Search

A series of ten 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

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, C29H32N4O2 2+·2Cl−·H2O (1), 3′-methyl-1′-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C29H29N5O4·H2O (2), 3′-methyl-1′-{5-[4-(4-nitrophenyl)piperazin-1-yl]pentyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C31H33N5O4 (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, C32H38N4O2 2+·2Cl−·0.613H2O (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 P21/n for 1 and 3, and P21/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.

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

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. Keywords: Rhodanine, Rhodanine-3-carboxyalkyl acids, Antibacterial activity, Antimicrobial activity, Thiazolidine-4-one

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, C15H23NO2, 1, and 1-[(2,3-dimethylphenoxy)ethyl]piperidin-4-ol, C15H23NO2, 2, crystallize in the orthorhombic system (space groups P212121 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, C15H23NO3·H2O, 3, crystallizes in the monoclinic space group P21/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.

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, C18H23NO2, 1, the salt N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium 3-hydroxybenzoate, C18H24NO2 +·C7H5O3 −, 2, and two polymorphs of the salt (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxy-1-phenylethan-2-aminium chloride, C18H24NO2 +·Cl−, 3 and 3p. Both polymorphs crystallize in the space group P21212 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.

This research allowed us to find the first highly potent 5-HT

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.

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, C15H17ClN4O, (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, C15H18ClN4O+·C17H19N2O3S2 −, (7). Both compounds crystallize in the space group P\overline{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.

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.

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 C18H16N2Se) and 1-(4-chlorophenyl)-4-methyl-6-phenylpyrimidine-2(1H)-selenone (4) (C17H13ClN2Se). Furthermore, the antibacterial and antifungal activities of these compounds were evaluated. All the presented derivatives crystallize in the space group P21/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.

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, C13H21NO2, 1, crystallizes in the space group P21/n, with two independent molecules in the asymmetric unit. The hydrochloride, (S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium chloride, C13H22NO2 +·Cl−, 2c, crystallizes in the space group P21, 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, C13H22NO2 +·C6H4NO2 −, 1p, and (R)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium pyridine-2-carboxylate, C13H22NO2 +·C6H4NO2 −, 2p, consists of one cation and one 2-picolinate anion. Salt 1p crystallizes in the triclinic centrosymmetric space group P\overline 1, while salt 2p crystallizes in the space group P41212. 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.

In the light of recent lines of evidence, 5-HT

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

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.

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 for1,2and3, respectively), C18H16N2OSe, showed very strong activity against selected strains of Gram-positive bacteria and fungi. Two compounds,1and2, crystallize in the monoclinic space groupP21/c, while3crystallizes in the space groupP21/n;1has two molecules in the asymmetric unit and the other two (2and3) have one molecule. The geometries of the investigated compounds differ slightly in the mutual orientations of the aromatic and pyrimidineselenone rings. The O atom in1stabilizes the conformation of the moleculesviaintramolecular C—H...O hydrogen bonding. The packing of molecules is determined by weak C—H...N and C—H...Se intermolecular interactions and additionally in1and2by C—H...O intermolecular interactions. The introduction of the methoxy substituent results in greater selectivity of the investigated compounds.

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), C13H22NO2 +·0.5C4H4O4 2−, and bis{(S)-(+)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium} succinate (2s), C13H22NO2 +·0.5C4H4O4 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 P21/n with one cation and half an anion in the asymmetric unit across an inversion centre, while (2s) crystallizes in the space group P21 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...Oδ− and O—H...Oδ− 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.

Four new crystal structures of sulfur and selenium analogues of 2[1H]-pyrimidinone derivatives were determined with the use of X-ray diffraction method. The molecular geometry and intermolecular interactions of the investigated molecules were analyzed in order to find the structural features and geometrical parameters, which can be responsible for antimicrobial activities. The influence of chalcogen substituents (sulfur and selenium) on the crystal packing was also studied. The main differences in the molecular structures exist in mutual arrangement of two aromatic rings. The intermolecular interactions in all investigated compounds are similar. Furthermore, the in vitro antibacterial and antifungal activities for these compounds were evaluated. Preliminary investigations have identified two highly potent antibacterial compounds containing selenium atom, which display selectivity towards staphylococci and micrococci. This selectivity was not observed for a control compound used as a drug, namely vancomycin. These compounds possess also good antifungal activity. This is the first report of biological activities of 2[1H]-pyrimidineselenone derivatives.

