Katarzyna Kieć-Kononowicz

Recent Advances in Multi-Drug Resistance (MDR) Efflux Pump Inhibitors of Gram-Positive Bacteria S. aureus

The paper focuses on recent achievements in the search for new chemical compounds able to inhibit multidrug resistance (MDR) mechanisms in Gram-positive pathogens. An analysis of the results of the search for new efflux pump inhibitors (EPIs) for Gram-positive bacteria, which have been performed over the last decade, indicates that almost all efforts are focused on the NorA (MFS) efflux pump in S. aureus. Considering the chemical structures of the NorA EPIs that have been identified, it can be observed that the most active agents belong to the families of compounds possessing conjugated double bonds, e.g., chalcones, piperine-like compounds, N-cinnamoylphenalkylamides or citral amide derivatives. Indole-, dihydronaphthyl-, 2-chloro-5-bromo-phenyl- or piperidine moieties seem to be profitable for the EPI properties, as well. These results, together with an increasing knowledge about a variety of efflux pumps that are involved in MDR of Gram-positive pathogens underline that further search for new EPIs should pay more attention to develop MDR efflux protein targets, including SMR, MATE, ABC or other members of the MFS family.

Molecular modeling of A1 and A2A adenosine receptors: Comparison of rhodopsin‐ and β2‐adrenergic‐based homology models through the docking studies

Adenosine receptors (ARs) are members of the superfamily of G protein‐coupled receptors. The homology models of adenosine A1 and A2A receptors were constructed. The high‐resolution X‐ray structure of bovine rhodopsin and crystal structure of β2‐adrenergic receptor were used as templates. The binding sites of the A1 and A2A ARs were constructed by using data obtained from mutagenesis experiments as well as docking simulations of the respective AR antagonsists DPCPX and XAC. To compare rhodopsin‐ and β2‐adrenergic‐based models, the binding mode of A1 (KW‐3902, LUF‐5437) and A2A (KW‐6002, ZM‐241385) ARs antagonists were also examined. The differences in the binding ability of both models were noted during the study. The β2‐adrenergic‐based A2A AR model was much more capable to stabilize the ligand in the binding site cavity than the corresponding rhodopsin‐based A2A AR model, however, such differences were not so clear in case of A1 AR models. It was suggested that for the A1 AR it is possible to use the crystal structure of rhodopsin as a template as well as β2‐adrenergic receptor, but for A2A AR, with the now available β2‐adrenergic receptor X‐ray structure, docking studies should be avoided on the rhodopsin‐based model. However, taking into account that the β2AR shares about 31% of the residues with the AR in comparison to 21% in case of bRho, we suggest using β2‐adrenergic‐based models for the A1 and A2A ARs for further in silico ligand screening also because of their generally better ability to stabilize ligands inside the binding pocket.

SYNTHESIS AND SPECTROSCOPIC PROPERTIES OF FUSED 5-ARYLIDENE-2-THIOHYDANTOIN DERIVATIVES

Abstract Imidazothiazole [(1)-(12)], imidazothiazine [(13)-(20)], and imidazothiazepine [(21), (22)] derivatives were obtained as the products of 1,2 or 2,3-dialkylation of 5-arylidene-2-thiohydantoin derivatives (ATH). The X-ray analysis of selected synthesized compounds showed their Z-configuration. The spectroscopic properties were described and examined for identification of 1,2-(type A) and 2,3-(type B)-substitution products. The reactivity of ATH was explained on the basis of X-ray analysis results and MNDO calculations.

Five-membered heterocycles. Part III. Aromaticity of 1,3-imidazole in 5+n hetero-bicyclic molecules

Abstract The aromaticity (in the form of HOMA index) of 1,3-imidazole ring and its bicyclic derivatives was studied on the basis of statistical data from Cambridge Structural Database and X-ray investigations performed by authors. As a starting point, aromaticity of the 1,3-imidazoles with exocyclic X substituent at C2 (XN, O or S) was calculated. Subsequently, the HOMA index was calculated for various 5+n bicyclic skeletons with N, O, and S as endocyclic heteroatoms in the second ring. For the isolated 1,3-imidazole ring, aromaticity depends on exocyclic substituent at C2 and decreases in sequence N, S, O. For bicyclic derivatives it was found that both rings are aromatic and coplanar in very few molecules (17% of investigated ones), and positive charge—located on endocyclic heteroatom—increases the aromaticity. For remaining compounds, presence of sp3 carbons excludes possibility of aromatic ring existence.

Reaction of 5,5-diphenyl-2-thiohydantoin with 1,3-dibromopropane under phase transfer catalytic conditions : Crystal and molecular structure of 2,3,4,5-tetrahydro-7,7-diphenylimidazo-[2,1-b]-thiazine -6(7H)-one

Abstract The reaction of the potassium salt of 5,5-diphenyl-2-thiohydantoin with 1,3-dibromopropane and triethylamine carried out under phase transfer catalytic conditions gave almost quantitatively two isomeric diphenylimidazothiazine 2 and 3 in a ratio ca 1:2. 2,3,4,5-Tetrahydro-7,7-diphenylimidazo- [2,1-b]-thiazine-6(7H)-one (3) crystallises from DMSO in the space group P212121 with a = 8.488(3), b = 11.682(4), c = 15.522(5)A. The 6-membered thiazine ring in 3 adopts a sofa conformation.

Design, synthesis, and anticonvulsant activity of new hybrid compounds derived from 2-(2,5-dioxopyrrolidin-1-yl)propanamides and 2-(2,5-dioxopyrrolidin-1-yl)butanamides.

