New Rigid Polycyclic Bis(phosphane) for Asymmetric Catalysis.

A simple, highly efficient synthesis of a series of novel chiral non-racemic rigid tetracyclic phosphorus ligands, applicable in important chemical asymmetric transformations, was performed. In a tandem cross-coupling/C-H bond activation reaction, a well-recognised and readily available ligand (R,R)-NORPHOS was used as the starting material. The palladium complexes of new ligands were obtained and characterised on the example of a crystalline dichloropalladium complex of [(1R,2R,9S,10S,11R,12R)-4-phenyltetracyclo[8.2.1.02,9.03,8]trideca-3,5,7-triene-11,12-diyl]bis(diphenylphosphane). A notably high activity and stereoselectivity of the palladium catalysts based on the new ligands were confirmed in a model asymmetric allylic substitution reaction. Herein, we discuss the geometry of the palladium complexes formed and its impact on the efficiency of the catalysts. A comparison of their geometric features with other bis(phosphane) ligand complexes found in the Cambridge Structural Database and built density functional theory (DFT) commutated models is also presented and rationalised.

Synthesis and Biological Evaluation of New 3-Phenyl-1-[(4-arylpiperazin-1-yl)alkyl]-piperidine-2,6-diones.

A set of 13 alkyl derivatives of 3-phenylpiperidine-2,6-dione were synthesized. Newly obtained compounds were investigated in vitro against HIV-1 and other selected viruses. The benzyl 3f and fluorophenyl 3g derivatives showed moderate protection against CVB-2 and the compound 3g also against HSV-1. Derivatives were tested also for their antibacterial and antifungal activity. The molecular structures of 3a and 3d were determined by an X-ray analysis.

NMR QSAR model for the analysis of 4-(5-arylamino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols.

We have developed a NMR data quantitative structure-activity relationship NMR-QSAR model based on (1)H- and (13)C-NMR experimental spectral data of 4-(5-arylamino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols. Compounds show in-vitro antiproliferative activity against some human cancer cell lines. Two-parameter equations obtained by the multiple linear regression procedure showed that chemical shifts of the protons of hydroxyl groups and carbon atoms of the 1,3,4-thiadiazole ring are the decisive descriptors of inhibition interactions of the compounds. The models gave leave-one-out (LOO) cross-validation ranges from 78% to 93%. The obtained NMR-QSAR equations provide a rapid, reliable, and simple way for predicting the antiproliferative activity of N-substituted 4-(5-amino-1,3,4-thiadiazol-2-yl)benzene-1,3-diols.

Synthesis and evaluation of in vitro biological activity of 4-substituted arylpiperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione.

A series of twenty arylpiperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione have been prepared. These derivatives were tested in vitro with the aim of identifying novel lead compounds active against emergent and re-emergent human and cattle infectious diseases (AIDS, hepatitis B and C, tuberculosis, bovine viral diarrhea). In particular, these compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA(+) viruses Yellow fever virus (YFV) and Bovine viral diarrhea virus (BVDV), both belonging to the Flaviridae. Compounds 2c, 2g and 3d showed a modest activity against CVB-2. The molecular structures of the starting imide 1 and one of propyl-piperazine derivatives, 3b, have been determined by an X-ray crystallography study.

Crystal structure, antitumour and antimetastatic activities of disubstituted fused 1,2,4-triazinones.

Molecular structure of 3,8-disubstituted 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones (8-14) was confirmed by X-ray crystallography of 14. All the compounds were evaluated for their antitumour and antimetastatic activities in vitro. Furthermore, their cytotoxicities towards human normal cell line-HSF cells were established, allowing us to point out some structure-activity relationships. Among them, imidazotriazinone 12, revealing remarkable dose-dependent viability decreases in human myeloma RPMI 8226 cells, was found to be completely non-toxic towards normal HSF cells. In addition, heterobicycles 8-12 were proved to exhibit significant antimetastatic potentials in the motility assay.

4-Azatricyclo[5.2.2.02,6]undecane-3,5,8-triones as potential pharmacological agents.

A series of twenty six arylpiperazine and aminoalkanol derivatives of 4-azatricyclo[5.2.2.0(2,6)]undecane-3,5,8-trione have been prepared. The synthesized compounds were evaluated for their cytotoxicity and anti-HIV-1 activity in MT-4 cells.

The synthesis, structure and properties of N-acetylated derivatives of ethyl 3-amino-1H-pyrazole-4-carboxylate.

