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1.
Molecules ; 27(2)2022 Jan 16.
Article in English | MEDLINE | ID: mdl-35056873

ABSTRACT

In this study, deep eutectic solvents (DESs) were used as green and eco-friendly media for the synthesis of substituted 2-mercaptoquinazolin-4(3H)-ones from different anthranilic acids and aliphatic or aromatic isothiocyanates. A model reaction on anthranilic acid and phenyl isothiocyanate was performed in 20 choline chloride-based DESs at 80 °C to find the best solvent. Based on the product yield, choline chloride:urea (1:2) DES was found to be the most effective, while DESs acted both as solvents and catalysts. Desired compounds were prepared with moderate to good yields using stirring, microwave-assisted, and ultrasound-assisted synthesis. Significantly, higher yields were obtained with mixing and ultrasonication (16-76%), while microwave-induced synthesis showed lower effectiveness (13-49%). The specific contribution of this research is the use of DESs in combination with the above-mentioned green techniques for the synthesis of a wide range of derivatives. The structures of the synthesized compounds were confirmed by 1H and 13C NMR spectroscopy.

2.
Eur J Med Chem ; 124: 794-808, 2016 Nov 29.
Article in English | MEDLINE | ID: mdl-27639370

ABSTRACT

The 4-substituted 1,2,3-triazole core in designed coumarin hybrids (4-35) with diverse physicochemical properties was introduced by eco-friendly copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition under microwave irradiation. Coumarin-1,2,3-triazole-benzofused heterocycle hybrids emerged as the class of compounds exhibiting the highest antiproliferative activity. The strong relationship between lipophilicity and antiproliferative activities was observed indicating that lipophilic 1,2,3-triazole-coumarin hybrids containing phenylethyl (13), 3,5-difluorophenyl (14), 5-iodoindole (30) and benzimidazole (33 and 35) subunits showed the most potent cytostatic effects. The 7-methylcoumarin-1,2,3-triazole-2-methylbenzimidazole hybrid 33 can be highlighted as a lead that exerted the highest cytotoxicity against hepatocellular carcinoma HepG2 cells with IC50 value of 0.9 µM and high selectivity (SI = 50). This compound induced cell death, mainly due to early apoptosis. Strong antiproliferative effect of 33 could be associated with its inhibition of 5-lipoxygenase (5-LO) activity and perturbation of sphingolipid signaling by interfering with intracellular acid ceramidase (ASAH) activity. Outlined considerable effect of lipophilicity on antiproliferative activity was not observed for antibacterial activity. The compounds with p-pentylphenyl (17), 2-chloro-4-fluorobenzenesulfonamide (23) and dithiocarbamate (27) moiety were endowed with high selectivity against Enterococcus species. Moreover, these compounds were found to be superior in inhibiting the growth of clinically isolated vancomycin-resistant Enterococcus faecium, while the reference antibiotics exhibited the lack of activity. Our findings indicate that coumarin-1,2,3-triazole could be used as the scaffold for structural optimization to develop more potent and selective anticancer agents and encourage further development of novel structurally related analogs of 33 as more effective 5-LO inhibitors.


Subject(s)
Computer Simulation , Coumarins/chemical synthesis , Coumarins/pharmacology , Drug Design , Triazoles/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Bacteria/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Coumarins/chemistry , Drug Screening Assays, Antitumor , Humans , Microbial Sensitivity Tests , Structure-Activity Relationship
3.
Bioorg Med Chem ; 23(23): 7448-63, 2015 Dec 01.
Article in English | MEDLINE | ID: mdl-26578325

ABSTRACT

Versatile 1,2,3-triazole pharmacophore-based benzofused heterocycles containing halogen-substituted aromatic (9-17 and 25-28), 7-substituted coumarin (18-23 and 29-30) or penciclovir-like subunit (31a,b-38a) were designed and synthesized to evaluate their antibacterial activities against selected Gram-positive and Gram-negative bacteria. Hybridization approach using environmentally friendly Cu(I)-catalyzed click reaction under microwave irradiation was adopted in the synthesis of regioselective 1,4-disubstituted 1,2,3-triazole tethered heterocycles (9-23 and 25-30), while post-N-alkylation of NH-1,2,3-triazoles afforded both 2,4- (31a-38a) and 1,4-disubstituted (31b-33b, 35b-37b) 1,2,3-triazole regioisomers. The compounds 18-23 and 25-30 revealed fluorescence in the violet region of the visible spectrum with a strong influence of phenyl spacer in 25-30 on both wavelength and emission intensity. Fusion of selected subunits led to new hybrid architecture, benzothiazole-1,2,3-triazole-coumarin 29 that demonstrated extremely narrow spectrum activity towards fastidious Gram-negative bacteria Moraxella catarrhalis. Selected hybrid showed the potency against Moraxella catarrhalis (MIC⩽0.25µg/mL) comparable to that of reference antibiotic azithromycin, which suggested that further investigations are necessary to optimize this potential hit compound as a new anti-Moraxella catarrhalis agent.