Selected rhodanine-3-carboxylic acids derivatives were synthesized to determine the influence of the structure and the length of the linker between the carboxyl group and the nitrogen atom (N-3) in the 2-thioxo-4-thiazolidinone ring on their activity, monitored via interactions with human serum albumin. Based on fluorescence studies, we concluded that the length of the linker has a limited impact on these interactions. Additionally, we proposed the static mechanism of quenching for all the tested compounds. These derivatives seem to possess an anticancer activity in the nanomolar range with 3 as the most potent compound in both A2780 and A2780cisR cell lines.

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&prime, ((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 &plusmn, 0.05 and favorable photostability. Diethyl 2,2&prime, ((Z)-4-(4-methoxybenzylidene)-2,5-dioxo- imidazolidine-1,3-diyl)diacetate (3b) was the most promising UVB-filter, with a SPFin vitro of 3.07 &plusmn, 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 &micro, M 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.

Selenocyanates represent an interesting class of organic selenium compounds. Due to their similarity with better known natural (iso-)thiocyanates, they promise high biological activity and may also be metabolized to other Reactive Selenium Species (RSeS), such as selenols, diselenides and seleninic acids. Thirteen arylmethyl selenocyanates (1–13) have been synthesized and evaluated for potential antimicrobial, nematicidal and cytotoxic activity. The compounds exhibit pronounced antimicrobial activity against various strains of Gram-positive and Gram-negative bacteria and yeasts, including multidrug resistant strains. The results obtained so far demonstrate that these arylmethyl selenocyanates are also non-mutagenic and have limited cytotoxicity against human cells. Here, benzyl selenocyanate (1) represents the most active anti-ESKAPE agent, with potent activity against multidrug resistant MRSA strains (HEMSA 5) – with a competitive MIC value of just 0.76 μg mL−1 (3.88 μM), whereas it exhibits low(er) cytotoxicity (IC50 = 31 μM) and no mutagenicity against mammalian cells. Due to this selective antimicrobial activity, aromatic selenocyanates may provide an interesting lead in the development of antimicrobial agents, particularly in the context of drug resistance.

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&ndash, 17), with fused aromatic rings at position 5, were designed and synthesized. Crystallographic X-ray analysis proved that the final compounds (7&ndash, 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&ndash, 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&ndash, 97%). The naphthyl-methylpiperazine derivative 9 showed the most potent &ldquo, dual action&rdquo, 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.

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-HT7R ligand with antidepressant activity on mice. The combination of DFT calculations of 1H 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-HT7R affinity and antagonistic action, with Ki and Kb 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.

In the light of recent lines of evidence, 5-HT6R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT6R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT6R 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 (Ki

Epilepsy, one of the most frequent neurological disorders, is still insufficiently treated in about 30% of patients. As a consequence, identification of novel anticonvulsant agents is an important issue in medicinal chemistry. In the present article we report synthesis, physicochemical, and pharmacological evaluation of N-trans-cinnamoyl derivatives of R and S-2-aminopropan-1-ol, as well as R and S-2-aminobutan-1-ol. The structures were confirmed by spectroscopy and for derivatives of 2-aminopropan-1-ols the configuration was evaluated by means of crystallography. The investigated compounds were tested in rodent models of seizures: maximal electroshock (MES) and subcutaneous pentetrazol test (scPTZ), and also in a rodent model of epileptogenesis: pilocarpine-induced status prevention. Additionally, derivatives of 2-aminopropan-1-ols were tested in benzodiazepine-resistant electrographic status epilepticus rat model as well as in vitro for inhibition of isoenzymes of cytochrome P450. All of the tested compounds showed promising anticonvulsant activity in MES. For R(-)-(2E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide pharmacological parameters were found as follows: ED50 = 76.7 (68.2-81.3) mg/kg (MES, mice i.p., time = 0.5 h), ED50 = 127.2 (102.1-157.9) mg/kg (scPTZ, mice i.p., time = 0.25 h), TD50 = 208.3 (151.4-230.6) mg/kg (rotarod, mice i.p., time = 0.25 h). Evaluation in pilocarpine status prevention proved that all of the reported compounds reduced spontaneous seizure activity and act as antiepileptogenic agents. Both enantiomers of 2-aminopropan-1-ols did not influence cytochrome P450 isoenzymes activity in vitro and are likely not to interact with CYP substrates in vivo. Chirality 28:482-488, 2016. © 2016 Wiley Periodicals, Inc.

