-
[show abstract]
[hide abstract]
ABSTRACT: The 1,2,4-triazoles are an important group of medicinal substances which exhibit a wide range of activity, such as analgesic, antibacterial, fungicidal, antinflammatory, antiviral and anticancer. As a part of our long-term study on 1,2,4-triazoles we synthesize 4-benzyl-3-[(1-methylpyrrol-2-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one which is characterized with anticancer activity. Here, we present an exhaustive studies of its electronic and molecular structure, aimed to rationalize the observed pharmacological activity, supported by the molecular docking to the EGFR kinase domain ATP binding site. The structural studies include X-ray analysis, experimental and computed spectral analysis (1H and 13C NMR, IR) as well as conformational analysis and the frontal molecular orbitals (FMO) analysis. The results of molecular docking indicate that interaction of 4-benzyl-3-[(1-methylpyrrol-2-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one with the EGFR kinase domain ATP binding site may be responsible for the observed anticancer activity of this 1,2,4-triazole derivative. Moreover, we find that formation of the respective ligand-protein complex is conditioned by the keto-enol tautomerism of the ligand, i.e. the energetic prevalence of the keto form.
Medicinal chemistry (Shāriqah (United Arab Emirates)) 06/2012; · 1.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Lipophilicity of several novel analgesic active 1-(1-arylimidazolidyn-2-ylidyn)-3-arylalkyl urea derivatives has been estimated by the use of chromatographic method. The investigated compounds were analyzed by reversed-phase high performance liquid chromatography (RP-HPLC) using mixtures of methanol or acetonitrile and water with addition of imidazolium based room temperature ionic liquids varying in an anion chaotropicity as the mobile phases. The relationships between log k values vs. concentration of organic solvent was used for determination of the log k(w) values by extrapolation technique. The partition coefficients (log P) values were calculated by means of the Pallas 3.1.1.2. and Spartan 10.0 softwares and further correlated with log k(w) measured experimentally in classical organic-aqueous eluent system and systems modified with ionic liquids addition. It was found that log k(w) values measured in eluent system modified with butyl-methyl imidazoilum chloride correlate the best with the logarithm of partition coefficient calculated by Pallas software (log P(calc.)). Furthermore, it was found that the examined compounds form H-bonding with imidazoilum cation of modifiers improving the chromatographic peak parameters (the symmetry factor, the theoretical plates number) especially when ionic liquid's anion was more chaotropic. Amphiphilic ionic liquid possessing longer alkyl chain substituent (OMIM BF(4)) can be considered as a new cationic surfactant. Micellar conditions improved separation selectivity of chloro- and methoxy substituted derivatives.
Journal of pharmaceutical and biomedical analysis 03/2012; 66:58-67. · 2.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The title compound, C(19)H(15)Cl(2)N(3)O(2), was obtained by a one-step cyclo-condensation of 2-amino-1-(4-chloro-phen-yl)imidazoline with diethyl (2-chloro-benz-yl)malonate under basic conditions. In the crystalline state, the mol-ecule exists as the 7-hy-droxy-5-oxo tautomer. The dihedral angles between the fused imidazopyrimidine and aromatic chloro-phenyl and chloro-benzyl rings are 14.2 (1) and 70.7 (1)°, respectively. The conformation of the mol-ecule is influenced by the intra-molecular C-H⋯O and C-H⋯N hydrogen bonds, giving a nearly planar five-ring fused system [maximum deviation from the mean plane = 0.296 (2) Å]. In the crystal structure, strong inter-molecular O-H⋯O hydrogen bonds link the mol-ecules into chains along the c axis. These chains are further stabilized by weak C-H⋯Cl and π-π inter-actions [centroid-centroid distance = 3.6707 (12) Å].
