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1.
Acta Chim Slov ; 64(4): 763-770, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29318318

ABSTRACT

Novel tetrachloridoruthenium(III) complex Na[trans-RuCl4(DMSO)(PyrDiaz)] (3) with pyridine-tethered diazenedicarboxamide PyrDiaz ligand (PyrDiaz = N1-(4-isopropylphenyl)-N2-(pyridin-2-ylmethyl)diazene-1,2-dicarboxamide) was synthesized by direct coupling of PyrDiaz with sodium trans-bis(dimethyl sulfoxide)tetrachloridoruthenate(III) (Na-[trans-Ru(DMSO)2Cl4]). Compound 3 is the analogue of the antimetastatic Ru(III) complex NAMI-A and NAMI-Pyr. Single crystal X.


Subject(s)
Antineoplastic Agents/chemical synthesis , Dimethyl Sulfoxide/analogs & derivatives , Organometallic Compounds/chemistry , Ruthenium/chemistry , Antineoplastic Agents/chemistry , Crystallography, X-Ray , Dimethyl Sulfoxide/chemistry , Imides/chemical synthesis , Imides/chemistry
2.
Acta Chim Slov ; 62(2): 371-7, 2015.
Article in English | MEDLINE | ID: mdl-26085419

ABSTRACT

Biologically active 4-nitro-substituted 1,3-diaryltriazene, a chemical analogue of 1,3-bis(4'-amidinophenyl)-triazene-berenil®, belongs to the novel, chemically modified class of potent antitumor agents. Its structural characterization by X-ray analysis and 1H NMR spectroscopy is performed to determine molecular overall conformation in view of its possible interaction to DNA.


Subject(s)
Antineoplastic Agents/chemical synthesis , Triazenes/chemical synthesis , Antineoplastic Agents/chemistry , Crystallography , Magnetic Resonance Spectroscopy , Molecular Conformation , Triazenes/chemistry
3.
Molecules ; 19(4): 3851-68, 2014 Mar 28.
Article in English | MEDLINE | ID: mdl-24686575

ABSTRACT

This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4-octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 µM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl)hydrazinecarboxamide (MIC=4 µM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria.


Subject(s)
Antitubercular Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Isoniazid/analogs & derivatives , Isoniazid/chemical synthesis , Oxidoreductases/antagonists & inhibitors , Amines/chemistry , Aniline Compounds/chemistry , Antitubercular Agents/pharmacology , Azoles/chemistry , Bacterial Proteins/chemistry , Cyclization , Drug Resistance, Bacterial , Humans , Isoniazid/pharmacology , Microbial Sensitivity Tests , Molecular Docking Simulation , Mycobacterium Infections, Nontuberculous/microbiology , Mycobacterium avium/drug effects , Mycobacterium avium/enzymology , Mycobacterium avium/growth & development , Mycobacterium kansasii/drug effects , Mycobacterium kansasii/enzymology , Mycobacterium kansasii/growth & development , Mycobacterium kansasii/isolation & purification , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/growth & development , Oxidoreductases/chemistry , Pyridines/chemistry , Structure-Activity Relationship
4.
Eur J Med Chem ; 77: 193-203, 2014 Apr 22.
Article in English | MEDLINE | ID: mdl-24631899

ABSTRACT

The rapid generation and spread of the drug resistant tuberculosis has led to an ongoing demand for novel compounds for therapeutic use. Identification and study of compounds with the ability to inhibit Mycobacterium tuberculosis is of paramount importance. For this reason, a library of substituted 1,3-diaryltriazenes based on the acting component of the anti-trypanosomal drug, diminazene aceturate was created and evaluated for its potential as anti-tubercular agent. Several compounds were identified with sub-micro molar inhibitory concentrations against M. tuberculosis and other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. Although the library of the compounds showed a considerable acute cytotoxicity, a genotoxicity could not be observed. Finally, the triazene 14 was selected with the best biological properties (IC50 = 3.26 µM, NI50 = 24.22 µM, SI = 7.44). The compound 14 showed the ability to inhibit the growth of intracellular replicating and multi-drug resistant M. tuberculosis. The results suggest the molecule to be an interesting scaffold for further study and optimization.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium avium/drug effects , Mycobacterium bovis/drug effects , Mycobacterium ulcerans/drug effects , Triazenes/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Cell Line , Cell Survival/drug effects , Dose-Response Relationship, Drug , Macrophages/drug effects , Mice , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium avium/growth & development , Mycobacterium bovis/growth & development , Mycobacterium ulcerans/growth & development , Structure-Activity Relationship , Triazenes/chemical synthesis , Triazenes/chemistry
5.
Eur J Med Chem ; 74: 85-94, 2014 Mar 03.
Article in English | MEDLINE | ID: mdl-24448419