A series of thirty N-(phenoxy)alkyl or N-{2-[2-(phenoxy)ethoxy]ethyl}aminoalkanols has been designed, synthesized and evaluated for anticonvulsant activity in MES, 6 Hz test, and pilocarpine-induced status epilepticus. Among the title compounds, the most promising seems R-(−)-2N-{2-[2-(2,6-dimethylphenoxy)ethoxy]ethyl}aminopropan-1-ol hydrochloride (22a) with proved absolute configuration with X-ray analysis and enantiomeric purity. The compound is effective in MES test with ED50 = 12.92 mg/kg b.w. and its rotarod TD50 = 33.26 mg/kg b.w. The activity dose is also effective in a neurogenic pain model—the formalin test. Within high throughput profile assay, among eighty one targets, the strongest affinity of the compound is observed towards σ receptors and 5-HT transporter and the compound does not bind to hERG. It also does not exhibit mutagenic properties in the Vibrio harveyi test. Moreover, murine liver microsomal assay and pharmacokinetics profile (mice, iv, p.o., ip) indicate that the liver is the primary site of biotransformation of the compound, suggesting that both 22a and its metabolite(s) are active, compensating probably low bioavailability of the parent molecule.

Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1&ndash, 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&ndash, 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 &micro, M. 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.

Epilepsy is one of the most frequent neurological disorders affecting about 1% of the world&rsquo, 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(+)-(2E)-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, ED50 = 13.21 mg/kg, i.p.), acute seizures induced electrically (maximal electroshock test ED50 = 44.46 mg/kg mice i.p., ED50 = 86.6 mg/kg mice p.o., ED50 = 27.58 mg/kg rats i.p., ED50 = 30.81 mg/kg rats p.o., 6-Hz psychomotor seizure model 32 mA ED50 = 71.55 mg/kg mice i.p., 44 mA ED50 = 114.4 mg/kg mice i.p.), chronic seizures induced electrically (corneal kindled mouse model ED50 = 79.17 mg/kg i.p., hippocampal kindled rat model ED50 = 24.21 mg/kg i.p., lamotrigine-resistant amygdala kindled seizure model in rats ED50 = 58.59 mg/kg i.p.), acute seizures induced chemically (subcutaneous metrazol seizure threshold test ED50 = 104.29 mg/kg mice i.p., ED50 = 107.27 mg/kg mice p.o., ED50 = 41.72 mg/kg rats i.p., seizures induced by picrotoxin in mice ED50 = 94.11 mg/kg i.p.) and the pilocarpine-induced status epilepticus model in rats (ED50 = 279.45 mg/kg i.p., ED97 = 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 &micro, M. Based on the results of anticonvulsant activity and safety profile, S(+)-(2E)-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.

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).

Selenocyanates form an interesting class of organic selenium compounds as they serve as multifunctional agents (being the precursors of seleninic acids and diselenides in synthetic chemistry and as antimicrobial and cytotoxic agent in biology) and, due to their similarity with better known thiocyanates promise high biological activity. Yet whilst selenocyanates are common in synthetic chemistry, they are rarely considered in pharmaceutical design. Arylmethyl selenocyanates (1-13) have been synthesized and an insight into their structural properties using X-ray crystallography has been obtained. The compounds subsequently have been evaluated for their potential antimicrobial, nematicidal and cytotoxic activity. ADMET properties in vitro, using mutagenicity (AMES) and permeability (PAMPA) tests, have been determined. The compounds exhibit pronounced activity against various strains of bacteria (both Gram-positive and Gram-negative) and yeasts. Among them, benzylselenocyanate (1) represents the most active anti-ESKAPE agent, with potent antibacterial activity, especially against multidrug resistant MRSA strains (HEMSA 5). Our results demonstrate that the arylmethyl selenocyantes are not only non-mutagenic but also possess moderate cytotoxic activity against cancer cells.