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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.

The paper presents the novel project that has been proposed and realized together with the implementation of the process of heating thermosetting components based on advanced industrial equipment and software tools. In the fundamental task of optimization, the phenomenon of process synchronization based on a centralized algorithm adapted to the specific requirements of production was taken into account. The proposed research station was optimized and located in the laboratory of the Interdisciplinary Computer Modelling of the University of Rzeszow, that specializes in raising the efficiency of industrial processes

Serotonin 5-HT 7 receptor (5-HT 7 R), one of the most recently discovered members of the serotonergic system, has become a promising target in the search for central nervous system disorders. Despite the number of preclinical results, none of the selective 5-HT 7 R agents has been approved; therefore, the clinical significance of this protein has not been confirmed yet. Recently, we described very promising, selective, and highly potent hydantoin-derived 5-HT 7 R antagonists with confirmed antidepressant activity in vivo and a very good ADMET profile; however, they have been tested in behavioral studies as racemates. In this work, the synthesis of optically pure hydantoin-derived 5-HT 7 R agents using cost-effective, classical methods has been presented for the first time. X-ray crystallographic analysis confirmed the absolute configuration on both stereogenic centers and allowed for the elucidation of the mechanism of introduction of epichlorohydrin into the hydantoin N3-position. The radioligand binding results showed a clear configuration preference for 5-HT 7 R affinity. The molecular modeling results further indicated the key interaction responsible for lower affinity (with amino acid I3 × 29). Finally, the comparison of the antidepressant and anxiolytic effects of racemates versus stereoisomers suggests an influence of additional, apart from the action on 5HT 7 R, factors responsible for the activity in vivo , which is worthy of deeper insight within further studies.

In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives ( 1 - 15 ) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7 - 9 . All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α 1 -adrenergic receptors (α 1 -AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α 1 -adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α 1A and α 1B , was conducted. Selected compounds were tested for their activity towards two α 1 -AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds ( 1 and 5 ), which possess o-methoxyphenylpiperazine fragments, strong activity (IC 50 < 100 nM) was observed. Some representatives ( 3 and 5 ), which contain alkyl linker, proved selectivity towards α 1A -AR, while two compounds with 2-hydroxypropyl linker ( 11 and 13 ) to α 1B -AR. Finally, hypotensive activity was examined in rats. The most active compound ( 5 ) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

Alzheimer's disease (AD), a neurodegenerative disorder with a complex aetiology, is the most common memory dysfunction particularly affecting the elderly. Various protein targets have been classified to be involved in the AD treatment, including 5-HT 6 receptor (5-HT 6 R). So far, the 5-HT 6 R ligands obtained by our research group have become a good basis for hydrophobicity modulation to give a chance for more effective action toward AD by additional influence on target enzymes, e.g. cyclin-dependent kinase 5 (CDK5). In the search for 5-HT 6 R agents with additional inhibitory action on the enzyme, a series of 25 new 1,3,5-triazines (7-31) as modifications of lead, 4-[1-(2,5-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (6), was rationally designed. Molecular modelling, synthesis, crystallographic studies, in vitro biological assays and behavioral studies in vivo were performed. The new triazines showed high affinity (K i  < 100 nM) and selectivity for 5-HT 6 R. The most effective one, 4-[1-(2,5-difluorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (8), exhibited the strong antagonistic action towards 5-HT 6 R (K i  = 5 nM, pK b  = 8.16), had an impact on the memory processes in the Novel Object Recognition test and displayed anxiolytic-like activity in the Elevated Plus Maze test in rats. Moreover, it had the antiplatelet effect as well as very good permeability (PAMPA model), high metabolic stability (RLMs) and satisfactory safety in vitro. Although the CDK5 inhibitory effects in vitro for the tested compounds (8, 10, 14, 18, 26-31) missed the potency expected from in silico simulations, the novel antagonist (8) with a very satisfying pharmacological and ADMET profile can serve as a new lead structure in further searches for innovative therapy against AD with accompanying symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one ( 7 - 9 ) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative ( 13 ) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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 P2 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.

A series of 10 aminoalkanol derivatives of 5-chloro-2- or 5-chloro-4-methylxanthone was synthetized and evaluated for anticonvulsant properties (MES test, mice, intraperitoneal) and compared with neurotoxicity rotarod test (NT, mice, i.p.). The best results both in terms of anticonvulsant activity and protective index value were obtained for 3: 5-chloro-2-([4-hydroxypiperidin-1-yl]methyl)-9H-xanthen-9-one hydrochloride. Compounds: 1-3, 7 and 10 revealed ED 50 values in MES test: 42.78, 31.64, 25.76, 46.19 and 52.50 mg/kg b.w., respectively. 3 showed 70% and 72% of inhibition control specific binding of sigma-1 (σ1) and sigma-2 (σ2) receptor, respectively. 3 exhibited also antinociceptive activity at dose 2 mg/kg b.w. after chronic constriction injury in mice. 1, 3, 7 and 10 were evaluated on gastrointestinal flora and proved safe. In genotoxicity test (UMU-Chromotest) compounds 1, 7 and 10 proved safe at dose 150-300 μg/ml. The pharmacokinetic analysis showed rapid absorption of all studied molecules from the digestive tract (t max  = 5-30 min). The bioavailability of the compounds ranged from 6.6% (1) to 16% (10). All studied compounds penetrate the blood-brain barrier with brain to plasma ratios varied from 4.15 (3) to 7.6 (compound 7), after i.v. administration, and from 1 (7) to 5.72 (3) after i.g. administration., (© 2022 John Wiley & Sons Ltd.)

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-HT 6 receptor (5-HT 6 R) 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-HT 6 R antagonist (K i = 11 nM) with promising ADMET and in vivo properties, were designed. The synthesized compounds were tested for their affinity towards 5-HT 6 R and other receptor (off)targets (serotonin 5-HT 2A , 5-HT 7 and dopamine D 2 ). 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-HT 6 R ligand (K i = 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-HT 6 R ligands.