ABSTRACT

Despite efforts made in chemotherapeutic research in the past and present, Mycobacterium tuberculosis (M.tb), the etiological agent of tuberculosis, still causes more than a million deadly casualties each year, second only to HIV. The rapid generation and spread of drug resistant strains, a problem exacerbated by co-infection with HIV demands further efforts in the investigation of novel classes of anti-tubercular compounds. A library of eight substituted diazenecarboxamides, three carbamoyldiazenecarboxylates and four diazene-1,2-dicarboxamides was synthesized in a straightforward manner followed by a biological evaluation of the compounds. We observed minimal inhibitory concentrations below 10 µg/mL against the H37Rv lab strain of M.tb. Three compounds that showed a potency of 90% growth inhibition of M.tb at a concentration lower than 10 µg/mL were further evaluated and showed potency against other clinically relevant mycobacterial species such as Mycobacterium bovis, Mycobacterium avium and Mycobacterium ulcerans. The selected compounds were examined for acute cell toxicity on a murine macrophage like monocyte cell line J774 A.1 in which the cell viability was reduced by 50% at concentrations ranging from 7.4 µg/mL to 20.7 µg/mL. Neither of the three compounds showed signs of genotoxicity by VITOTOX or by Comet assay. The study was complemented by demonstration of the inhibition of intracellular replication of M.tb H37Rv inside J774 A.1 cells at 2 µg/mL concentration and the susceptibility of a MDR LAM-1 strain at concentrations between 5 and 1 µg/mL of the most active compound.


Subject(s)
Antitubercular Agents/pharmacology , Imides/pharmacology , Drug Screening Assays, Antitumor
6.
Anticancer Drugs ; 25(3): 289-95, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24322543

ABSTRACT

Previously, we described the synthesis and biological activity of a new class of anticancer molecules that preferentially target malignant cells and may serve as potential antitumor agents. Among several synthesized agents, we selected 3-acetyl-1,3-bis(2-chloro-4-nitrophenyl)-1-triazene (8b) as a representative of the group of 4-nitro-substituted 1,3-diaryltriazenes. The aim of this study was to further investigate the mechanism of cell response to the 8b compound. The HeLa human cervical carcinoma cell line was used as an experimental model to further investigate the mechanism of cell response to the 8b compound. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay was used to address cell survival, and western blot (immunoblotting) was used for the expression of relevant proteins after 8b drug exposure. The pretreatment of HeLa cells with salubrinal, a specific inhibitor of endoplasmic reticulum (ER) stress, confirmed the importance of ER stress in apoptosis induced by 8b. We also demonstrate that 8b triggers the activation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) in a time-dependent and dose-dependent manner. Moreover, the inhibition of SAPK/JNK activity by JNK II before 8b treatment increased the survival rate of HeLa cells relative to survival in the presence of 8b alone, indicating the importance of this kinase in cell death. The simultaneous inhibition of ER stress induction and SAPK/JNK activation increased the survival of HeLa cells upon 8b treatment more than inhibition of both pathways independently, suggesting the separate triggering of both signaling pathways. Our data indicate that cytotoxic activity of the novel compound 8b is based on its ability to induce ER stress and SAPK/JNK signaling pathways independently, driving cells to cell death.


