New 4-iminohydantoin sulfamide derivatives with antiviral and anticancer activity

A number of sulfamides were obtained by reaction of (5-(dichloromethylene)-2-oxoimidazolidin-4-ylidene)sulfamoyl chloride with anilines, benzylamines, Boc-protected piperazine, methylalylamine, and amino acids methyl esters with primary and secondary amino group. The antiviral and anticancer activity of new derivatives was evaluated. The most effective compounds against Human cytomegalovirus were sulfamides based on anisidine (1b), N-Boc-piperazine (1h), and the derivatives 1n,o with fragments of nipecotic and azetidine-3-carboxylic acids, respectively. Anticancer activity was most significant for sulfamides based on p-methoxybenzylamine (compound 1d), benzylmethylamine (compound 1f), and allylmethylamine (compound 1g).

Synthesis of novel pyrazoline-thiazolidin-4-one hybrids and evaluation their biological activity

In the present work, the synthesis of pyrazoline-thiazolidin-4-one hybrids and their pharmacological properties are described. The structure of compounds is characterized using 1H, 13C NMR, and LC-MS spectra. The antioxidant (DPPH assay), antimicrobial (Gram-positive bacterium Lactobacillus plantarum, Gram-negative bacterium Escherichia coli, and yeasts Candida albicans, MIC determination), redox (cyclic voltammetry) as well as herbicidal activity (against grass species Agrostis stolonifera) of compounds have been studied. All derivatives have demonstrated radical scavenging activity with IC50 values in the range from 4.67-7.12 mM in the DPPH test. The tested compounds presented very low antimicrobial and herbicidal activity and no redox peaks were observed in the cyclic voltammetry studies.

In vitro and in silico study of 1,3-oxazol-4-yltriphenylphosphonium salts as potential inhibitors of Candida albicans transglycosylase

The previously established in vitro high antimicrobial potential of triphenylphosphonium salts (TPPs) against bacterial (Staphylococcus aureus ATCC 25923 and multi-drug resistant (MDR)) and fungal (Candida albicans ATCC 10231 and MDR) strains made it possible to propose a molecular mechanism of action of these compounds associated with transglycosylase (TG) activity. The hypothesis was based on the well-known literature data on TPPs as inhibitors of S. aureus TG. The created homology model of TG C. albicans is optimal in terms of such quality indicators as GMQE (0.61), ERRAT (overall quality factor 95.904) and Ramachandran plot analysis (90% amino acid residues in the favored regions). Molecular docking of the most active ligands 1a-d, 3c into the active center of the created homology C. albicans TG model demonstrated the formation of stable ligand-protein complexes with binding energies in the range from -8.9 to -9.7 kcal/mol due to the various types of interactions. An important role in complex formation belongs to amino acid residues TYR307, TYR107, GLU275, ALA108 and PRO136. The presented qualitative homologous model of C. albicans TG can be used to search and create new agents with a dual mechanism of antimicrobial action. 1,3-oxazol-4-yltriphenylphosphonium salts 1a-d, 3c perform the perspective objects for further study as antimicrobials against infectious MDR pathogens.

In silico study the interaction of heterocyclic bases with peptide moieties of proteins in the "fragment-to-fragment" approach

The binding affinity of model peptide moieties (Pept) and heterocyclic bases involving 1,3-oxazoles that are condensed with pyridine and pyrimidine as pharmacophores (Pharm) was investigated in silico and analyzed within the «fragment-to-fragment» approach. The anellation of the heterocyclic rings increasing their acceptor properties is accompanied by gaining stability of the [Pharm-Pept] complexes formed by the π,π-stacking interaction. It was found that elongation of the polypeptide chain led to a twofold increase of the stabilization energy of the [Pharm-Pept] complexes. The stability of the hydrogen bonding ([HB]) [Pharm-BioM] complexes formed by means of the interaction between the dicoordinated nitrogen atom of the heterocycle and the functional groups of peptide amino acids (-OH, -NH2, -SH) was evaluated. It was demonstrated that [HB]-complexes that were formed by hydrogen bonds formation with amino acid that contained OH groups had the largest stabilization effect. The anellation with pyridine and pyrimidine rings led to stability increase of the complexes formed by the hydrogen bonding mechanism. The binding energy of [HB]-complexes for compounds 2b and 3 with a «free» peptide bond of the extended part of the protein is lower compared to amino acids with OH-functional groups. On the contrary, the binding energy of compound 4 with peptides was 2 kcal/mol higher. Compound 4 demonstrated the most pronounced biological activity in vitro studies.