Lymphomas are still difficult to treat even with modern therapies as, among others, multidrug resistance (MDR) is often counteracting a successful cancer therapy. P-gp/ABC-transporters are well-known for their crucial role in the main tumour MDR mechanism, eliminating drugs and cytotoxic substances from the cancer cell by efflux, and their modulators are promising for innovative therapy, but none has been approved in the pharmaceutical market yet. Herein, we have designed, synthesised and analysed 30 novel seleno- and thioether 1,3,5-triazine derivatives conducting comprehensive studies to evaluate their potential application in human JURKAT lymphoma cells. Among the new compounds, four (11, 12, 13 and 23) were much more effective than the reference inhibitor verapamil, being potent ABCB1 inhibitors already at 2 μM, while 5 and 15 showed very potent ABCB1 inhibitory activity only at 20 μM. Results of P-gp ATPase assays, supported with docking studies, indicated the competitive substrate mode of modulating action for 15, while ABCB1, ABCC1 and ABCG2 genes expression induction by 15 with q-PCR was confirmed. All compounds were evaluated for their cytotoxic and antiproliferative properties in both sensitive (PAR) and resistant (MDR) mouse T-lymphoma cell lines, and compound 15, also considering its promising ABCB1 inhibition properties, was revealed to be the best compound in terms of its cytotoxic effect (IC 50 : 16.73 μM) as well as concerning the antiproliferative effect (IC 50 : 5.35 μM) in MDR cells. Regarding the mechanistic studies looking at the cell cycle, the thioether 15 and selenium derivatives 26 and 29 were significantly effective in the regulation of cell cycle-related genes alone or in co-treatment with doxorubicin counteracting Cyclin D1 and E1 expression and increasing p53 and p21 levels, shedding first light on their mechanism of action. In summary, we explored the chemical space of seleno- and thioether 1,3,5-triazine derivatives with interesting activity against lymphoma. Especially compound 15 is worthy of being studied deeper to evaluate its precise mode of action further as well it can be improved regarding its potency and drug-likeness., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

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.

The constant increase in the resistance of pathogenic bacteria to the commonly used drugs so far makes it necessary to search for new substances with antibacterial activity. Taking up this challenge, we obtained a series of rhodanine-3-carboxyalkyl acid derivatives containing 2- or 3- or 4-pyridinyl moiety at the C-5 position. These compounds were tested for their antibacterial and antifungal activities. They showed activity against Gram-positive bacteria while they were inactive against Gram-negative bacteria and yeast. In order to explain the relationship between the activity of the compounds and their structure, for selected derivatives crystal structures were determined using the X-ray diffraction method. Modeling of the isosurface of electron density was also performed. For all tested compounds their lipophilicity was determined by the RP-TLC method and by calculation methods. On the basis of the carried-out research, it was found that the derivatives with 1.5 N···S electrostatics interactions between the nitrogen atom in the pyridine moiety and the sulfur atom in the rhodanine system showed the highest biological activity.

This research allowed us to find the first highly potent 5-HT 6 /5-HT 2A receptor (5-HT 6 /5-HT 2A R) dual antagonists in a group of 1,3,5-triazine compounds as a result of an exit beyond the hydrophobic feature of the pharmacophore model for 5-HT 6 R antagonists. Design and synthesis of the series (2-16) of new O- and S-containing ether derivatives of 1,3,5-triazines with the double-ring aromatic region have been performed. The new compounds were examined within the comprehensive pharmacological screening, including: radioligand binding assays, functional and ADMET studies in vitro as well as behavioral tests in rats. Crystallographic aspects and computer-aided structure-activity relationship were analyzed, as well. The comprehensive approach led to selection of compound 12 (4-(4-methylpiperazin-1-yl)-6-(2-(naphthalen-2-ylthio)propan-2-yl)-1,3,5-triazin-2-amine) with the most significant dual 5-HT 6 /5-HT 2A R antagonistic action (5-HT 6 R K i  = 11 nM, 5-HT 2A R K i  = 39 nM). Moreover, the compound 12 has satisfactory ADMETox properties in vitro, i.e.: the high permeability through biological membranes, high metabolic stability, neither mutagenic nor hepatotoxic effects, and moderate ability to inhibit CYP3A4. Above all, 12 showed ability to reverse the pharmacologically-induced (MK-801) memory impairment at low doses (1-3 mg/kg) in Novel Object Recognition (NOR) test in rats. Our results indicate a promising potency of dual 5-HT 6 /5-HT 2A R antagonism in the search for novel strategy to fight Alzheimer's disease, which remains an unmet clinical need., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The treatment of parasitic infections requires the application of chemotherapy. In view of increasing resistance to currently in-use drugs, there is a constant need to search for new compounds with anthelmintic activity. A series of 16 cinnamylidene derivatives of rhodanine, including newly synthesized methoxy derivatives ( 1 - 11 ) and previously obtained chloro, nitro, and diethylamine derivatives ( 12 - 16 ), was investigated towards anthelmintic activity. Compounds ( 1 - 16 ) were evaluated against free-living nematodes of the genus Rhabditis sp. In the tested group of rhodanine derivatives, only compound 2 shows very high biological activity (LC 50 = 0.93 µg/µL), which is higher than the reference drug albendazole (LC 50 = 19.24 µg/µL). Crystal structures of two compounds, active 2 and inactive 4 , were determined by the X-ray diffraction method to compare molecular geometry and search for differences responsible for observed biological activity/inactivity. Molecular modelling and selected physicochemical properties prediction were performed to assess the potential mechanism of action and applied in the search for an explanation as to why amongst all similar compounds only one is active. We can conclude that the tested compound 2 can be further investigated as a potential anthelmintic drug.