Acta Crystallographica Section E Structure Reports Online 01/2010; 66(Pt 11):o2742-3. · 0.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Japanese encephalitis (JE) is a significant cause of human morbidity and mortality throughout Asia and Africa. Vaccines have reduced the incidence of JE in some countries, but no specific antiviral therapy is currently available. The NS3 protein of Japanese encephalitis virus (JEV) is a multifunctional protein combining protease, helicase and nucleoside 5'-triphosphatase (NTPase) activities. The crystal structure of the catalytic domain of this protein has recently been solved using a roentgenographic method. This enabled structure-based virtual screening for novel inhibitors of JEV NS3 helicase/NTPase. The aim of the present research was to identify novel potent medicinal substances for the treatment of JE. In the first step of studies, the natural ligand ATP and two known JEV NS3 helicase/NTPase inhibitors were docked to their molecular target. The refined structure of the enzyme was used to construct a pharmacophore model for JEV NS3 helicase/NTPase inhibitors. The freely available ZINC database of lead-like compounds was then screened for novel inhibitors. About 1,161,000 compounds have been screened and 15 derivatives of the highest scores have been selected. These compounds were docked to the JEV NS3 helicase/NTPase to examine their binding mode and verify screening results by consensus scoring procedure.
FEMS Immunology & Medical Microbiology 10/2009; 58(1):91-101. · 2.44 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The study proposes the first complete model of an ionotropic glutamate receptor (GluR6). The model is in accordance with available experimental data from single-particle electron microscopy images and exhibits correct shape and dimensions and the appropriate symmetry: 2-fold in the N-terminal domain (NTD), ligand-binding domain (LBD), and external part of the transmembrane region, whereas it is 4-fold deeper in the channel. The methodology applied for GluR6 receptor model building was validated in the docking procedure of competitive and uncompetitive antagonists. The constructed model was used to study molecular interactions of novel noncompetitive GluR6 antagonists with their molecular target. A new binding site in the GluR6 receptor transduction domain has been identified. It is situated between two subunits in the receptor dimer. The following residues were recognized as crucial for interactions: Arg663A, Arg663B (M3-S2 linker), Ser809B (S2-M4 linker), and Phe553A (S1-M1 linker).
Journal of Chemical Information and Modeling 05/2009; 49(4):1094-104. · 4.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: There is numerous experimental and conceptual proof that the extracellular portion of ionotropic glutamate receptors (iGluRs), i.e., N-terminal domain (NTD) and ligand-binding core (LBD), exhibits 2-fold rotational symmetry and thus dimer of dimers architecture. However, the problem of the structure and symmetry of the transmembrane channel forming region of iGluRs has not been solved yet. According to the most common approach, glutamate ion channels possess 4-fold symmetry, similar to homologous potassium channels. This results in a symmetry mismatch between the extracellular fragment of the receptor and its transmembrane domain. To overcome the above discrepancies in iGluR symmetry, homology modeling was applied to propose an alternative model of GluR5 channel transmembrane region. Because of modification of M3 helix structure, as indicated by experimental results, the obtained model is generally characterized by 2-fold rotational symmetry. As a validation of the applied methodology, IEM-1754 was docked to the obtained GluR5 receptor transmembrane fragment model. However, because there are no affinity values available for IEM-1754, the applied methodology was additionally validated by building of NMDA receptor transmembrane region model and its evaluation in the docking of dextrorphan, (+)-MK-801, and IEM-1925. Moreover, the NMDA and GluR5 channel models are consistent with all available experimental data, including the latest single-particle electron microscopy images of iGluRs.
Journal of Medicinal Chemistry 08/2008; 51(13):3765-76. · 4.80 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In the crystal structure of the title compound, C(17)H(17)ClN(4)O, the existence of only one 2-imino-oxo of the five possible N-amino-imino/O-keto-hydr-oxy tautomers is observed and the dihedral angle between the aromatic rings is 29.78 (11)°. The mol-ecular conformation is stabilized by intra-molecular C-H⋯N, N-H⋯O and C-H⋯O hydrogen bonds, in each case generating a six-membered ring. In the crystal structure, the glide-plane-related mol-ecules are linked into C(4) amide chains by inter-molecular N-H⋯O hydrogen bonds, and an inter-molecular C-H⋯O link also occurs.