Subject(s)
Antineoplastic Agents/pharmacology , JNK Mitogen-Activated Protein Kinases/metabolism , Oxidative Stress/drug effects , Signal Transduction/drug effects , Triazenes/pharmacology , Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , Enzyme Activation , Glutathione/metabolism , HeLa Cells , Humans , Reactive Oxygen Species/metabolism
8.
Acta Chim Slov ; 60(4): 842-52, 2013.
Article in English | MEDLINE | ID: mdl-24362988

ABSTRACT

To increase the effectiveness of cancer treatment, more effective anti-cancer drugs, as well as the new improved strategies of cancer treatment, are urgently needed. Our previous results have shown that various diazenes are cytotoxic to different tumor cells and can even revert the resistance to cisplatin and vincristine. We also demonstrated that unsymmetrical diazenedicarboxamides 1 and 2 exhibited promising cytotoxicity. The aim of the present study was to synthesize new diazenedicarboxamides with acceptable solubility and good cytotoxicity. Here we report the synthesis and biological evaluation of new N,N'-disubstituted diazenedicarboxamides. We found that a modification of either 1 or 2 led to the more active compounds. The most effective among them was diazenedicarboxamide 11, which can be considered as a new potential anticancer agent for the tumors of different origin, as well as for the drug resistant tumors.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Azo Compounds/chemistry , Azo Compounds/pharmacology , Cell Proliferation/drug effects , Dicarboxylic Acids/chemistry , Cell Death/drug effects , HeLa Cells , Humans , Molecular Structure
9.
Eur J Med Chem ; 62: 89-97, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23353746

ABSTRACT

The aldo-keto reductase AKR1C3 is an important target for the development of new drugs. Selective inhibitors of this enzyme are needed because they should not inhibit other, structurally closely related AKR1C isoforms. A comprehensive series of 2,3-diarylpropenoic acids was synthesized and evaluated for the inhibition of AKR1C1-AKR1C3. We found that the 4-methylsulfonylphenyl substituent at position 2 of these acids is required to exhibit the selective inhibition of AKR1C3. The best results were obtained for the compounds that fulfill the above requirement and possess a 4-bromophenyl, 4-methylthiophenyl, 4-methylphenyl or 4-ethylphenyl substituent at position 3 of the substituted propenoic acids (i.e., acids 28, 29, 37, and 39, respectively). These compounds represent an important step toward the development of drug candidates for a treatment of the hormone-dependent and hormone-independent forms of prostate and breast cancers.


Subject(s)
3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Acrylates/pharmacology , Enzyme Inhibitors/pharmacology , Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors , Phenylpropionates/pharmacology , 3-Hydroxysteroid Dehydrogenases/metabolism , Acrylates/chemical synthesis , Acrylates/chemistry , Aldo-Keto Reductase Family 1 Member C3 , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydroxyprostaglandin Dehydrogenases/metabolism , Models, Molecular , Molecular Structure , Phenylpropionates/chemical synthesis , Phenylpropionates/chemistry , Structure-Activity Relationship
10.
J Org Chem ; 77(6): 2857-64, 2012 Mar 16.
Article in English | MEDLINE | ID: mdl-22352708

ABSTRACT

The application of activated carbon (Darco KB) for the acceleration and direction of the transformation of various 2H-pyran-2-ones with N-substituted maleimides toward isoindole derivatives through the reaction sequence cycloaddition/elimination/dehydrogenation is described. In this reaction, the catalyst mainly influences the dehydrogenation step, which is essential to avoid the formation of bicyclo[2.2.2]octenes as the other possible products. We found that the combination of Darco KB, as the metal-free catalyst, and decalin, as the solvent in a closed vessel, represents the most successful conditions. A comparison of the effect of various dehydrogenation catalysts and reaction conditions is also presented. In addition, we have proven that the aromatization occurs via a hydrogen transfer from the cyclohexadiene intermediate to the maleimide derivative (therefore producing succinimides). This transfer is facilitated by the active surface of the heterogeneous carbon-based catalyst.