The aroxyalkylaminoalcohol derivatives are a group of compounds known for their pharmacological action. The crystal structures of four new xylenoxyaminoalcohol derivatives having anticonvulsant activity are reported, namely, 2-{[2-(2,6-dimethylphenoxy)ethyl]amino}-1-phenylethan-1-ol, C 18 H 23 NO 2 , 1, the salt N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium 3-hydroxybenzoate, C 18 H 24 NO 2 + ·C 7 H 5 O 3 - , 2, and two polymorphs of the salt (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium chloride, C 18 H 24 NO 2 + ·Cl - , 3 and 3p. Both polymorphs crystallize in the space group P2 1 2 1 2 and each has two cations and two anions in the asymmetric unit (Z' = 2). The molecules in the polymorphs show differences in their molecular conformations and intermolecular interactions. The crystal packing of neutral 1 is dominated by intermolecular O-H...N hydrogen bonds, resulting in the formation of one-dimensional chains. In the crystal structures of the salt forms (2, 3 and 3p), each protonated N atom is engaged in a charge-assisted hydrogen bond with the corresponding anion. The protonation of the N atom also influences the conformation of the molecular linker between the two aromatic rings and changes the orientation of the rings. The crystal packing of the salt forms is dominated by intermolecular O-H...O hydrogen bonds, resulting in the creation of chains and rings. Structural studies have been enriched by the calculation of Hirshfeld surfaces and the corresponding fingerprint plots.

Derivatives of 4-methyl-1,6-diphenylpyrimidine-2(1H)-selenone show very strong antimicrobial activity. In order to extend the current knowledge about the features responsible for the biological activity, crystal structure analyses are presented for 4-methyl-1-(2-methylphenyl)-6-phenylpyrimidine-2(1H)-selenone (1), 4-methyl-1-(3-methylphenyl)-6-phenylpyrimidine-2(1H)-selenone (2), 4-methyl-1-(4-methylphenyl)-6-phenylpyrimidine-2(1H)-selenone (3) (all C 18 H 16 N 2 Se) and 1-(4-chlorophenyl)-4-methyl-6-phenylpyrimidine-2(1H)-selenone (4) (C 17 H 13 ClN 2 Se). Furthermore, the antibacterial and antifungal activities of these compounds were evaluated. All the presented derivatives crystallize in the space group P2 1 /c with one molecule in the asymmetric unit. The molecular geometries differ slightly in the mutual orientation of the rings. The packing of molecules in the crystals is dominated by C-H...N and C-H...Se intermolecular interactions. Additionally, in the crystal structure of 4, C-H...Cl intermolecular interactions are observed. The introduction of a methyl or chlorine substituent improves the biological activity, while its position significantly affects biological activity only in case of the chlorine substituent.

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 P2 1 /n for 1 and 3, and P2 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.

A series of 17 arylpiperazine derivatives of the 5-spiroimidazolidine-2,4-diones (6-22) has been explored, including variations in (i) the number of aromatic rings at position 5, (ii) the length of the linker, as well as (iii) the kind and position of the linked arylpiperazine terminal fragment. Synthesis (6-16) and X-ray crystallographic studies for representative compounds (8, 10, 14 and 18) have been performed. The ability to inhibit the tumor multidrug resistance (MDR) efflux pump P-glycoprotein (P-gp, ABCB1) overexpressed in mouse T-lymphoma cells was investigated. The cytotoxic and antiproliferative actions of the compounds on both the reference and the ABCB1-overproducing cells were also examined. The pharmacophore-based molecular modeling studies have been performed. ADMET properties in vitro of selected most active derivatives (6, 11 and 12) have been determined. All compounds, excluding 18, inhibited the cancer P-gp efflux pump with higher potency than that of reference verapamil. The spirofluorene derivatives with amine alkyl substituents at position 1, and the methyl group at position 3 (6-16), occurred the most potent P-gp inhibitors in the MDR T-lymphoma cell line. In particular, compounds 7 and 12 were 100-fold more potent than verapamil. Crystallography-supported pharmacophore-based SAR analysis has postulated specific structural properties that could explain this excellent cancer MDR-inhibitory action., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds ( 7 - 23 ) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14 - 16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7 - 23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds ( 10 , 15 ) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% ( 19 ). The 4-phenylbenzylidene derivative ( 15 ) demonstrated significant MDR-reversal "dual action" for β -lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes . 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro.

This study concerns synthesis and evaluation of pharmacodynamic and pharmacokinetic profile for all four stereoisomers of MF-8 (5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione), the previously described, highly potent 5-HT 7 R ligand with antidepressant activity on mice. The combination of DFT calculations of 1 H NMR chemical shifts with docking and dynamic simulations, in comparison to experimental screening results, provided prediction of the configuration for one of two present stereogenic centers. The experimental data for stereoisomers (MF-8A-MF-8D) confirmed the significant impact of stereochemistry on both, 5-HT 7 R affinity and antagonistic action, with K i and K b values in the range of 3-366 nM and 0.024-99 μM, respectively. We also indicated the stereochemistry-dependent influence of the tested compounds on P-glycoprotein efflux, absorption in Caco-2 model, metabolic pathway as well as CYP3A4 and CYP2C9 activities., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In the light of recent lines of evidence, 5-HT 6 R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT 6 R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT 6 R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K i  < 100 nM) and selectivity towards 5-HT 6 R, with respect to 5-HT 2A R, 5-HT 7 R and D 2 R. The crystallography-supported docking studies, including quantum-polarized ligand docking (QPLD), indicated that chlorine atoms may be involved in different type of halogen bonding, however, the linker properties seem to predominately affect the 5-HT 6 R affinity. 4-[1-(2,5-Dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (9), which displayed: the highest affinity (K i  = 6 nM), very strong 5-HT 6 R antagonistic action (K B  = 27 pM), procognitive effects in vivo in novel object recognition (NOR) test in rats, a very good permeability in PAMPA model and satisfying safety in vitro, was identified as the most potent 1,3,5-triazine agent so far, useful as a new lead for further research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives ( 1 - 15 ) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure-activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis . The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis . Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter.