Acta Crystallographica Section E Structure Reports Online 01/2008; 65(Pt 1):o40. · 0.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The electron ionization mass spectra of the 1-phenyl-, 1-benzyl- and 6-benzyl-1-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidine-5,7(1H,6H)-dione derivatives were recorded at 70 eV to find out the effects of substituents on their fragmentations. Fragmentation pathways were studied using B/E and B(2)/E scans. Some fragmentations involved the loss of C(3)HO(2) or carbon suboxide. The possibility of keto-enol tautomerism was also studied. For comparison selected compounds were studied using (1)H and (13)C NMR spectroscopy to reveal the presence of possible tautomerism. Some ions including [M-OH](+) and [M-HCO](+) and NMR results indicate that the enol form is predominant both in the gas and in the liquid phase.
Rapid Communications in Mass Spectrometry 02/2007; 21(23):3891-7. · 2.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The electron ionization mass spectra of the title compounds (1: a R = H, b 2-CH(3), c 4-CH(3), d 2,3-diMe, e 2-OCH(3), f 4-OCH(3), g 2-Cl, h 3-Cl, i 4-Cl, j 3,4-diCl) were recorded at 70 eV to determine the effects of substituents and the possible keto-enol tautomerism. The compounds showed several common fragment ions but also fragment ions which divided them into three classes, namely 1a-1d (parent compound and Me-substituted derivatives), 1e and 1f (MeO-substituted derivatives), and 1g-1j (Cl-substituted derivatives). The presence of the HOCN(+.) ion as well as the exponential dependence of its total ion current in the case of p- and also 3-Cl-substituted compounds (1a, c, f, h-j) on the Hammett sigma constants and the loss of CHO or one or two HOCN moieties can be somewhat easier explained by the presence of the enol form but as a whole the results support the predominance of the keto form, in parallel to the situation in solution.
Rapid Communications in Mass Spectrometry 02/2006; 20(17):2548-52. · 2.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2H,8H-6,7-dihydroimidazo[2,1-c] [1,2,4]triazines (A) are presented. The title compounds were obtained from 1-aryl-2-hydrazinoimidazolines (1) by cyclization reaction with ethyl oxalate (2). They were tested for pharmacological activity in behavioral animal tests (A1, A3, A5, A6, A8, A9). With relatively low acute toxicity (LD50 in range from 1100 to over 2000 mg kg(-1), intraperitoneally, i.p.), some of them exhibited significant antinociceptive activity as the result of the 'writhing' test indicated. Especially strong antinociception for compound A8 and significant for A6 was observed in doses of 12.5-200 mg (0.00625-0.1 LD50) and 37.5-150 mg (0.025-0.1 LD50), respectively. Reversion of the antinociception for A1 and A8 produced in the 'writhing' test by 5 mg kg(-1) dose of naloxon can suggest an opioid-like mechanism of their analgesic activity. Additionally, compound A9 reduced number of the "head twitch" episodes after 5-hydroxytryptophan (5-HTP) administration with no antinociceptive effect at all and compound A3 showed significant protection in the pentylentetrazol-induced seizure model. Differences observed in the activity spectrum between A8 and A9 derivatives can be explained on the base of difference in the amido-imido tautomeric equilibrium observed between these two compounds.
European Journal of Medicinal Chemistry 03/2005; 40(2):127-34. · 3.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The influence of the nature of typical organic modifiers, used in reversed-phase systems diluted with water, on retention and selectivity of chiral acetylated diamines and acetonitriles possessing pharmacological activity was investigated. Linear, semi-logarithmic relationships between the logarithm of the retention factor, k, of the enantiomer and the volume fraction, phi, of the organic modifier in the binary aqueous-organic eluent were established for chiral stationary phases. The slope of a plot of log k vs. the modifier volume fraction depends not only on the chemical structure of the chromatographed enantiomers, but also on the nature of the modifier. Moreover, the enantioselectivity of the studied racemates also depends on the nature and concentration of the modifier and is higher for a methanol mobile phase than for acetonitrile.
