Martin Gazvoda

A way to avoid using precious metals: the application of high-surface activated carbon for the synthesis of isoindoles via the Diels-Alder reaction of 2H-pyran-2-ones.

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.

N-substituted 2-isonicotinoylhydrazinecarboxamides--new antimycobacterial active molecules.

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.

2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17β-hydroxysteroid dehydrogenase (AKR1C3).

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.

Combining [Arene–Ru] with Azocarboxamide to Generate a Complex with Cytotoxic Properties

Azocarboxamide (azcH) has been combined for the first time with [Ru-Cym] to generate metal complexes with N,N- and N,O-coordination mode, [(Cym)Ru(azc)Cl] and [(Cym)Ru(azcH)Cl](+) [PF6 ](-). Geometric and electronic structures of the complexes are reported along with their in vitro activities against different tumour cell lines and preliminary results on solution chemistry. Compound [(Cym)Ru(azc)Cl] exhibited remarkable cytotoxic properties. It was cell-type specific and had comparable IC50 values towards both cancer cells and their drug-resistant subline. A tenfold increase in the sensitivity towards [(Cym)Ru(azc)Cl] was noted for the tumour cells with depleted intracellular glutathione (GSH) level, suggesting the essential role of GSH in cell response to this compound.

Systematic Evaluation of 2-Arylazocarboxylates and 2-Arylazocarboxamides as Mitsunobu Reagents

2-Arylazocarboxylate and 2-arylazocarboxamide derivatives can serve as replacements of typical Mitsunobu reagents such as diethyl azodicarboxylate. A systematic investigation of the reactivity and physical properties of those azo compounds has revealed that they have an excellent ability as Mitsunobu reagents. These reagents show similar or superior reactivity as compared to the known azo reagents and are applicable to the broad scope of substrates. p Ka and steric effects of substrates have been investigated, and the limitation of the Mitsunobu reaction can be overcome by choosing suitable reagents from the library of 2-arylazocarboxylate and 2-aryl azocarboxamide derivatives. Convenient recovery of azo reagents is available by one-pot iron-catalyzed aerobic oxidation, for example. SC-DSC analysis of representative 2-arylazocarboxylate and 2-arylazocarboxamide derivatives has shown high thermal stability, indicating that these azo reagents possess lower chemical hazard compared with typical azo reagents.

Synthesis of Bis(1,2,3-Triazole) Functionalized Quinoline-2,4-Diones

Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title compounds. The procedure involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned intermediates by the reaction of them with propargyl bromide in N,N-dimethylformamide (DMF) in presence of a potassium carbonate and the subsequent formation of a second triazole ring by copper catalyzed cyclisation reaction with azido compounds. The products were characterized by 1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC) with 1H–15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.

En Route to 2-(Cyclobuten-1-yl)-3-(trifluoromethyl)-1H-indole

A six-step synthetic route from 4-chloro-2-methylaniline to 5-chloro-2-(cyclobut-1-en-1-yl)-3-(trifluoromethyl)-1H-indole (1) has been reported. Compound 1a is a key impurity of reverse transcriptase inhibitor efavirenz, an important anti-HIV/AIDS drug. Synthetic challenges, dead ends, and detours are discussed.

Versatile Coordination of Azocarboxamides: Redox-Triggered Change of the Binding Chelate in Ruthenium Complexes

Azocarboxamides occupy a special place among azo ligands owing to their versatility for metal coordination. Herein ruthenium complexes with two different azocarboxamide ligands that differ in the presence (or not) of a coordinating pyridyl heterocycle are presented. By making full use of the O,N(amide), N(azo), and N(pyridyl) coordinating sites, the first diruthenium complex that is bridged by an azo ligand containing two different binding pockets was obtained. Moreover, it was conclusively proven that, in the mononuclear complexes, oxidation at the ruthenium center leads to a complete change of coordination at the chelating binding pocket. The complexes were characterized by NMR spectroscopy, mass spectrometry, and single-crystal X-ray diffraction. Additionally, the mechanism of the aforementioned redox-triggered change in the chelating binding pocket and the electronic structures of all the complexes were investigated by a combination of electrochemistry, UV/Vis/NIR/EPR spectroelectrochemistry, and DFT calculations. This is first instance in which a redox-driven change in the complete chelating binding pocket has been observed in a ruthenium complex as well as with azo-based ligands. These results thus show the potential of these versatile azocarboxamide ligands to act as redox-driven switches with possible relevance to electrocatalysis.

Synthesis of 1,4-Benzodiazepine-2,5-diones by Base Promoted Ring Expansion of 3-Aminoquinoline-2,4-diones

An unprecedented reactivity of 3-aminoquinoline-2,4-diones is reported. Under basic conditions, these compounds undergo molecular rearrangement to furnish 1,4-benzodiazepine-2,5-diones. The transformations take place under mild reaction conditions by using 1,1,3,3-tetramethylguanidine, NaOEt, or benzyltrimethylammonium hydroxide as a base. A proposed mechanism of the rearrangement and the conformational equilibrium of 1,4-benzodiazepine-2,5-dione rings are discussed.