Four crystal structures of 2-amino-N-(dimethylphenoxyethyl)propan-1-ol derivatives, characterized by X-ray diffraction analysis, are reported. The free base (R,S)-2-amino-N-[2-(2,3-dimethylphenoxy)ethyl]propan-1-ol, C 13 H 21 NO 2 , 1, crystallizes in the space group P2 1 /n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride, C 13 H 22 NO 2 + ·Cl - , 2c, crystallizes in the space group P2 1 , with one cation and one chloride anion in the asymmetric unit. The asymmetric unit of two salts of 2-picolinic acid, namely, (R,S)-N-[2-(2,3-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C 13 H 22 NO 2 + ·C 6 H 4 NO 2 - , 1p, and (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C 13 H 22 NO 2 + ·C 6 H 4 NO 2 - , 2p, consists of one cation and one 2-picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P-1, while salt 2p crystallizes in the space group P4 1 2 1 2. The conformations of the amine fragments are contrasted and that of 2p is found to have an unusual antiperiplanar arrangement about the ether group. The crystal packing of 1 and 2c is dominated by hydrogen-bonded chains, while the structures of the 2-picolinate salts have hydrogen-bonded rings as the major features. In both salts with 2-picolinic acid, the specific R 1 2 (5) hydrogen-bonding motif is observed. Structural studies have been enriched by the generation of fingerprint plots derived from Hirshfeld surfaces.

Epilepsy is one of the most frequent neurological disorders affecting about 1% of the world's human population. Despite availability of multiple treatment options including antiseizure drugs, it is estimated that about 30% of seizures still remain resistant to pharmacotherapy. Searching for new antiseizure and antiepileptic agents constitutes an important issue within modern medicinal chemistry. Cinnamamide derivatives were identified in preclinical as well as clinical studies as important drug candidates for the treatment of epilepsy. The cinnamamide derivative presented here: S (+)-(2 E )- N -(2-hydroxypropyl)-3-phenylprop-2-enamide ( S (+)- N -(2-hydroxypropyl)cinnamamide, compound KM-568) showed anticonvulsant activity in several models of epilepsy and seizures in mice and rats. It was active in a genetic animal model of epilepsy (Frings audiogenic seizure-susceptible mouse model, ED 50 = 13.21 mg/kg, i.p .), acute seizures induced electrically (maximal electroshock test ED 50 = 44.46 mg/kg mice i.p ., ED 50 = 86.6 mg/kg mice p.o ., ED 50 = 27.58 mg/kg rats i.p ., ED 50 = 30.81 mg/kg rats p.o ., 6-Hz psychomotor seizure model 32 mA ED 50 = 71.55 mg/kg mice i.p ., 44 mA ED 50 = 114.4 mg/kg mice i.p .), chronic seizures induced electrically (corneal kindled mouse model ED 50 = 79.17 mg/kg i.p ., hippocampal kindled rat model ED 50 = 24.21 mg/kg i.p ., lamotrigine-resistant amygdala kindled seizure model in rats ED 50 = 58.59 mg/kg i.p .), acute seizures induced chemically (subcutaneous metrazol seizure threshold test ED 50 = 104.29 mg/kg mice i.p ., ED 50 = 107.27 mg/kg mice p.o ., ED 50 = 41.72 mg/kg rats i.p ., seizures induced by picrotoxin in mice ED 50 = 94.11 mg/kg i.p .) and the pilocarpine-induced status epilepticus model in rats (ED 50 = 279.45 mg/kg i.p ., ED 97 = 498.2 mg/kg i.p .). The chemical structure of the compound including configuration of the chiral center was confirmed by NMR spectroscopy, LC/MS spectroscopy, elemental analysis, and crystallography. Compound KM-568 was identified as a moderately stable derivative in an in vitro mouse liver microsome system. According to the Ames microplate format mutagenicity assay performed, KM-568 was not a base substitution or frameshift mutagen. Cytotoxicity evaluation in two cell lines (HepG2 and H9c2) proved the safety of the compound in concentrations up to 100 µM. Based on the results of anticonvulsant activity and safety profile, S (+)-(2 E )- N -(2-hydroxypropyl)-3-phenylprop-2-enamide could be proposed as a new lead compound for further preclinical studies on novel treatment options for epilepsy.

Two series of rhodanine-3-acetic and rhodanine-3-propionic acids derivatives having benzylidene and cinnamylidene substituents with additional electron donating and withdrawing groups at the C-5 position, were synthesised. The structures of the obtained derivatives were confirmed by spectroscopic methods and their lipophilicity was screened. The crystal structures were determined for selected compounds. The antibacterial activity of the derivatives was depended on the type of carboxyalkyl group in the N-3 position and on the type of the substituent in the C-5 position. The derivatives of rhodanine-3-propionic acid demonstrated the highest activity against Gram-positive bacteria. However, none of tested derivatives showed activity against Gram-negative bacteria and yeast. We believe that the presence of the N,N-diethylamine group in the aromatic system and the number of carbon atoms in the carboxyalkyl group is more significant for the biological activity than the fact that the benzylidene or cinnamylidene substituent was present at the C-5 position., (© 2020 The Author(s).)

Derivatives of pyrimidine-2(1H)-selenone are a group of compounds with very strong antimicrobial activity. In order to study the effect of the position of the methoxy substituent on biological activity, molecular geometry and intermolecular interactions in the crystal, three derivatives were prepared and evaluated with respect to their antimicrobial activities, and their crystal structures were determined by X-ray diffraction. The investigated compounds, namely, 1-(X-methoxyphenyl)-4-methyl-6-phenylpyrimidine-2(1H)-selenones (X = 2, 3 and 4 for 1, 2 and 3, respectively), C 18 H 16 N 2 OSe, showed very strong activity against selected strains of Gram-positive bacteria and fungi. Two compounds, 1 and 2, crystallize in the monoclinic space group P2 1 /c, while 3 crystallizes in the space group P2 1 /n; 1 has two molecules in the asymmetric unit and the other two (2 and 3) have one molecule. The geometries of the investigated compounds differ slightly in the mutual orientations of the aromatic and pyrimidineselenone rings. The O atom in 1 stabilizes the conformation of the molecules via intramolecular C-H...O hydrogen bonding. The packing of molecules is determined by weak C-H...N and C-H...Se intermolecular interactions and additionally in 1 and 2 by C-H...O intermolecular interactions. The introduction of the methoxy substituent results in greater selectivity of the investigated compounds.