Journal of Separation Science 04/2004; 27(4):304-10. · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Synthesis and pharmacological activity of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[1,2-a]imidazoles (D) are presented. The title compounds were obtained from 1-aryl-2-iminoimidazolidines (1) by cyclization reaction with oxalic acid derivatives-ethyl ester (2) or chloride (3). They were tested for pharmacological activity in animal and binding assay tests. With moderate acute toxicity (LD(50) approximately 200 mg kg(-1), i.p.), they exhibited significant analgesic and serotonergic activities as results of the 'writhing' and the 'hot plate' tests indicated, and reduced number of 'head twitch' episodes after 5-HTP (5-hydroxytryptophan) administration. Reversion of the antinociception produced in the 'writhing' test by small dose of naloxon (5 mg kg(-1)) can suggest an opioid-like mechanism of their analgesic activity. The probable receptor inhibition mechanism of their analgesic and serotonergic activity was confirmed in the binding assay tests (by radioligand displacement) toward the opioid mu and serotonin 5-HT(2) receptors. Additionally, they exhibited affinity toward the benzodiazepine (BZD) receptor as well, although in behavioral tests compounds did not produce any clear depressive effect on the central nervous system (CNS) of mice. Simple chemical structure of the title compounds, in comparison to other carbonyl derivatives of 1-aryl-2-iminoimidazolidine presented in this series of papers, underline very important role both of a hydrophobic moiety (aromatic ring) and polar groups (hydrogen-bond acceptors) in the serotonin receptor interaction. The co-existence of opioid-like, serotonergic and BZD receptor inhibition activity can be very interesting and can lead to creation of the novel group of antidepressants.
European Journal of Medicinal Chemistry 11/2002; 37(10):845-53. · 3.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This paper is the second part of the review on opioid receptor ligands and deals with the progress in the field of non-peptide opioid receptor antagonists (starting from the pioneering opiate studies in the early seventies) with particular stress on the last decade accomplishments. As X-ray high resolution structure determination of the ligand-receptor systems for G protein-coupled receptors meets with considerable experimental obstacles, the knowledge about ligand interactions with the membrane-bound receptors traditionally derives from structure-activity studies. Hence, such a concise summary, collecting chemically distinct but pharmalogically relative compounds, may be a convenient information source for any research concerning ligand-opioid receptor binding or rational drug design.
Current Medicinal Chemistry 10/2002; 9(17):1591-603. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo-[1,2-a][1,3,5]triazines (C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents--phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1H)-dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazine (C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD(50) > 2000 mg kg(-1) i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg(-1)) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid mu receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT(2) and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar') at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT(2) expressed in the binding assay test.
European Journal of Medicinal Chemistry 10/2002; 37(9):761-72. · 3.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Developments in the domain of non-peptide opioid receptor agonists, beginning from the first evidence of opiate binding to definite receptors, are briefly summarized. The recent achievements are in a more detailed way depicted and discussed. Novel agonists for each of three opioid receptor basic types (delta, kappa and micro) are presented with the special emphasis on one-type-selective ligands. Such selective or even specific agonists have been synthesized with a moderate success. Considerably more serious difficulties concern searching for selective ligands for opioid receptor subtypes (micro(1), micro(2), delta(1), delta(2, kappasub>1), kappasub>2, kappasub>3) which may be connected with the fact that dissimiliarities observed in vivo result from postbinding processes (signaling). For the large number of opioid receptor ligands, their structural diversity and relative easiness of generating them from combinatorial libraries (not comparable even with that of orphanine receptors) it is justified to consider the plasticity of opioid receptors (micro-receptor especially). This remark, in conjunction with the existence of opioid receptor types and subtypes, may enable to create new drugs with significantly reduced side-effects. The above facts and brand new reports about highly-active opioid agonists possessing no moieties thought to be essential for agonist activity make the need of reevaluation of classical opioid receptor pharmacophore model extremely important. In general, research results suggest that selective agonists of opioid receptors can be found both in morphine type of ligands and new structures like pyrido-acridine derivatives (COMP1) or diphenylmethylpiperazine derivatives (SNC 80). Better understanding of the structural prerequisites of the opioid receptors binding domains will certainly lead to even more potent and more selective ligands in a near future.
