Structural aspects of intermolecular interactions in the solid state of 1,4-dibenzylpiperazines bearing nitrile or amidine groups.

The crystal structures of the title 1,4-bis(4-cyanobenzyl)piperazine (1) and 1,4-bis(4-amidinobenzyl)piperazine tetrahydrochloride tetrahydrate (2) are reported. Compound (1) crystallizes in the triclinic space group P\bar 1 and compound (2) in the monoclinic space group P21/n. In both (1) and (2) the asymmetric unit contains one half of the molecule because the central piperazine rings were located across a symmetry center. The packing of both molecules was dominated by hydrogen bonds. The crystal lattice of (1) was formed by weak C-H...N and C-H...π interactions. The crystal structure of (2) was completely different, with cations as well as chloride anions and water molecules taking part in intermolecular interactions. Single-crystal X-ray diffraction studies combined with density functional theory (DFT) calculations allowed the characterization of the intermolecular interactions in those two systems having different types of very strong electrophilic groups: non-ionic nitrile and ionic amidine. Chemical shift data from (13)C CP/MAS (Cross Polarization Magic Angle Spinning) NMR spectra were analyzed using the different procedures for the theoretical computation of shielding constants.

Model structure-activity relationship studies of potential tropane 5HT1A, 5HT2A, and D2 receptor ligands.

The two-stages studies of structure-activity relationship for model ligands of 5HT1A, 5HT2A, and D2 receptors were performed. On the first stage, the pharmacophores of two potential ligands of known in vitro binding to 5HT1A, 5HT2A, D2 receptors and model pharmacophore of strongly interacting D2 receptor ligands were found and their parameters were related to affinity data. The analyzed parameters were hydrophobic, hydrophilic, aromatic, donor and acceptor of proton centers. The geometry of spatial distribution of these properties was also investigated in comparative analysis. The studied, model compounds were two 3ß-acylamine derivatives of tropane. The second stage includes docking of studied compounds to D2 receptor model and the comparison of its quality with in vivo binding data. The obtained results are consistent with in vitro binding data and applied procedure accurate estimates the affinity of potential ligands to D2 receptors.

Microwave-assisted preparation and antimicrobial activity of O-alkylamino benzofurancarboxylates.

ABSTRACT: A series of derivatives of 2 and 3-benzofurancarboxylates were synthesized under microwave-assisted conditions. Their in-vitro antimicrobial properties were assessed. Inhibition by the compounds of the growth of antibiotic-susceptible standards and clinically isolated strains of Gram-positive and Gram-negative bacteria, yeasts, and a human fungal pathogen was moderate to significant. Methyl 5-bromo-7-[2-(N,N-diethylamino)ethoxy]-6-methoxy-2-benzofurancarboxylate hydrochloride was identified as the most active compound (MIC 3-12 × 10-3 µmol/cm3 against Gram-positive bacteria; MIC 9.4 × 10-2 µmol/cm3 against Candida and Aspergillus brasiliensis). The molecular and crystal structures of 2-(N,N-diethylamino)ethyl 6-acetyl-5-hydroxy-2-methyl-3-benzofurancarboxylate were established by single-crystal X-ray diffraction. GRAPHICAL ABSTRACT: .

Synthesis and characterization of selected methyl 5-methoxy-2-methyl-1-benzofuran-3-carboxylate derivatives with potential antimicrobial activity.

Halogen and aminoalkyl derivatives of methyl 5-methoxy-2-methyl-1-benzofuran-3-carboxylate were prepared using 5-hydroxy-2-methyl-3-benzofuranocarboxylic acid as starting material. (1)H-NMR spectra were obtained for all of the synthesized structures, and for compounds 1 and 2 X-ray crystal structures were obtained too. All derivatives were tested for antimicrobial activity against a selection of Gram-positive cocci, Gram-negative rods and yeasts.

Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1.

The synthesis, structure, in vitro and in vivo pharmacological activities of 3ß-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3ß position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents.

Synthesis and pharmacological activity of O-aminoalkyl derivatives of 7-hydroxycoumarin.

A series of novel O-aminoalkyl substituted 7-hydroxycoumarins were synthesized and evaluated for antibacterial and anticancer toxicity. Two different synthetic procedures, conventional and microwave assisted were used, and the structures of the compounds were confirmed by IR, 1H, 13C NMR and MAS spectroscopic data. The molecular and crystal structures of 8-acetyl-7-[2-(1-morpholino)ethoxy]4-methylchromen-2-one in solid state were analyzed by single crystal X-ray diffraction. The compound crystallizes in the monoclinic space group P2(1)/c. The main driving forces for the supramolecular structure are the C-H⋯O hydrogen bonds and the π⋯π intermolecular interactions. The most active compounds are those, where the O-aminoalkyl substituent has N,N-diethylamino part, and acetyl group is at C6 or at C8 atoms.