Aminoalkanol derivatives have attracted much interest in the field of medicinal chemistry as part of the search for new anticonvulsant drugs. In order to study the influence of the methyl substituent and N-oxide formation on the geometry of molecules and intermolecular interactions in their crystals, three new examples have been prepared and their crystal structures determined by X-ray diffraction. 1-[(2,6-Dimethylphenoxy)ethyl]piperidin-4-ol, C 15 H 23 NO 2 , 1, and 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol, C 15 H 23 NO 2 , 2, crystallize in the orthorhombic system (space groups P2 1 2 1 2 1 and Pbca, respectively), with one molecule in the asymmetric unit, whereas the N-oxide 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol N-oxide monohydrate, C 15 H 23 NO 3 ·H 2 O, 3, crystallizes in the monoclinic space group P2 1 /c, with one N-oxide molecule and one water molecule in the asymmetric unit. The geometries of the investigated compounds differ significantly with respect to the conformation of the O-C-C linker, the location of the hydroxy group in the piperidine ring and the nature of the intermolecular interactions, which were investigated by Hirshfeld surface and corresponding fingerprint analyses. The crystal packing of 1 and 2 is dominated by a network of O-H...N hydrogen bonds, while in 3, it is dominated by O-H...O hydrogen bonds and results in the formation of chains.

Here we report studies on the synthesis of 12 new heterocyclic derivatives that differ in three structural motifs and the simultaneous evaluation of the impact of these three variables on the biological properties. The examined compounds are based on rhodanine and 2-thiohydantoin cores equipped with hydrogen or carboxymethyl substituents at the N-3 position and linked to a triphenylamine moiety through 1,4-phenylene, 1,4-naphthalenylene and 1,9-anthracenylene spacers at the C-5 position of the heterocycles. All the compounds were synthesized very quickly, selectively and in high yields according to the developed microwave-assisted Knoevenagel condensation protocol, and they were characterized thoroughly with NMR, FT-IR and ESI-HRMS techniques. The derivatives were tested for their activity against selected strains of Gram-positive and Gram-negative bacteria and yeast. Two compounds showed good activity against Gram-positive bacteria, and all of them showed low cytotoxicity against three cell lines of the human immune system. Based on membrane permeability assays it was demonstrated that the active compounds do not penetrate the cell membrane, and thus they must act on the bacterial cell surface. Finally, we proved that the evaluated structure modifications had a synergistic effect and the simultaneous presence of a 1,4-phenylene spacer and carboxymethyl group at N-3 caused the highest boost in antimicrobial activity., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Effective protection from the harmful effects of UV radiation may be achieved by using sunscreens containing organic or inorganic UV filters. The number of currently available UV filters is limited and some of the allowed molecules possess limitations such as systemic absorption, endocrine disruption properties, contact and photocontact allergy induction, and low photostability. In the search for new organic UV filters we designed and synthesized a series consisting of 5-benzylidene and 5-(3-phenylprop-2-en-1-ylidene)imidazolidine-2,4-dione (hydantoin) derivatives. The photoprotective activity of the tested compounds was confirmed in methanol solutions and macrogol formulations. The most promising compounds possessed similar UV protection parameter values as selected commercially available UV filters. The compound diethyl 2,2'-(( Z )-4-(( E )-3-(4-methoxyphenyl)allylidene)-2,5-dioxoimidazolidine-1,3-diyl)diacetate ( 4g ) was characterized as an especially efficient UVA photoprotective agent with a UVA PF of 6.83 ± 0.05 and favorable photostability. Diethyl 2,2'-(( Z )-4-(4-methoxybenzylidene)-2,5-dioxo- imidazolidine-1,3-diyl)diacetate ( 3b ) was the most promising UVB-filter, with a SPF in vitro of 3.07 ± 0.04 and very good solubility and photostability. The main photodegradation products were geometric isomers of the parent compounds. These compounds were also shown to be non-cytotoxic at concentrations up to 50 µM when tested on three types of human skin cells and possess no estrogenic activity, according to the results of a MCF-7 breast cancer model.

In order to extend knowledge about pharmacophoric features responsible for ABCB1 inhibitory properties of imidazolidin-2,4-dione derivatives, 1'-[4-(4-(o-methoxyphenyl)-piperazin-1-yl)butyl]-3'-methyl-spiro(fluoren-9,5'-imidazolidine)-2',4'-dione (3) and its salt (4) with rhodanine-3-acetic acid (RA) were prepared and investigated by X-ray diffraction method, as well as their efflux modulating effects in cancer cells (mouse T-lymphoma), cytotoxic and antiproliferative activities were evaluated in vitro. The molecular geometry, intermolecular interactions, and crystal packing of base and acid forms of 3 were analyzed to see, if conformational changes influence the biological activities. The geometry of 2-methoxyphenylpiperazine and 5-spirofluorenehydantoin moieties was compared with other crystal structures containing these fragments. Our results indicated a very potent inhibitory action on ABCB1 pump, and significant cytotoxic and antiproliferative properties of 3 in T-lymphoma, even more potent in the case of multidrug resistance cells. Furthermore, the compound 3 converted into the salt 4 of inactive acid (RA) has maintained both, the efflux pump inhibitory and antiproliferative activities, showing strong synergism with doxorubicin. A comparison of geometry of 3 in both crystal structures (3 and 4) shows a significant difference in the arrangement of piperazine ring with respect to the aliphatic linker., (© 2019 John Wiley & Sons A/S.)

