatiotemporal estimation of the river state

Gomolka, Zbigniew ; Krutys, Pawel ; Twarog, Boguslaw ; [et al.]

Elsevier BV ; 2020

In: Journal of Process Control Vol. 94 ( 2020-10), p. 125-143

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In: Journal of Process Control, Elsevier BV, Vol. 94 ( 2020-10), p. 125-143

Type of Medium: Online Resource

ISSN: 0959-1524

URL: Article

DOI: 10.1016/j.jprocont.2020.08.008

Language: English

Publisher: Elsevier BV

Publication Date: 2020

detail.hit.zdb_id: 2000438-2

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