Three-component cascade reaction of 3-ketonitriles, 2-unsubstituted imidazole N-oxides, and aldehydes.

A three-component condensation of 2-unsubstituted imidazole N-oxides, 3-ketonitriles, and aldehydes is described. The reaction proceeds via sequential Knoevenagel condensation/Michael addition under mild, catalyst-free conditions with various substrates. Furthermore, the corresponding 2-functionalized imidazole N-oxides can be further dehydrated to (Z)-2-aroyl-3-(1H-imidazol-2-yl)-acrylonitriles, which may also be directly prepared by changing the reaction conditions as a cascade of Knoevenagel condensation/Michael addition/dehydration.

Assembly of isoxazol-5-one with 2-unsubstituted imidazole N-oxides and aldehydes.

A new synthetic protocol has been developed to construct polyfunctional isoxazol-5-one derivatives with imidazole moiety. It is based on the Knoevenagel condensation of isoxazol-5-one with aldehydes and subsequent Michael addition of imidazole N-oxides as part of a tandem three-component process. This reaction proceeds smoothly in moderate-to-good yield under catalyst-free conditions.

A novel approach to bis(1,3-azol-2-yl)acetonitriles and bis(1,3-azol-2-yl)methanes via the [3 + 2]-dipolar cycloaddition of imidazole N-oxides and 2-heteroaryl-3,3-dimethylacrylonitriles.

A new synthetic approach for obtaining previously unknown bis(1,3-azol-2-yl)acetonitriles and bis(1,3-azol-2-yl)methanes has been developed. It is based on 1,3-dipolar cycloaddition between 2-unsubstituted imidazole N-oxides and 2-(1,3-azol-2-yl)-3,3-dimethylacrylonitriles, which are easily available through the condensation of (1,3-azol-2-yl)acetonitriles with acetone. The method allows for the construction of various unsymmetric derivatives based on imidazole, oxazole, thiazole, and 1,3,4-thiadiazole cyclic molecules. Its potential has been demonstrated via the synthesis of 24 diverse derivatives with yields of 29-92%. Bis(1,3-azol-2-yl)acetonitriles can be converted to the corresponding bis(1,3-azol-2-yl)methanes via simple acid hydrolysis followed by subsequent spontaneous decarboxylation at nearly quantitative yields.

Structure-based inhibitors targeting the alpha-helical domain of the Spiroplasma melliferum histone-like HU protein.

Here we report bisphenol derivatives of fluorene (BDFs) as a new type of chemical probes targeting a histone-like HU protein, a global regulator of bacterial nucleoids, via its dimerization interface perturbation. BDFs were identified by virtual screening and molecular docking that targeted the core of DNA-binding ß-saddle-like domain of the HU protein from Spiroplasma melliferum. However, NMR spectroscopy, complemented with molecular dynamics and site-directed mutagenesis, indicated that the actual site of the inhibitors' intervention consists of residues from the α-helical domain of one monomer and the side portion of the DNA-binding domain of another monomer. BDFs inhibited DNA-binding properties of HU proteins from mycoplasmas S. melliferum, Mycoplasma gallicepticum and Escherichia coli with half-maximum inhibitory concentrations in the range between 5 and 10 µM. In addition, BDFs demonstrated antimicrobial activity against mycoplasma species, but not against E. coli, which is consistent with the compensatory role of other nucleoid-associated proteins in the higher bacteria. Further evaluation of antimicrobial effects of BDFs against various bacteria and viruses will reveal their pharmacological potential, and the allosteric inhibition mode reported here, which avoids direct competition for the binding site with DNA, should be considered in the development of small molecule inhibitors of nucleoid-associated proteins as well as other types of DNA-binding multimeric proteins.

One-pot synthesis of substituted pyrrolo[3,4-b]pyridine-4,5-diones based on the reaction of N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamide with amines.

The condensation of primary amines with N-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-arylethyl)acetamides was explored. Thus, a previously unknown recyclization of the starting material was observed in acidic ethanol in the presence of an amine, which provided the corresponding dihydropyrrolone derivative as the major reaction product. Based on this transformation, a practical and convenient one-pot synthetic method for substituted pyrrolo[3,4-b]pyridin-5-ones could be devised.