Searching for new chemosensitizers of bacterial multidrug resistance (MDR), chemical modifications of (Z)-5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-4(5H)-one ( 6 ) were performed. New compounds ( 7 ⁻ 17 ), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds ( 7 ⁻ 17 ) were substituted with tertiary amine-propyl moiety at position 3 and primary amine group at 2 due to intramolecular Dimroth rearrangement. New compounds were evaluated on their antibiotic adjuvant properties in either Gram-positive or Gram-negative bacteria. Efflux pump inhibitor (EPI) properties towards the AcrAB-TolC pump in Enterobacter aerogenes (EA289) were investigated in the real-time efflux (RTE) assay. Docking and molecular dynamics were applied to estimate an interaction of compounds 6 ⁻ 17 with penicillin binding protein (PBP2a). In vitro ADME-Tox properties were evaluated for compound 9 . Most of the tested compounds reduced significantly (4-32-fold) oxacillin MIC in highly resistant MRSA HEMSA 5 strain. The anthracene-morpholine derivative ( 16 ) was the most potent (32-fold reduction). The tested compounds displayed significant EPI properties during RTE assay (37⁻97%). The naphthyl-methylpiperazine derivative 9 showed the most potent "dual action" of both oxacillin adjuvant (MRSA) and EPI ( E. aerogenes ). Molecular modeling results suggested the allosteric mechanism of action of the imidazolones, which improved binding of oxacillin in the PBP2a active site in MRSA.

The arylidene-imidazolone derivatives are a group of compounds of great interest in medicinal chemistry due to their various pharmacological actions. In order to study the possible conformations of an arylidene-imidazolone derivative, two new crystal structures were determined by X-ray diffraction, namely (Z)-5-(4-chlorobenzylidene)-2-(4-methylpiperazin-1-yl)-3H-imidazol-5(4H)-one, C 15 H 17 ClN 4 O, (6), and its salt 4-[5-(4-chlorobenzylidene)-5-oxo-4,5-dihydro-3H-imidazol-2-yl]-1-methylpiperazin-1-ium 3-{5-[4-(diethylamino)benzylidene]-4-oxo-2-thioxothiazolidin-3-yl}propionate, C 15 H 18 ClN 4 O + ·C 17 H 19 N 2 O 3 S 2 - , (7). Both compounds crystallize in the space group P-1. The basic form (6) crystallizes with two molecules in the asymmetric unit. In the acid form of (6), the N atom of the piperazine ring is protonated by proton transfer from the carboxyl group of the rhodanine acid derivative. The greatest difference in the conformations of (6) and its protonated form, (6c), is observed in the location of the arylidene-imidazolone substituent at the N atom. In the case of (6c), the position of this substituent is close to axial, while for (6), the corresponding position is intermediate between equatorial and axial. The crystal packing is dominated by a network of N-H...O hydrogen bonds. Furthermore, the crystal structures are stabilized by numerous intermolecular contacts of types C-H...N and C-H...Cl in (6), and C-H...O and C-H...S in (7). The geometry with respect to the location of the substituents at the N atoms of the piperazine ring was compared with other crystal structures possessing an N-methylpiperazine moiety.

A series of 17 new phenoxyacetamides has been prepared via multistep chemical synthesis as a continuation of the research carried out by our group on di- and tri-substituted phenoxyalkyl and phenoxyacetyl derivatives of amines. The obtained compounds vary in an amide component, for example aminoalkanol or (un)modified amino acid moieties were introduced. The structures of selected products were confirmed by means of crystallographic methods. All 17 compounds were the subject of preliminary screening for potential anticonvulsant activity (MES, 6 Hz and/or scMET tests) and neurotoxicity (rotarod) in mice after intraperitoneal administration, while several active compounds were subsequently examined in additional models ( e.g. MES and rotarod - rats, p.o. or i.p. , hippocampal kindling - rats, i.p. ). Finally, safety studies (cytotoxicity and cell proliferation assays on astrocytes, metabolic stability assessment, mutagenicity evaluation) were performed for several active compounds, including the most promising one ( R -(-)-2-(2,6-dimethylphenoxy)- N -(1-hydroxypropan-2-yl)acetamide, MES ED 50 = 12.00 mg per kg b.w., rats, p.o. ).

Background/aim: Multidrug resistance leads to therapeutic difficulties. There is great interest in experimental chemotherapy regarding multidrug resistance inhibitors and new anticancer agents. The aim of this study was to evaluate the anticancer activity of exocyclic sulfur and selenoorganic compounds on mouse T-lymphoma cell lines., Materials and Methods: A series of eighteen sulfur and selenium analogues of 2[1H]-pyrimidinone and hydantoin derivatives were evaluated towards their efflux modulating, cytotoxic and antiproliferative effects in mouse T-lymphoma cells. The combination assay with doxorubicin on multidrug resistant mouse T-lymphoma cells was performed in order to see the nature of drug interactions. Crystal structures were determined for two selected compounds with the highest efflux-modulating activity., Results: The sulfur analogues with aromatic rings almost perpendicular to pyrimidinethione ring at positions 1 and 6 showed the highest efflux inhibitory action, while all selenium analogues showed good antiproliferative and cytotoxic activities., Conclusion: The sulfur analogues can be modified towards improving their efflux inhibitory activity, whereas the selenium towards antiproliferative and cytotoxic activities., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aminoalkanol and aroxyalkyl derivatives are known as potential anticonvulsants. Two new salts, namely bis{(R,S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium} succinate (1s), C 13 H 22 NO 2 + ·0.5C 4 H 4 O 4 2- , and bis{(S)-(+)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium} succinate (2s), C 13 H 22 NO 2 + ·0.5C 4 H 4 with four cations and two anions in the asymmetric unit. The hydroxy group of the cation of 1s is observed in two R/S disorder positions. The crystals of these two salts display similar supramolecular architectures (i.e. two-dimensional networks), built mainly by intermolecular N 4 2- , have been prepared and characterized by single-crystal X-ray diffraction. The N atoms are protonated by proton transfer from succinic acid. Salt 1s crystallizes in the space group P2 1 /n with one cation and half an anion in the asymmetric unit across an inversion centre, while (2s) crystallizes in the space group P2 1 with four cations and two anions in the asymmetric unit. The hydroxy group of the cation of 1s is observed in two R/S disorder positions. The crystals of these two salts display similar supramolecular architectures (i.e. two-dimensional networks), built mainly by intermolecular N + -H...O δ- and O-H...O δ- hydrogen bonds, where `δ-' represents a partial charge. The succinate anions are engaged in hydrogen bonds, not only with protonated N atoms, but also with hydroxy groups.