Current Medicinal Chemistry 09/2002; 9(17):1567-89. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The retention of aromatic hydrocarbons with polar groups has been correlated as log k1 versus log k2 for reversed-phase high-performance liquid chromatography systems with different binary aqueous mobile phases containing methanol, acetonitrile or tetrahydrofuran as modifiers. Distinct changes in separation selectivity have been observed between tetrahydrofuran and acetonitrile or methanol systems. Methanol and acetonitrile systems show lower diversity of separation selectivity. The changes in retention and selectivity of aromatic hydrocarbons with various polar groups between any two chromatographic systems with binary aqueous eluents (tetrahydrofuran vs. acetonitrile, tetrahydrofuran vs. methanol and methanol vs. acetonitrile) have been interpreted in terms of molecular interactions of the solute with especially one component of the stationary phase region, i.e. extracted modifier, and stationary phase ordering. The ordering of the stationary phase region caused by modifier type influences the chromatographic selectivity of solutes with different molecular shape.
Journal of Chromatography 03/2002; 947(2):167-83. · 4.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The synthesis and physicochemical properties of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine are presented. Isomeric 1-(1-arylimidazolidine-2-ylidene)-3-arylureas (series A) and 1-aryl-2-imine-3-arylaminocarbonylimidazolidines (series B) were obtained after the condensation reaction of 1-aryl-2-iminoimidazolidines and arylisocyanates. 1-Aryl-2-iminoimidazolidines were synthesised in a two-step reaction from the respective anilines. The molecular structure of 1-(1-phenylimidazolidine-2-ylidene)-3-(4-chlorophenyl)urea (A2) has been determined by X-ray crystallography. The representatives of both investigated series were evaluated in behavioural animal tests. They exhibited significant, especially analgesic, activity on the animal central nervous system (CNS). They displayed substantial effect on the serotonine and catecholamine neurotransmission as well, at very low toxicity (LD50 over 2000 mg kg−1 i.p.). In the binding affinity tests they exhibited moderate affinity (on the micromolar level) toward opioid (μ) and serotonine (5HT2) receptors. The derivatives of series A had moderate affinity toward benzodiazepine (BZD) receptor as well. Distinctive differences observed in their activity spectra can be connected with the presence of particular structural features such as relative orientation of the two aromatic rings and the carbonyl moiety.
European Journal of Medicinal Chemistry 11/2001; · 3.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Keto–enol tautomerism is a key phenomenon which determines the pharmacological activity of compounds possessing the carbonyl group. In the present study we use X-ray analysis, IR spectroscopy as well as quantum chemical calculation to address the keto–enol tautomerism of 4-substituted 3-[1-methylpyrrol-2-yl)methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one derivatives with antimicrobial activity. In the gas phase and in the crystalline state all the investigated molecules exist in the keto form while in the chloroform solution a small amount of the enol form in the equilibrium with the keto form is observed. The results of the calculations are in good agreement with experimental data obtained from X-ray analysis and IR spectroscopy in KBr but do not confirm the shift of the tautomeric equilibrium into the enol form in a chloroform solution.Highlights► We study the keto-enol tautomerism of substituted 1,2,4-triazol-5-one derivatives. ► In the gas phase and in the crystalline state all molecules exist in the keto form. ► In chloroform a small amount of the enol in the equilibrium with the ketone occurs.
Journal of Molecular Structure. 994:313-320.
-
[show abstract]
[hide abstract]
ABSTRACT: In the reaction of ethyl N-(1-arylimidazolidine-2-ylidene) carbamic acid ester with 4-chlorobenzylamine new derivatives of 1-(1-arylimidazolidine-2-ylidene)-3-arylurea (I-VI) were obtained. Cyclic derivatives of dihydroimidazo[l ,2-a][1,3,5]trizines were synthesized by condensation of 1-(1-arylimidazolidine-2-ylidene)-3-(4-chlorobenzyl)urea with carbonyldiimidazole (CDI) (VII-XII). The effect of compounds X, XI on the central nervous system of mice in some behavioral tests was investigated.
Acta poloniae pharmaceutica 69(6):1270-5. · 0.66 Impact Factor