The library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5-dioxopyrrolidin-1-yl)propanamides and (2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed the broad spectra of activity across the preclinical seizure models, namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg). This molecule did not impair the motor coordination of animals in the chimney test even at high doses (TD50 > 1500 mg/kg), yielding superb protective indexes (PI MES > 16.97, PI PTZ > 25.04, PI 6 Hz > 71.43). As a result, 11 displayed distinctly better safety profile than clinically relevant AEDs ethosuximide, lacosamide, or valproic acid.

Atypical cardiostimulant β-adrenoceptor in the rat heart: stereoselective antagonism by bupranolol but lack of effect by some bupranolol analogues

Atypical β‐adrenoceptors resistant to propranolol, but blocked by bupranolol, increase contractile force and/or frequency of the heart in humans and rats. We compared the potencies of the enantiomers of bupranolol and examined the possible effects of seven bupranolol analogues including bevantolol (BEV) at this receptor in pithed and vagotomized rats. CGP 12177, an agonist of the atypical β‐adrenoceptor, increased heart rate dose‐dependently. Its dose–response curve was shifted to the right by S‐(−)‐bupranolol 10 μmol kg−1 by a factor of 8.4, but not affected by the same dose of R‐(+)‐bupranolol. Desmethylbupranolol and compounds BK‐21, BK‐22, BK‐23 and BK‐25 also increased heart rate dose‐dependently. The β1‐adrenoceptor antagonist CGP 20712 given in combination with the β2‐adrenoceptor antagonist ICI 118,551 (0.1 μmol kg−1 each) reduced the positive chronotropic action of the five bupranolol analogues without affecting that of CGP 12177. The potencies of the bupranolol analogues to increase heart rate were correlated (r=0.91, P<0.05) with their affinities for β1‐adrenoceptor binding sites in rat brain cortex membranes labelled with [3H]CGP 12177 (in the presence of ICI 118,551). BK‐26 and BEV, 10 μmol kg−1 each, had only minor effects on heart rate by themselves and did not antagonize the effect of CGP 12177. However, at 1 μmol kg−1, they antagonized the increase in heart rate elicited by the β1‐adrenoceptor agonist prenalterol. In conclusion, bupranolol is a stereoselective antagonist at the atypical cardiostimulant β‐adrenoceptor. The effects of the bupranolol analogues are related to the activation or blockade of β1‐adrenoceptors, but not of atypical β‐adrenoceptors.

REACTION OF 5,5-DIPHENYL-2-THIOHYDANTOIN WITH 1,4-DIBROMOBUTANE. THE CRYSTAL AND MOLECULAR STRUCTURE OF 2,3,4,5-TETRAHYDRO-7,7-DIPHENYLIMIDAZO-[2,1-b]-THIAZEPINE-8(7H)-ONE

Abstract The reaction between the potassium salt of 5,5-diphenyl-2-thiohydantoin (1) and 1,3-dibromopropane carried out in DME under anhydrous conditions has been found to give two isomeric diphenylimidazothiazines 2 and 3. When the reaction of 1 with 1,3-dibromopropane was performed in protic solvents (EtOH, HOH, NaOH) 2 and 3-(3-mercaptopropyl) - 5,5 - diphenylthiohydantoin (4) were formed. The latter is the product of hydrolysis of 3 taking place under the reaction conditions. 2,3,4,5 - Tetrahydro - 6,6 - diphenylimidazo [2,1-b] - thiazine - 7 (6H) - one (2) crystallises in space group P21/n with a =10.812(3), b =14.905(7), c =9.885(4) A, β = 104.91(2)°. The 5-membered ring in 2 is planar whereas the 6-membered thiazine ring adopts the sofa conformation.

Micellar liquid chromatography for lipophilicity determination of new biologically active 1,3-purinodiones.

A series of newly synthesized 1,3-purinodiones with potential anticonvulsant activity, exhibiting affinity to adenosine A(1) and/or A(2A) receptors, were subjected to micellar LC (MLC) with SDS as micelle-forming agent and n-propanol as organic modifier. Two C18 silica-based columns were employed in MLC: a particle one and a monolithic. In parallel, those derivatives were also analyzed in RP-LC on four silica-based columns and on an immobilized artificial membrane column. The correlations between the relevant logarithms of the retention factors of analytes obtained in MLC, immobilized artificial membrane and RP-LC systems on the one hand, and the calculated log P (clog P) and log D values (clog D) on the other, were examined. The level of the correlations of retention data from MLC and RP-LC systems with clog P and clog D obtained is similar but it could be stressed that MLC allows increasing the speed of analysis and using only one mobile phase. Moreover, there is no need of applying an extrapolation procedure in lipophilicity determination. Therefore, the MLC systems, providing chromatographic data in a fast and efficient manner, were demonstrated as promising alternatives to the classical RP-LC systems to estimate the lipophilicity of drugs and drug candidates.

Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

A series of twelve novel non-imidazole-based ligands (3–14) was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R). The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3–14) tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES)-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally), whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ) model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR) but not the brain-penetrant H2R antagonist zolantidine (ZOL), demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR) model. Moreover, the experimental and in silico estimation of properties such as metabolism was performed for five selected test compounds. Also, lipophilicity using planar reversed-phase thin-layer chromatography method was included for better understanding of the molecular properties of the tested compounds. Additionally, the absorption, distribution, metabolism, and elimination and toxicity parameters were evaluated for the most promising compounds 2, 4, 6, 7, and 14 utilizing in vitro methods. These interesting results highlight the potential of H3R ligands as new antiepileptic drugs or as adjuvants to available epilepsy medications.