Ethyl 3-amino-1H-pyrazole-4-carboxylate (1) was yielded through total synthesis and reacted with acetic anhydride to give the acetylated products 2-6. Compounds 1-6 were studied with HPLC, X-ray, FT-IR, (1)H-NMR, (13)C-NMR and MS. Acetylation was carried out in solvents of various polarity, namely; chloroform; dioxane; DMF; acetic anhydride, at room temperature and at boiling points; and in the presence and absence of DMAP. The acetylated products are mainly nitrogen atoms in the ring. The position of the ring proton in the solution was based on NOESY; multinuclear HMBC, HSQC spectra and calculations. For equivalent amounts (1-1.5 mol) of acetic anhydride at room temperature two products of monoacetylation are produced in the ring: 2 and 3, ca. 2 : 1 and at the same time only small amount of the third product of monoacetylated, 5 in DMF, as well the product diacetylated, 4. The greatest amount of the product 4 is produced during the reaction with chloroform. However, in this solvent and in dioxane no product 5 is produced. Compound 2 is, largely, formed in dimethylformamide, in the presence DMAP, 0.2 eq. In the presence of this catalytic base, for the first hour, there is a mixture 2 and 3 to the ratio ca. 95 : 5. With 8 eq of Ac(2)O at reflux, after another hour, the compounds 3, 4 and 6 appear about equal amounts. After a longer time, the compound, which appears most in this mixture is triacetylated derivative 6. The structural and spectroscopic characteristics of compounds 1-6 have been given and the methods for their preparation have been provided.

Identification of antitumour activity of novel derivatives of 8-aryl-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-dione and 8-aryl-4-imino-2,3,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3(6H)-one.

The series of 8-aryl-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-diones (11-20) and 8-aryl-4-imino-2,3,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3(6H)-ones (21-25) were designed and their in vitro cytotoxic activities against human LS180, HeLa, T47D, A549 and RPMI 8226 carcinoma cells are presented. In the crystalline state molecule 12 exists as the predominant tautomeric 3-oxo form, whereas the second possible 3-hydroxy tautomer is not observed. Compound 19 revealed a strong affection to LS180 cancer cells at lower tested concentration (37.9 microM) and simultaneously was found to be non-toxic towards the normal cell line investigated--GMK cells. Furthermore, this compound was proved to possess the efficiency for DNA strand breakage of the examined cancer cell lines. However, imidazotriazin-3,4-dione 20 was able to cause significant viability decreases in human RPMI 8226 peripheral blood myeloma cells. Compound 22 has exhibited remarkable inhibitory effects against LS180 and A549 carcinoma cells, whereas 24 revealed the highest growth inhibition against A549 cell line. Simultaneously, at lower tested concentration these compounds were proved to be completely non-toxic for GMK cells. Moreover, cytotoxic and antibacterial properties of starting, tautomeric 1-aryl-2-hydrazonoimidazolidines (1-6 and 8-9) are presented. Six of them (1-2, 4-6 and 9) proved active as antimicrobials. All these compounds revealed MIC values in the range of 15.0-78.6 microM. Their activities were compared to those of ampicillin and chloramphenicol.

Novel derivatives of methyl and ethyl 2-(4-oxo-8-aryl-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetates from biologically active 1-aryl-2-hydrazinoimidazolines: synthesis, crystal structure and antiproliferative activity.

The 1-aryl-2-hydrazinoimidazolines (2a-h) were directly obtained from appropriate 1-aryl-2-methylthioimidazolines (1a-h) by condensation reaction with hydrazine hydrate. Antimicrobial activities of two 1-aryl-2-hydrazinoimidazolines (2b and 2e) are presented. Their chemical structures were confirmed by IR, (1)H NMR, EI-MS and elemental analysis. The susceptibility of Gram-positive and Gram-negative bacterial strains, mould and yeast-like fungi strains to synthesized compounds and the MIC values against two reference strains of bacteria were determined. The strongest antibacterial activity for compound 2b in relation to reference Gram-negative Escherichia coli ATCC 25922 bacterial strain with minimal inhibitory concentration (MIC) value of 3.91micro g mL(-1) was found. Compound 2b showed superior activity (MIC) to ampicillin and comparable to chloramphenicol. A novel compound 2e was found to be effective against E. coli ATCC 25922 and Staphylococcus aureus ATCC 25923 at concentrations of 7.81micro g mL(-1) and 15.62micro g mL(-1), respectively. Compound 2e revealed antibacterial activity against E. coli ATCC 25922, superior to ampicillin and inferior to chloramphenicol. Against S. aureus ATCC 25923 strain tested, compound 2e demonstrated MIC value inferior to ampicillin and chloramphenicol. Moreover, the synthesis, crystal structure and antiproliferative activity of novel derivatives of methyl and ethyl 2-(4-oxo-8-aryl-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetates (3a-f and 3g-j) are presented. These compounds were obtained from 1-aryl-2-hydrazinoimidazolines (2a-f) by the addition and cyclization reactions with fumaric acid esters. Molecular structures of these compounds were confirmed by elemental analysis, IR, (1)H NMR, (13)C NMR, EI-MS and by X-ray crystallography (for 3g). The tested imidazotriazines 3e, 3i and 3j exhibited anticancer activities towards the following cancer cells: LS180 (ECACC 87021202, human Caucasian colon adenocarcinoma cells), SiHa (ECACC 85060701, uterus cancer cells), and T47D (ECACC 85102201, human breast carcinoma cells). Compounds 3i and 3j having comparable GI values (above 50%) towards uterus cancer cell line (SiHa) at both examined concentrations (10micro g mL(-1) and 50micro g mL(-1)) were found to be the most effective against this cancer cell line; their GI factors were 53%, 51% and 62%, 55%, respectively, in both examined concentrations (10micro g mL(-1) and 50micro g mL(-1)). Furthermore, the distinctly marked lower cytotoxicity of tested imidazotriazines 3i and 3j against normal cell lines (HSF, human skin fibroblast cells and Vero African Green Monkey Kidney cells, GMK clone) and almost 2-times higher against the majority of cancer cell lines was confirmed.