Synthesis and preliminary evaluation of the antimicrobial activity of selected 3-benzofurancarboxylic acid derivatives.

Halogen derivatives of selected 3-benzofurancarboxylic acids were prepared using 6-acetyl-5-hydroxy-2-methyl-3-benzofuranocarboxylic acid as starting material. (1)H-NMR spectra were obtained for all of the synthesized structures, and for compound VI, an X-ray crystal structure was also obtained. All derivatives were tested for antimicrobial activity against a selection of Gram-positive cocci, Gram-negative rods and yeasts. Three compounds, III, IV, and VI, showed antimicrobial activity against Gram-positive bacteria (MIC 50 to 200 microg/mL). Compounds VI and III exhibited antifungal activity against the Candida strains C. albicans and C. parapsilosis (MIC-100 microg/mL).

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: part 2.

Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT(1A) receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT(1A) receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT(1A) receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with -OCH(3) or -F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT(1A) receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.

Novel 3,3'-diindolylmethane derivatives: synthesis and cytotoxicity, structural characterization in solid state.

A series of 3,3'-dindolylmethane derivatives have been synthesized and their structures were characterized in solid state by (13)C CP/MAS NMR and two of them by X-ray diffraction measurements. They exhibited well expressed cytotoxicity against human melanoma cell lines. Derivatives bearing fluoro, bromo, iodo, and nitro substituents in indole or benzene rings caused 50% inhibition of the viability of ME18 and ME18/R cell lines at concentration ranging 9.7-17.3 microM.

DNA-based electrochemical biosensors for monitoring of bis-indoles as potential antitumoral agents, chemistry, X-ray crystallography.

Facile and practical electrochemical DNA bioassay, X-ray diffraction analysis, synthesis and 1H and 13C NMR data of the 5,5'-disubstituted-3,3'-methanediyl-bis-indoles are reported. On the basis of electrochemical measurements we have hypothesized that the analyzed bis-indoles have an effect on human tumor cells due to DNA binding at adenine-thymidine deoxynucleotides rich region in a concentration/substituent dependent manner. Interesting N-H...pi and hydrogen-bonding intermolecular interactions were observed which may differentiate their biological features. The 5,5'-dimethoxy-3,3'-methanediyl-bis-indole (2) was found to reduce considerably the growth of cancer cell lines HOP-92 (lung), A498 (renal) and MDA-MB-231/1TCC (breast). The results indicate that title compounds could be interesting as potential antitumoral chemotherapeutics.

Synthesis and structural characterization of derivatives of 2- and 3-benzo[b]furan carboxylic acids with potential cytotoxic activity.

Derivatives of 2- and 3-benzo[b]furancarboxylic acids were prepared and evaluated for their cytotoxic potential in the National Cancer Institute, Bethesda, USA. Six compounds: 7-acetyl-6-hydroxy-3-methyl-2-benzofurancarboxylic acid (2), 6-hydroxy-7-(p-methoxycinnamoyl)-3-methyl-2-benzofurancarboxylic acid (4), 5-bromo-7-hydroxy-6-methoxy-2-benzofurancarboxylic acid methyl ester (6a), 6-acetyl-5-(O-ethyl-2'-diethylamino)-2-methyl-3-benzofurancarboxylic acid methyl ester (1f), 6-(O-ethyl-2'-diethylamino)-7-p-methoxycinnamoyl)-3-methyl-2-benzofurancarboxylic acid methyl ester hydrochloride (4b), 5-bromo-7-(O-ethyl-2'-diethylamino)-6-methoxy-2-benzofurancarboxylic acid methyl ester (6b) showed significant cytotoxic activities against human cancer cell lines. In addition the crystal structures of 7-methoxy-2-benzofurancarboxylic acid methyl ester (7a) has been solved by X-ray structure analysis of single crystals.

Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors.

Synthesis applied to prepare compounds 5-15 and 17-22 discussed in this paper has been presented in Scheme 1. Multi-stage preparation techniques were used to obtain 4-aryl-hexahydro 1-4 and (R,R) and (S,S) 4-aryl-octahydropyrido[1,2-c]pyrimidine-1,3-dione (16) derivatives, being the starting compounds for further modification. N-Alkylation of the imide group in compounds 1-4 and 16 followed, using 1,4-dibromobutane to yield monobromobutyl derivatives 5-8 and 17. Subsequent condensation of those compounds with appropriate 1-aryl or 1-heteroarylpiperazine led to the final hexahydro- 9-15 and octahydro- 18-22 pyrido[1,2-c]pyrimidine-1,3-dione derivatives. The final products were subjected to screening test to elucidate the affinity to 5-HT1A and 5-HT2A receptors.