Subject(s)
Anti-Bacterial Agents/pharmacology , Benzothiazoles/pharmacology , Heterocyclic Compounds, 2-Ring/pharmacology , Moraxella catarrhalis/drug effects , Triazoles/pharmacology , Umbelliferones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Azithromycin/pharmacology , Benzothiazoles/chemical synthesis , Click Chemistry , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Hydrophobic and Hydrophilic Interactions , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Umbelliferones/chemical synthesis
4.
Nucl Med Biol ; 39(2): 235-46, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21958846

ABSTRACT

INTRODUCTION: We report on the synthesis, radiolabeling, in vitro and in vivo characterization of N-Me-[(18)F]FHBT (6-(3-[(18)F]fluoro-2-(hydroxymethyl)propyl)-1,5-dimethylpyrimidin-2,4(1H,3H)-dione), a C-6-substituted N-1-methylated pyrimidine derivative as a reporter probe for imaging herpes simplex virus type 1 thymidine kinase (HSV1-TK) expression. METHODS: N-Me-[(18)F]FHBT was synthesized via a standard nucleophilic substitution reaction followed by acidic cleavage of the methoxytrityl protecting group. Cell uptake was studied in vitro with control HEK293 (human embryonic kidney cells) and HEK293 cells stably transfected with nonmutant HSV1-tk (HEK293TK+ cells). Positron emission tomography (PET) imaging and biodistribution studies of N-Me-[(18)F]FHBT or [(18)F]FHBG were performed in nude mice bearing xenografts of HEK293 control and TK+ cells. RESULTS: N-Me-[(18)F]FHBT was obtained in a two-step reaction in an overall maximal radiochemical yield (decay-corrected) of 5% and a radiochemical purity >96%. The tracer uptake in HSV1-TK containing HEK293TK+ cells was 14.5 times (at 30 min) and 55.4 times (at 240 min) higher than in control HEK293 cells. In mice, N-Me-[(18)F]FHBT and [(18)F]FHBG accumulated significantly and exhibited similar radioactivity levels in the HEK293TK+ xenografts; however, standardized uptake values ratios between HEK293TK+ and HEK293 control xenografts were higher for [(18)F]FHBG than for N-Me-[(18)F]FHBT. Both tracers showed high gall bladder and abdominal activity. CONCLUSION: The biological evaluations demonstrated the feasibility of using N-methylated C-6-substituted pyrimidine derivative N-Me-[(18)F]FHBT as a PET radiotracer for monitoring HSV1-TK expression in vivo.


Subject(s)
Fluorine Radioisotopes/pharmacokinetics , Herpesvirus 1, Human/metabolism , Positron-Emission Tomography/methods , Pyrimidines/pharmacokinetics , Thymidine Kinase/metabolism , Animals , Female , Herpesvirus 1, Human/genetics , Humans , Mice , Mice, Nude , Pyrimidines/chemical synthesis , Thymidine Kinase/genetics , Thymine/analogs & derivatives , Thymine/chemical synthesis , Thymine/pharmacokinetics , Tissue Distribution
5.
Bioorg Med Chem Lett ; 22(1): 308-12, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-22130132

ABSTRACT

The synthesis of the novel 5-alkyl pyrimidine derivatives, 5,6-dihydrofuro[2,3-d]pyrimidines and 5-alkyl N-methoxymethyl pyrimidine derivatives and evaluation of their cytostatic activities are described. The mechanism of antiproliferative effect of 5-(2-chloroethyl)-substituted pyrimidine 3 that exerted the pronounced cytostatic activity was studied in further details on colon carcinoma (HCT116) cells. The cell cycle perturbation analysis demonstrated severe DNA damage (G2/M arrest) pointing to a potential DNA alkylating ability of 3. Preliminary ADME data of 3 and its 6-methylated structural congener (6-Me-3) showed their high permeability and good metabolic stability.


Subject(s)
Pyrimidines/chemical synthesis , Alkylating Agents/pharmacology , Animals , Cell Division , Cell Line, Tumor , Cell Proliferation , Chemistry, Pharmaceutical/methods , Cytostatic Agents/pharmacology , DNA/chemistry , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor/methods , G2 Phase , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Permeability , Pyrimidines/chemistry , Rats
6.
Molecules ; 16(6): 5113-29, 2011 Jun 20.
Article in English | MEDLINE | ID: mdl-21694675

ABSTRACT

Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).