Synthesis, crystal structure and anticancer activity of novel derivatives of ethyl 1-(4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)formate.

Synthesis and anticancer activity of ethyl 1-(4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)formates (7-12) are presented. The title compounds were obtained by two independent synthesis methods from 1-aryl-2-hydrazono-imidazolidines (1-aryl-2-hydrazino-imidazolines) (1-6) by cyclocondensation reaction with diethyl 2-(hydroxyimino)malonate (A) and diethyl 2-oxomalonate (B). Molecular structure of synthesized compounds was confirmed by IR, (1)H NMR, EI-MS spectra, elemental analysis and X-ray crystallography for 12. Compounds 10 and 11 exhibited anticancer activity towards following cancer cells: LS180 (ECACC 87021202, human Caucasian colon adenocarcinoma cells), SiHa (ECACC 85060701, uterus cancer cells), T47D (ECACC 85102201, human breast carcinoma cells). Compound 10 was found to be the most active against SiHa cancer line; its GI was 41 and 52%, respectively in both examined concentrations (10 and 50 microg ml(-1)), whereas compound 11 had the highest potential to reduce the growth of LS180 and SiHa cancer lines, especially in a higher dose (50 microg ml(-1)). Moreover, the distinctly marked lower cytotoxicity of tested compounds against normal cell lines (HSF, human skin fibroblast cells and Vero African Green Monkey Kidney cells, GMK clone) and almost two-times higher against cancer cell lines was confirmed. Also antibacterial activity of starting 1-(2-chlorophenyl)-2-hydrazonoimidazolidine hydroiodide (4) is presented. Molecular structure of 4 was confirmed by IR, (1)H NMR, (13)C NMR, EI-MS spectra, elemental analysis and (1)H-(1)H COSY, HMBC and HMQC correlations. The marked antibacterial activity for this compound in relation to Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 with equal minimal inhibitory concentration values of 15.62 and 15.62 microg ml(-1) was found.

Conformational investigation of alpha, beta-dehydropeptides. XI. Molecular and crystal structure of Ac-(Z)-deltaPhe-NMe2 as compared to those of related molecules.

A series of three homologous dimethyldiamides Ac-(Z)-deltaPhe-NMe2, Ac-L-Phe-NMe2 and Ac-DL-Phe-NMe2 have been synthesized and their structures determined from single-crystal X-ray diffraction data. To learn more about the conformational preferences of the compounds studied, the fully relaxed phi, psi conformational energy maps on the free molecules of Ac-deltaAla-NMe2 and Ac-(Z)-deltaPhe-NMe2 were obtained with the HF/3-21G method and the calculated minima re-optimized with the DFT/B3LYP/6-31G** method. The crystal state results have been compared with the literature data. The studied dimethyldiamide Ac-deltaXaa-NMe2 combines the double bond in positions alpha, beta and the C-terminal tertiary amide within one molecule. As the representative probe with deltaXaa = deltaAla, (Z)-deltaLeu and (Z)-deltaPhe shows, in the solid state they adopt the conservative conformation with phi, psi approximately -45 degrees, approximately 130 degrees and with a non-planar tertiary amide bond, whatever the packing forces are. This conformation is located on the Ramachandran map in region H/F, which is of high-energy for common amino acids, but not so readily accessible to them. The free molecule calculations on Ac-deltaAla-NMe2 and Ac-(Z)-deltaPhe-NMe2 reveal that, in spite of dissimilar overall conformational profiles of these molecules, this structure is one of their low-energy conformers and for Ac-(Z)-deltaPhe-NMe2 it constitutes the global minimum. So, the theoretical results corroborate those experimental results proving that this structure is robust enough to avoid conformational distortion due to packing forces. In contrast to Ac-deltaXaa-NMe2, the saturated Ac-L/DL-Xaa-NMe2 shows the constancy of the associative patterns but do not prefer any molecular structure in the solid state.

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Part 3. Synthesis and pharmacological activity of 1-aryl-5,6(1H)dioxo-2,3-dihydroimidazo[1,2-a]imidazoles.

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.

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1H)dioxo-2,3-dihydroimidazo[1,2-a][1,3,5]triazines.

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.