A number of cinnamamide derivatives possess anticonvulsant activity due to the presence of a number of important pharmacophore elements in their structures. In order to study the correlations between anticonvulsant activity and molecular structure, the crystal structures of three new cinnamamide derivatives with proven anticonvulsant activity were determined by X-ray diffraction, namely (R,S)-(2E)-N-(2-hydroxybutyl)-3-phenylprop-2-enamide-water (3/1), C 13 H 17 NO 2 ·0.33H 2 O, (1), (2E)-N-(1-hydroxy-2-methylpropan-2-yl)-3-phenylprop-2-enamide, C 13 H 17 NO 2 , (2), and (R,S)-(2E)-N-(1-hydroxy-3-methyl-butan-2-yl)-3-phenylprop-2-enamide, C 14 H 19 NO 2 , (3). Compound (1) crystallizes in the space group P-1 with three molecules in the asymmetric unit, whereas compounds (2) and (3) crystallize in the space group P2 1 /c with one and two molecules, respectively, in their asymmetric units. The carbonyl group of (2) is engaged in an intramolecular hydrogen bond with the hydroxy group. This type of interaction is observed for the first time in these kinds of derivatives. A disorder of the substituent at the N atom occurs in the crystal structures of (2) and (3). The crystal packing of all three structures is dominated by a network of O-H...O and N-H...O hydrogen bonds, and leads to the formation of chains and/or rings. Furthermore, the crystal structures are stabilized by numerous C-H...O contacts. We analyzed the molecular structures and intermolecular interactions in order to propose a pharmacophore model for cinnamamide derivatives.

In order to search for active and selective serotonin 5-HT 7 R antagonists among 3,5-disubstituted arylpiperazine-imidazolidine-2,4-diones, the role of the introduction/deletion and the mutual orientation of aromatic rings was analyzed. Chemical modifications of 2nd generation lead structure of 3-(3-(4-(diphenylmethyl)piperazin-1-yl)-2-hydroxypropyl)-5-(4-fluorophenyl)-5-methylimidazolidine-2,4-dione ( 2 , KKB16) were performed. New derivatives ( 4-18 ) were designed and synthesized. X-ray crystallographic analysis of the representative compound 5-(4-fluorophenyl)-3-[2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl]-5-methylimidazolidine-2,4-dione ( 3 ) was performed to support molecular modeling and SAR studies. The affinity for 5-HT 7 R, D 2 R and 5-HT 1A R in radioligand binding assays for the entire series and ADME-Tox parameters in vitro for selected compounds ( 7 , 10 , and 13 ) were evaluated. Molecular docking and pharmacophore model assessment were performed. According to the obtained results, 5-methyl-5-naphthylhydantoin derivatives were found to be the new highly active 5-HT 7 R agents ( K i ≤ 5 nM) with significant selectivity over 5-HT 1A R and D 2 R. On the contrary, the (1-naphthyl)piperazine moiety was gained with the potent dual 5-HT 7 R/5-HT 1A R action ( K i : 11 nM/19 nM).

This paper presents a computer-aided insight into the receptor-ligand interaction for novel analogs of the lead structure 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (1, MF-8), as part of the search for potent and selective serotonin 5-HT 7 receptor (5-HT 7 R) agents. New hydantoin derivatives (4-19) were designed and synthesized. For 5-phenyl-3-(2-hydroxy-3-(4-(2-ethoxyphenyl)piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione (4), its crystal structure was determined experimentally. Molecular modeling studies were performed, including both pharmacophore and structure-based approaches. New compounds were investigated in radioligand binding assays (RBA) for their affinity toward 5-HT 7 R and selectivity over 5-HT 1A R, dopamine D 2 R and α 1 -, α 2 -and β-adrenoceptors. Selected compounds (5-8) were assessed for their antidepressant and anxiolytic effects in vivo in mice. Most of the tested compounds displayed potent affinity and selectivity for 5-HT 7 R in RBA, in particular seven compounds (4, 5, 7, 8 and 10-12,K i  ≤ 10 nM). Antidepressant-like activity in vivo for all tested compounds (5-8) was confirmed. SAR analysis based on both crystallography-supported molecular modeling and RBA results indicated that mono-phenyl substituents at both hydantoin and piperazine are more favorable for 5-HT 7 R affinity than the di-phenyl ones., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The 2-amine derivatives of 5-arylidene-3H-imidazol-4(5H)-one are a new class of bacterial efflux pump inhibitors, the chemical compounds that are able to restore antibiotic efficacy against multidrug resistant bacteria. 5-Arylidene-3H-imidazol-4(5H)-ones with a piperazine ring at position 2 reverse the mechanisms of multidrug resistance (MDR) of the particularly dangerous Gram-negative bacteria E. coli by inhibition of the efflux pump AcrA/AcrB/TolC (a main multidrug resistance mechanism in Gram-negative bacteria, consisting of a membrane fusion protein, AcrA, a Resistant-Nodulation-Division protein, AcrB, and an outer membrane factor, TolC). In order to study the influence of the environment on the conformation of (Z)-5-(4-chlorobenzylidene)-2-[4-(2-hydroxyethyl)piperazin-1-yl]-3H-imidazol-4(5H)-one, (3), two different salts were prepared, namely with picolinic acid {systematic name: 4-[(Z)-4-(4-chlorobenzylidene)-5-oxo-3,4-dihydro-1H-imidazol-2-yl]-1-(2-hydroxyethyl)piperazin-1-ium pyridine-2-carboxylate, C 16 H 20 ClN 4 O 2 + ·C 6 H 4 NO 2 - , (3a)} and 4-nitrophenylacetic acid {systematic name: 4-[(Z)-4-(4-chlorobenzylidene)-5-oxo-3,4-dihydro-1H-imidazol-2-yl]-1-(2-hydroxyethyl)piperazin-1-ium 2-(4-nitrophenyl)acetate, C 16 H 20 ClN 4 O 2 + ·C 8 H 6 NO 4 - , (3b)}. The crystal structures of the new salts were determined by X-ray diffraction. In both crystal structures, the molecule of (3) is protonated at an N atom of the piperazine ring by proton transfer from the corresponding acid. The carboxylate group of picolinate engages in hydrogen bonds with three molecules of the cation of (3), whereas the carboxylate group of 4-nitrophenylacetate engages in hydrogen bonds with only two molecules of (3). As a consequence of these interactions, different orientations of the hydroxyethyl group of (3) are observed. The crystal structures are additionally stabilized by both C-H...N [in (3a)] and C-H...O [in (3a) and (3b)] intermolecular interactions. The geometry of the imidazolone fragment was compared with other crystal structures possessing this moiety. The tautomer observed in the crystal structures presented here, namely 3H-imidazol-4(5H)-one [systematic name: 1H-imidazol-5(4H)-one], is also that most frequently observed in other structures containing this heterocycle.