Aldol Addition-Cyclization Reaction Cascade on a Platform of Chiral Ni(II) Complex of Glycine Schiff Base

Using platform of a new type of chiral Ni(II) complex of glycine Schiff base we designed addition-cyclization reaction cascade to explore aspects of kinetic/thermodynamic formation of the corresponding (S)(2S,3S)/(S)(2S,3R) diastereomers. It was found that the final lactone products reflect the thermodynamic stereocontrol due to much greater rates of the reversible aldol addition vs. subsequent cyclization step. The observed 4/1 (S)(2S,3S)/(S)(2S,3R) diastereoselectivity in the reactions of new type of (S)-Ni(II) complexes constitute an improvement over the previously reported 1.7/1 ratio.

Synthesis and evaluation of new thiazole-containing rhodanine-3-alkanoic acids as inhibitors of protein tyrosine phosphatases and glutathione S-transferases

Thiazole-containing derivatives of rhodanine-3-alkanoic acids with propanoic or undecanoic acid groups were synthesized and evaluated as inhibitors of some protein tyrosine phosphatases and glutathione S-transferases. The rhodanines bearing longer carboxylated N-alkyl chain were found to inhibit PTP1B, MEG1, MEG2, and VE-PTP as well as GST from equine liver and GSTA1-1 with IC50 values in the low micromolar range. The inhibitory effect on protein tyrosine phosphatase activity depends on substituent at position 2 of the thiazole ring. The best compound showed a competitive type of VE-PTP inhibition. In case of GST from equine liver, the inhibition was of mixed or non-competitive type with respect to glutathione or CDNB substrate, respectively. Possible binding modes of the inhibitors were discussed based on molecular docking calculations.

In silico study of binding affinity of nitrogenous bicyclic heterocycles: fragment-to-fragment approach

The binding affinity of model aromatic amino acids and heterocycles and their derivatives condensed with pyridine were investigated in silico and are presented in the framework of fragment-to-fragment approach. The presented model describes interaction between pharmacophores and biomolecules. Scrupulous data analysis shows that expansion of the π-electron system by heterocycles annelation causes the shifting up of high energy levels, while the appearance of new the dicoordinated nitrogen atom is accompanied by decreasing of the donor-acceptor properties. Density Functional Theory (DFT) wB97XD/6-31(d,p)/calculations of π-complexes of the heterocycles 1-3 with model fragments of aromatic amino acids, which were formed by π-stack interaction, show an increase in the stabilization energy of π-complexes during the moving from phenylalanine to tryptophan. DFT calculation of pharmacophore complexes with model proton-donor amino acid by the hydrogen bonding mechanism (H-B complex) shows that stabilization energy (DE) increases from monoheterocycles to their condensed derivatives. The expansion of the π-electron system by introducing phenyl radicals to the oxazole cycle as reported earlier [18] leads to a decrease in the stabilization energy of the [Pharm-BioM] complexes in comparison with the annelated oxazole by the pyridine cycle.

Features of the synthesis and biological evaluation of 3-(carboxyphenyl)chromones

Flavonoids and their derivatives have historically been a source of therapeutic agents. Every year, more and more data is published on new flavonoid compounds, both synthetic and isolated from natural sources, and their innumerable physiological and pharmacological activities. This review presents synthetic routes towards 3-(carboxyphenyl)chromones and evaluation of their biological activity as published in both journal and patent literature. We have focused specifically on the 3-(carboxyphenyl)chromones, because while methods of synthesis and biological activity of 2(3)-substituted and 2,3-disubstituted chromones are well studied, literature data on isoflavones containing a carboxyl, ester, or amide group in ring B is scarce and fragmentary. The presented generalization of synthetic strategies and biological activity of 3-(carboxyphenyl)chromone derivatives demonstrates that this class of compounds can be targeted for discovery of new drugs and can be readily prepared owing to recent advances in synthetic organic and medicinal chemistry.

Amino acid sulfonamides based on 4-(1-oxo-1H-isochromen-3-yl)benzenesulfonyl chloride

The creation of new amino acid derivatives of 4-(1-oxo-1H-isochromen-3-yl)benzenesulfonyl chloride 1 was investigated. The interaction of the sulfonyl chloride 1 with amino acid methyl esters (hydrochlorides) in 1,4-dioxane in the presence of triethylamine led to the corresponding amino acid sulfonamide derivatives of isocoumarin. The reaction of the sulfonyl chloride 1 with phenylalanine in the basic aqueous solution was complicated by the lactone system disclosure and led to 2'-carboxydeoxybenzoin ultimately (namely, 2-(2-(4-(N-(1-carboxy-2-phenylethyl)sulfamoyl)phenyl)-2-oxoethyl)benzoic acid). Similar product was obtained by the alkali hydrolysis of methyl ((4-(1-oxo-1H-isochromen-3-yl)phenyl)sulfonyl)leucinate.