Synthesis, Structural Characterization, and Biological Activity of New Pyrazolo[4,3-e][1,2,4]triazine Acyclonucleosides.

A series of new pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides 2-5 and 8 were prepared and evaluated for their anticancer activity against human cancer cell lines (MCF-7, K-562) and CDK2/E, as well as Abl protein kinases inhibitors. Lipophilicity of the compounds was determined using C-18 and immobilized artificial membrane (IAM) chromatography. In order to confirm the molecular structures and synthesis pathway of new acyclonucleosides, X-ray analysis was performed for model compound 3. Theoretical calculations at the DFT/B3LYP/6-311++G(d,p) level were used for the characterization of electronic structures of 1-8. The potential antiviral activity of acyclonucleosides 2-8 was tested in silico using molecular docking method.

Synthesis, In Vitro Screening and Docking Studies of New Thiosemicarbazide Derivatives as Antitubercular Agents.

A series of thiosemicarbazide derivatives was designed and synthesized by reaction of carboxylic acid hydrazide with isothiocyanates. The molecular structures of the investigated thiosemicarbazides were confirmed and characterized by spectroscopic analysis. The conformational preference of carbonylthiosemicarbazide chain and intra- and intermolecular interactions in the crystalline state were characterized using X-ray analysis. The antituberculosis activity of the target compounds were tested in vitro against four Mycobacterium strains: M. H37Ra, M. phlei, M. smegmatis, M. timereck. The most active compounds were those with 2-pyridine ring. They exhibited lower minimal inhibitory concentration (MIC) values in the range 7.81⁻31.25 µg/mL in comparison to the other isomers. Compound 5 had activity against M. smegmatis at a concentration of 7.81 µg/mL whereas compound 2 had activity against all tested strains at a concentration of 15.625 µg/mL. The molecular docking studies were performed for investigated compounds using the Mycobacterium tuberculosis glutamine synthetase MtGS as their molecular target.

Polysubstituted 3-trifluoromethylpyrazoles: regioselective (3 + 2)-cycloaddition of trifluoroacetonitrile imines with enol ethers and functional group transformations.

Non-catalysed addition of trifluoroacetonitrile imines to enol ethers provided fully regioselectively (3 + 2)-cycloadducts, which either spontaneously or via Brønsted acid-induced elimination of ROH molecules led to the formation of 3-trifluoromethylated pyrazoles. In the case of 2,3-dihydrofuran, the respective bicyclic intermediate was isolated and its structure was confirmed by X-ray analysis. Using the developed protocol the synthesis of a known antitumor compound SC-560 was performed in 45% yield. Subsequent functionalisations of selected 4-(ω-hydroxyalkyl)pyrazoles at C(5) through lithiation/addition, cross-coupling reactions or via intramolecular Pd-catalysed C-H arylations opened up an access to polysubstituted pyrazoles including unusual tricyclic systems comprising 7-membered rings (oxepane, thiepane and azepane) as the central unit.

Synthesis, Structure and Antiproliferative Activity of New pyrazolo[4,3- e]triazolo[4,5-b][1,2,4]triazine Derivatives.

BACKGROUND: Triazoles and their fused derivatives are an important class of compounds that exhibit interesting biological properties, such as antiasthmatic, antimicrobial, antifungal, analgesic, antiallergic, antiinflammatory, herbicidal, plant growth regulative activity, and anti-HIV-1 activities. Moreover, anticancer activity of 1,2,4-triazole containing derivatives has been documented. Due to the fact a convenient approach toward polycyclic frameworks containing fused 1,2,4-triazoles was described. OBJECTIVE: The objective of this article is the synthesis of new pyrazolo[4,3-e]triazolo[4,5- b][1,2,4]triazine derivatives with potential antiproliferative activity. METHODS: Cancer cell proliferation was analysed by means of MTT assay after 96 h treatment. IC50 was calculated using computerized linear regression analysis of quantal log doseprobit functions, according to the method of Litchfield and Wilcoxon. X-ray data were collected on the Bruker SMART APEX II CCD diffractometer; The structure was solved by direct methods using SHELXS-2013 and refined by full-matrix least-squares with SHELXL-2014/7. All calculations were performed using WINGX version 2014.1 package. RESULTS: The series of pyrazolo[4,3-e]triazolo[4,5-b][1,2,4]triazine derivatives were synthesized. MTT assay revealed that the compounds inhibited cancer cells growth at concentrations below 10 µM. The tested compounds showed higher antiproliferative activity than popular cytostatics cisplatin (lung carcinoma) and 5-fluorouracil (colon adenocarcinoma). X-ray examinations showed that final products in the crystalline phase have a linear form. CONCLUSION: In the paper we have reported the synthesis and spectroscopic analysis of new condensed tricyclic derivatives of the pyrazolo[4,3-e]triazolo[4,5-b][1,2,4]triazine. MTT analysis revealed concentration-dependent decrease in lung A549 and colon LS180 cancer cells proliferation. In order to explain the molecular mechanisms involved in anticancer activity of pyrazolo[4,3- e]triazolo[4,5-b][1,2,4]triazine derivatives, our research will be continued.

Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors.

A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure-activity for the obtained purinediones was established. Docking experiments of the investigated library to homology models of the human and rat A1 and A2A ARs allowed to compare the expected binding modes for selected compounds. The detailed analysis of binding cavities within individual AR subtypes indicated small but significant structural variations that may underlie the observed differences in binding affinities of purinediones at particular subtypes and species.

Discovery of nitroaryl urea derivatives with antiproliferative properties.

A series of urea derivatives bearing nitroaryl moiety has been synthesized and assayed for their potential antiproliferative activities. Some of the tested compounds displayed activity in RK33 laryngeal cancer cells and TE671 rhabdomyosarcoma cells while being generally less toxic to healthy HSF human fibroblasts cells. One compound was demonstrated to be a moderate CDK2 inhibitor with IC50 = 14.3 µM. Its structure was solved by an X-ray crystallography and molecular modelling was performed to determine structure-activity relationship. Obtained compounds constitute novel structures and generally demonstrated greater cytotoxicity in comparison to cisplatin. This study offers new structural motifs with potential for further development.

Phenylethyl-substituted pyrimido[2,1-f]purinediones and related compounds: structure-activity relationships as adenosine A(1) and A(2A) receptor ligands.

The synthesis of N-(un)substituted-phenylalkylpyrimido[2,1-f]purinediones was performed starting with 7-(3-chloropropyl)-8-bromotheophylline and 7-(3-chloropropyl)-8-bromo-1,3-dipropylxanthine. Compounds with unsubstituted or substituted ethylene spacer to an aromatic ring were synthesized. Additionally variations in the spacer-elongation of the linker containing more than two atoms, introduction of a double bond or heteroatoms were performed. Physicochemical properties of the synthesized compounds were described. The obtained compounds envisaged as sterically fixed and configurationally stable analogs of 8-styrylxanthines, were evaluated for their affinity to adenosine A(1) and A(2A) receptors, the receptor subtypes that are predominant in the brain. Selected compounds were also investigated for the affinity to the A(2B) and A(3) receptor subtypes. It was stated that phenylethyl pyrimido[2,1-f]purinediones and their analogs with variations of the ethylene spacer (substituted or extended) exhibit micromolar or submicromolar affinity for A(2A) ARs (adenosine receptors); for example compound 2Ac with p-hydroxy substituent displayed a K(i) value of 0.23 microM at the rat A(2A) receptor. In comparison to the previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones compounds with a shorter spacer, phenethyl derivatives were optimal for A(2A) AR. The kind of substituent at the aromatic ring was important for the affinity. Oxygen and nitrogen atoms in the spacer resulted frequently in a slight decrease of the A(2A) AR affinity, introduction of more heteroatoms into the spacer-in carbamates-caused distinctly negative effect on the activity. In this series of compounds more frequently the adenosine A(1) activity was observed, also in submicromolar range as for dipropyl derivative 2Ba with K(i) value of 0.62 microM at the rat A(2A) AR. 3D-QSAR models were developed for the compounds presented in this paper as well as in the previous publications showing activity at adenosine A(1) and A(2A) ARs. It was concluded that for the activity at adenosine A(1) and A(2A) receptors lipophilicity, steric effects along with the molecule's electrostatic surface properties had greatest value. Chosen compounds were evaluated in vivo as anticonvulsants in MES, scMet tests and examined for neurotoxicity. Contrary to previously obtained phenyl and benzyl pyrimido[2,1-f]purinediones, all tested compounds were inactive as anticonvulsants.