Subject(s)
Carbon/chemistry , Isoindoles/chemistry , Isoindoles/chemical synthesis , Metals/chemistry , Pyrones/chemistry , Cyclization , Molecular Structure , Stereoisomerism
11.
Org Biomol Chem ; 10(6): 1300-10, 2012 Feb 14.
Article in English | MEDLINE | ID: mdl-22215139

ABSTRACT

1,4-Diazabicyclo[2.2.2]octane (DABCO) has been evaluated as a starting material for the synthesis of 1-alkyl-4-(2-phenoxyethyl)piperazines and related derivatives. We found that 1-alkyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, resulting from the alkylation of DABCO, efficiently react with a variety of nucleophiles in polyethyleneglycol (PEG) or diglyme at high temperatures to give piperazine products resulting from the nucleophilic ring-opening reaction. The benzylation side reaction was found to be relevant with softer nucleophiles when using 1-benzyl-1,4-diazabicyclo[2.2.2]octan-1-ium salts, while other types of alkylations were not observed. One-pot methodologies allow for the synthesis of piperazines directly from primary alcohols, alkyl halides or sulfonates, using phenols, or other nucleophile sources, and DABCO.


Subject(s)
Ethylene Glycols/chemistry , Methyl Ethers/chemistry , Phenols/chemistry , Piperazines/chemical synthesis , Polyethylene Glycols/chemistry , Quaternary Ammonium Compounds/chemistry , Molecular Structure , Piperazines/chemistry , Salts/chemistry
12.
Eur J Med Chem ; 46(12): 5902-9, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22018878

ABSTRACT

A series of new isoniazid hydrazones was synthesized by two procedures. In the first isoniazid was activated with diethoxymethyl acetate and condensed with the appropriate anilines. Alternatively, substituted anilines were activated by diethoxymethyl acetate and subsequently condensed with isoniazid. NMR study confirmed that both synthetic approaches gave the same tautomer. All compounds were screened for in vitro antimycobacterial activity. Most of them exhibited the same activity against Mycobacterium tuberculosis (MIC 1 µmol L(-1)) as isoniazid (INH), better activity against Mycobacterium kansasii 325/80 (MIC 0.125-0.250 µmol L(-1)), high value of selectivity index (SI) and IC(50) between 0.0218 and 0.326 mmol L(-1). Compound 2o with the best SI was used as a model compound for the stability test and was found to be stable at neutral pH, but under acidic conditions it slowly hydrolysed.


Subject(s)
Anti-Bacterial Agents/pharmacology , Hydrazones/pharmacology , Isoniazid/pharmacology , Mycobacterium kansasii/drug effects , Mycobacterium tuberculosis/drug effects , Anti-Bacterial Agents/chemistry , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Cell Survival/drug effects , Hep G2 Cells , Humans , Hydrazones/chemistry , Isoniazid/chemistry , Microbial Sensitivity Tests , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium avium Complex/drug effects , Mycobacterium avium-intracellulare Infection/drug therapy , Tuberculosis/drug therapy
13.
Eur J Med Chem ; 46(10): 4937-45, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21855181

ABSTRACT

Several new fluorine-containing hydrazones were synthesized and screened for their in vitro antimycobacterial activity. Nine of these derivatives have shown a remarkable activity against MDR-TB strain with MIC 0.5 µg/mL and high value of selectivity index (SI). Compound 3h with the highest SI (1268.58) was used for stability evaluation with putative metabolites (ciprofloxacin and formylciprofloxacin) detection. Compound 3h was stable at pH 7.4 of aqueous buffer and rat plasma, in acidic buffers (at pH 3 and 5) slow decomposition was observed. Interestingly, no formylciprofloxacin was detected in the solution, and only slightly increased concentration of ciprofloxacin was observed instead. Trifluoromethyl hydrazones 3f and 3g exhibited the best activity also against two strains of Mycobacterium kansasii (MIC 1-4 µmol/L). All evaluated compounds were found to be non-cytotoxic.


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Hydrazones/chemistry , Hydrazones/pharmacology , Mycobacterium/drug effects , Tuberculosis, Multidrug-Resistant/drug therapy , Animals , Antitubercular Agents/metabolism , Cell Line , Fluorine/chemistry , Fluorine/metabolism , Fluorine/pharmacology , Humans , Hydrazones/metabolism , Microbial Sensitivity Tests , Mycobacterium kansasii/drug effects , Plasma/metabolism , Rats
14.
Eur J Med Chem ; 46(7): 2971-83, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21550697