A cinnamamide (3-phenylprop-2-enamide) core is present in many pharmacologically active compounds. We report three new crystal structures of N-substituted cinnamamide derivatives which were screened for anticonvulsant activity, namely (R,S)-(2E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide, C 12 H 15 NO 2 , (1), (R,S)-(2E)-N-(1-hydroxybutan-2-yl)-3-phenylprop-2-enamide, C 13 H 17 NO 2 , (2), and (2E)-1-(4-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one, C 14 H 17 NO 2 , (3). Compounds (1) and (2) crystallize in the Pbca space group with one molecule in the asymmetric unit, whereas compound (3) crystallizes in the P2 1 /c space group with two molecules in the asymmetric unit. All the crystal structures are stabilized by intermolecular O-H...O hydrogen bonds and additionally by N-H...O hydrogen bonds in the structures of (1) and (2). The investigated compounds possess fragments that are considered as beneficial for anticonvulsant activity. The conformations of these compounds were analyzed in comparison with the characteristic features of the proposed pharmacophore model of anticonvulsants active in the maximal electroshock test, i.e. a phenyl ring or other hydrophobic unit, an electron-donor atom and a hydrogen-bond acceptor/donor domain. In the reported series, two calculated distances fitted the reference model, while the third did not. Structure-activity analysis suggests that anticonvulsant properties may be related to the N-atom substituent. It is beneficial to combine an electron-donor atom (e.g. an O atom) with an H atom in the substituent to ensure appropriate interactions with the molecular target. We analyzed the intermolecular interactions in order to find an appropriate spatial arrangement of the important features responsible for anticonvulsant activity.

A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, and additionally, thermal analysis showed that it exists in one crystalline form. The compound was evaluated in vivo in rodents as anticonvulsant, antiepileptogenic, analgesic, and neuroprotective agent. The beneficial properties of the compound were found in animal models of seizures evoked electrically (maximal electroshock test, 6-Hz) and chemically (subcutaneous pentylenetetrazole seizure test) as well as in three animal models of epileptogenesis: corneal-kindled mice, hippocampal-kindled rats, and lamotrigine-resistant amygdala-kindled rats. Quantitative pharmacological parameters calculated for the tested compound were comparable to those of currently used antiepileptic drugs. In vivo pharmacological profile of KM-608 corresponds with the activity of valproic acid., (© 2017 John Wiley & Sons A/S.)

Unnatural cyclic α-amino acids play an important role in the search for biologically active compounds and macromolecules. Enantiomers of natural amino acids with a D configuration are not naturally encoded, but can be chemically synthesized. The crystal structures of two enantiomers obtained by a method of stereoselective synthesis, namely (5R,8S)-8-tert-butyl-7-methoxy-8-methyl-9-oxa-6-azaspiro[4.5]decane-2,10-dione, (1), and (5S,8R)-8-tert-butyl-7-methoxy-8-methyl-9-oxa-6-azaspiro[4.5]decane-2,10-dione, (2), both C 14 H 21 NO 4 , were determined by X-ray diffraction. Both enantiomers crystallize isostructurally in the space group P2 1 , with one molecule in the asymmetric unit and with the same packing motif. The crystal structures are stabilized by C-H...O hydrogen bonds, resulting in the formation of chains along the [100] and [010] directions. The conformation of the 3,6-dihydro-2H-1,4-oxazin-2-one fragment was compared with other crystal structures possessing this heterocyclic moiety. The comparison showed that the title compounds are not exceptional among structures containing the 3,6-dihydro-2H-1,4-oxazin-2-one fragment. The planar moiety was more frequently observed in derivatives in which this fragment was not condensed with other rings.

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH 3 or 2-CH 3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED 50 MES=42.56, ED 50 scPTZ=58.38, ED 50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i.p.) administration); R,S-(2E)-3-(4-chlorophenyl)-N-(1-hydroxybutan-2-yl)prop-2-enamide (6) (ED 50 MES=53.76, ED 50 scPTZ=90.31, ED 50 6-Hz 44mA=92.86mg/kg mice, i.p.); and R,S-(2E)-3-(4-chlorophenyl)-N-(2-hydroxypropyl)prop-2-enamide (11) (ED 50 MES=55.58, ED 50 scPTZ=102.15, ED 50 6-Hz 44mA=51.27mg/kg mice, i.p.). Their structures and configurations were confirmed by crystal X-ray diffraction method. The structure-activity studies among the tested series showed that chlorine atom in position para or methyl group in position ortho of phenyl ring were beneficial for anticonvulsant activity. Methyl group in position para of phenyl ring decreased anticonvulsant activity in reported series of cinnamamide derivatives., (Copyright © 2016 Elsevier Ltd. All rights reserved.)