Subject(s)
Carbon/chemistry , Nitrogen/chemistry , Pyrimidines/chemistry , Nitrogen/metabolism , Pyrimidines/chemical synthesis
7.
Nucleosides Nucleotides Nucleic Acids ; 30(4): 293-315, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21623543

ABSTRACT

Novel C-6 substituted pyrimidine derivatives are good substrates of herpes simplex virus type 1 thymidine kinase (HSV1-TK). Enzyme kinetic experiments showed that our lead compound, N-methyl DHBT (N-methyl-6-(1,3-dihydroxyisobutyl) thymine; N-Me DHBT), is phosphorylated at a similar rate compared to "gold standard" 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine, FHBG, (K(m) = 10 ± 0.3 µM; k(cat) = 0.036 ± 0.015 sec(-1)). Additionally, it does not show cytotoxic properties on B16F1 cells up to a concentration of 10 mM. The x-ray analysis of the crystal structures of HSV1-TK with N-Me DHBT and of HSV1-TK with the fluorinated derivative N-Me FHBT confirmed the binding mode predicted by docking studies and their substrate characteristics. Moreover, the crystal structure of HSV1-TK with N-Me DHBT revealed an additional water-mediated H-bond interesting for the design of further analogues.


Subject(s)
Gene Expression/drug effects , Thymine/chemistry , Thymine/pharmacology , Animals , Biocatalysis , Catalytic Domain , Cell Line, Tumor , Crystallography, X-Ray , Halogenation , Herpesvirus 1, Human/enzymology , Humans , Methylation , Mice , Models, Molecular , Purines/chemistry , Purines/metabolism , Reproducibility of Results , Substrate Specificity , Thymidine Kinase/chemistry , Thymidine Kinase/genetics , Thymidine Kinase/metabolism , Thymine/analogs & derivatives , Thymine/chemical synthesis , Transduction, Genetic
8.
Bioorg Med Chem ; 18(7): 2704-12, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20211564

ABSTRACT

5,6-Disubstituted pyrimidine derivatives (3-20) were prepared by intramolecular cyclization reaction of alpha-(1-carbamyliminomethylene)-gamma-butyrolactone (2) with sodium ethoxide and subsequent chemical transformation of 2-hydroxy group in C-5 side chain as well as lithiation reaction for introduction of acyclic side chain at C-6. All compounds were characterized by (1)H NMR, (13)C NMR and mass spectra. Structures of compounds 4, 7 and 14 were unambiguously confirmed by X-ray crystal structural analysis. Supramolecular structures of these three compounds differ significantly. Two N-H...O and one C-H...O hydrogen bonds in 4 form three-dimensional network. One O-H...N hydrogen bond and one pi...pi interaction self-assemble the molecules of 7 into sheets. In supramolecular aggregation of 14, only pi...pi stacking interactions participate, so forming chains. The compounds were evaluated for their cytostatic activities against human malignant cell lines. Of all tested compounds, 2,4-dimethoxy-5-methoxytritylethylpyrimidine (9) and 2,4-dichloro-5-chloroethylpyrimidine (14) exhibited the most prominent inhibitory effects. Furthermore, compound 14 showed marked activity against human colon carcinoma (IC(50)=0.4microM).


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Pyrimidines/chemistry , Spectrophotometry, Ultraviolet
9.
Molecules ; 14(12): 4866-79, 2009 Nov 27.
Article in English | MEDLINE | ID: mdl-20032865

ABSTRACT

The synthetic route for introduction of fluorophenylalkyl (compounds 5, 7, 14 and 15) and fluorophenylalkenyl (compounds 4E and 13) side chains at C-6 of the pyrimidine nucleus involved the lithiation of the pyrimidine derivatives 1, 2 and 11 and subsequent nucleophilic addition or substitution reactions of the organolithium intermediate thus obtained with 2-fluorophenylacetone, 4-fluoroacetophenone or ethyl 4-fluorobenzoate as electrophiles. The structures of novel compounds were confirmed by (1)H-, (19)F- and (13)C-NMR and MS. Compounds 8 and 10 containing unsaturated fluorophenylalkyl side chains showed better inhibitory effect than their saturated fluorophenylalkylated pyrimidine counterparts 7 and 9. A conformational study based on NOE enhancements showed the importance of the double bond and substitution in the side chain for the conformational preferences in relation to inhibitory activity. Among all tested compounds, C-5 furyl (12) and phenyl (13 and 15) substituted pyrimidine derivatives showed significant cytostatic activities against all tested tumor cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Antineoplastic Agents/chemistry , Cell Cycle , Cell Line, Tumor , Chromatography, Thin Layer , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Pyrimidines/chemistry
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