ABSTRACT

We describe the synthesis and biological activity of a new class of 1,3-diaryltriazenes, namely 4-nitro-substituted 1,3-diaryltriazenes. Structure-activity relationship analysis reveals that 1,3-diaryltriazenes can be modified from inactive to highly cytotoxic compounds by the introduction of two nitro groups at the para positions of benzene rings and two additional electron-withdrawing groups (bromo, chloro, trifluoromethyl or fluoro substituents) at their ortho position. In order to increase the solubility of the modified compounds, we introduced various acyl groups to their triazene nitrogen. The results of LC-MS/MS analysis showed that N-acyltriazenes can be considered as prodrugs of non-acylated triazenes. Selected 3-acetyl-1,3-bis(2-chloro-4-nitrophenyl)-1-triazene (8b) is highly cytotoxic against different tumor cell lines, including cisplatin-resistant laryngeal carcinoma cells. Notably, its antiproliferative activity is significantly higher against tumor cells than against normal cells. DNA binding analysis suggests that neither 8b nor its non-acylated derivative 8a bind into the minor groove of DNA. Instead, 8b induces reactive oxygen species that could provoke endoplasmic reticulum (ER(a)) stress finally leading to apoptosis. Our data suggest that 4-nitro-substituted 1,3-diaryltriazenes are a new class of anticancer molecules which preferentially target malignant cells and may serve as potential antitumor agents.


Subject(s)
Antineoplastic Agents/chemical synthesis , Nitrophenols/chemistry , Prodrugs/chemical synthesis , Triazenes/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , DNA, Neoplasm/chemistry , Drug Resistance, Neoplasm/drug effects , Endoplasmic Reticulum Stress/drug effects , Humans , Prodrugs/pharmacology , Reactive Oxygen Species/agonists , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Triazenes/pharmacology
15.
Bioorg Med Chem ; 18(7): 2375-87, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20338766

ABSTRACT

A series of pyrazolone-fused combretastatins and precursors were synthesized and their cytotoxicity as well as antitubulin potential was evaluated. The hydrazide 9f and the pyrazolone-fused combretastatins 12a, 12b and 12c were highly cytotoxic against various tumor cell lines including cisplatin resistant cells. The same compounds were also the best inhibitors of tubulin polymerization. Molecular modeling results showed that they bind the colchicine binding site at the tubulin heterodimer. The hydrazide 9f arrested HeLa cells in the G2/M phase of the cell cycle and strongly affected cell shape and microtubule network.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Bibenzyls/chemical synthesis , Bibenzyls/pharmacology , Pyrazolones/chemical synthesis , Pyrazolones/pharmacology , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Computational Biology , Cyclization , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Hydrogen Bonding , Indicators and Reagents , Microscopy, Fluorescence , Microtubules/drug effects , Microtubules/ultrastructure , Models, Molecular , Polymers/metabolism , Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism
16.
Acta Chim Slov ; 57(1): 29-36, 2010 Mar.
Article in English | MEDLINE | ID: mdl-24061652

ABSTRACT

Phenolic compounds can be efficiently O-methylated with tetramethylammonium chloride in diglyme or polyethyleneglycol (PEG) at temperatures of 150-160 °C and in the presence of either K2CO3 or NaOH. When applying benzyltrimethylammonium chloride as a reagent, the benzylation and methylation of phenols occurs, with the benzylation product always predominating. With allyl-substituted phenols as substrates and using NaOH as a base it was possible to achieve both the alkylation and the double-bond isomerization of the allyl group to obtain (E/Z)-propenyl-substituted methyl and benzyl aryl ethers in a single preparative step.

17.
Bioorg Med Chem Lett ; 19(5): 1376-9, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19196510

ABSTRACT

The Van enzymes are ATP-dependant ligases responsible for resistance to vancomycin in Staphylococcus aureus and Enteroccoccus species. The de novo molecular design programme SPROUT was used in conjunction with the X-ray crystal structure of Enterococcus faeciumd-alanyl-d-lactate ligase (VanA) to design new putative inhibitors based on a hydroxyethylamine template. The two best ranked structures were selected and efficient syntheses developed. The inhibitory activities of these molecules were determined on E. faecium VanA, and due to structural similarity and a common reaction mechanism, also on d-Ala-d-Ala ligase (DdlB) from Escherichia coli. The phosphate group attached to the hydroxyl moiety of the hydroxyethylamine isostere within these systems is essential for their inhibitory activity against both VanA and DdlB.


Subject(s)
Bacterial Proteins/antagonists & inhibitors , Carbon-Oxygen Ligases/antagonists & inhibitors , Drug Design , Ethylamines/chemical synthesis , Peptide Synthases/antagonists & inhibitors , Bacterial Proteins/metabolism , Carbon-Oxygen Ligases/metabolism , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Ethylamines/pharmacology , Peptide Synthases/metabolism
18.
Langmuir ; 24(20): 11523-32, 2008 Oct 21.
Article in English | MEDLINE | ID: mdl-18816014

ABSTRACT

Self-assembled monolayers (SAMs) provide a simple route to functionalize electrode surfaces with organic molecules. Herein we use cavity-containing derivatives of calix[4]arenes in SAMs. Bound to noble metal surface, the assembled molecules are candidates to serve as molecular sieves for H 2 molecules and H (+) ions, which could have relevance for fuel cell applications. Tetra- O-alkylated calix[4]arenes with thiolacetate and thiolamide wide-rim anchoring groups in cone and partial-cone conformations were designed, synthesized and self-assembled onto Au, Pt, and Pd surfaces. The resulting SAMs were systematically examined. Single crystal X-ray diffraction of 5,11,17,23-tetrakis(thioacetyl)-25,26,27,28-tetra- i-propoxycalix[4]arene confirmed the cone conformation and revealed the cavity dimensions of the SAMs that were formed by immersing noble metal substrates (Au, Pt and Pd deposited on Si-wafers) in solutions of calix[4]arenes. Surface characterization techniques including ellipsometry, cyclic voltammetry (CV) and X-ray photoelectron spectroscopy (XPS) were used, indicating that the metal surface is terminated with a monomolecular layer. Experimental thicknesses obtained from the ellipsometry are consistent with the calculated values. CV results showed 50 to 80% physical passivation against the Fe(CN) 6 (3-/4-) couple, implying an overall relatively low concentration of defects and pinholes in the films. The binding energies of the S2p core level in the XPS were consistent with the literature values and revealed that up to 3.2 out of four anchoring groups were bonded to the noble metal surface.

19.
Bioorg Med Chem Lett ; 17(7): 2047-54, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17267218

ABSTRACT

D-Alanine-D-alanine ligase (Ddl) catalyzes the biosynthesis of an essential bacterial peptidoglycan precursor D-alanyl-D-alanine and it represents an important target for development of new antibacterial drugs. A series of semicarbazides, aminocarbonyldiazenecarboxylates, diazenedicarboxamides, and hydrazinedicarboxamides was synthesized and screened for inhibition of DdlB from Escherichia coli. Compounds with good inhibitory activity were identified, enabling us to deduce initial structure-activity relationships. Thirteen diazenedicarboxamides were better inhibitors than D-cycloserine and some of them also possess antibacterial activity, which makes them a promising starting point for further development.


Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Chemistry, Pharmaceutical/methods , Imides/chemistry , Peptide Synthases/antagonists & inhibitors , Adenosine Diphosphate/chemistry , Carboxylic Acids/chemistry , Catalysis , Crystallography, X-Ray , Cycloserine/chemistry , Drug Design , Escherichia coli/metabolism , Imides/pharmacology , Models, Chemical , Molecular Conformation , Phosphorylation
20.
Bioorg Med Chem ; 15(7): 2551-9, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17306980

ABSTRACT

The connection of two active molecules across an easily released bridge as a new type of potentially active molecule has been studied. The synthesis is based on derivatives that originate from isonicotinoyl hydrazide, pyrazinamide, p-aminosalicylic acid (PAS), ethambutol, and ciprofloxacin. The lipophilicity, hydrolysis (stability of the compounds), and antituberculotic activity as well as the structure-lipophilicity and structure-activity relationships are discussed.


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Antitubercular Agents/chemical synthesis , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Half-Life , Isoniazid/chemical synthesis , Isoniazid/pharmacology , Kinetics , Lipids/chemistry , Microbial Sensitivity Tests , Mycobacterium avium/drug effects , Mycobacterium kansasii/drug effects , Pyrazinamide/chemical synthesis , Pyrazinamide/pharmacology , Quantitative Structure-Activity Relationship
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