Formation of 3-(glutathion-S-yl)-N-methyl-4-aminoazobenzene and inhibition of aminoazo dye-nucleic acid binding in vitro by reaction of glutathione with metabolically-generated N-methyl-4-aminoazobenzene-N-sulfate

The reaction of glutathione (GSH) with metabolically-formed N-methyl-4-aminoazobenzene-N-sulfate (MAB-N-sulfate), a presumed ultimate carcinogenic metabolite of N,N-dimethyl-4-aminoazobenzene (DAB), was investigated using a hepatic sulfotransferase incubation mixture containing GSH and the proximate carcinogen, N-hydroxy-N-methyl-4-aminoazobenzene (N-HO-MAB). Under these conditions, 6–16% of the MAB-N-sulfate formed could be trapped as an aminoazo dye-GSH adduct. Upon subsequent purification, the adduct was shown to be chromatographically and spectrally identical to 3-(glutathion-S-yl)-N-methyl-4-aminoazobenzene (3-GS-MAB), a known biliary metabolite of DAB and a product of the reaction of the synthetic ultimate carcinogen, N-benzoyloxy-N-methyl-4-aminoazobenzene(N-BzO-MAB), with GSH. Neither 2′- nor 4′-GS-MAB, both products of the latter reaction, were detected in the sulfotransferase incubation mixture.GSH-S-transferases did not appear to be involved in the reaction of MAB-N-sulfate or N-BzO-MAB with GSH. The addition of triethyltin, a potent GSH-S-transferase inhibitor, had no effect on the yield of 3-GS-MAB in (N-HO-MAB sulfotransferase)-GSH incubations; and the addition of cytosol or purified GSH transferases A and B to a (N-BzO-MAB)-GSH reaction mixture did not increase the amount of 3-GS-MAB formed.GSH was shown to inhibit only partially the covalent binding of [³H]-MAB-N-sulfate to DNA and rRNA. At 10 and 100 mM GSH, the sulfotransferase-mediated binding of [³H]N-HO-MAB to both nucleic acids was reduced by 30% and 70%, respectively. The role of GSH in the detoxification of chemical carcinogens is discussed.     

Identification of 4'-sulphonyloxy-N-(glutathion-S-methylene)-4-aminoazobenzene, a compound conjugated with both sulphate and glutathione, which is a major biliary metabolite of N,N-dimethyl-4-aminoazobenzene

A major biliary metabolite in the rat of the hepatocarcinogen N,N-dimethyl-4-aminoazobenzene (DAB) has been identified as 4′-sulphonyloxy-N-(glutathion-S-methylene)-4-aminoazobenzene. This conjugate can be synthesized by the condensation of 4′-sulphonyloxy-4-aminoazobenzene with formaldehyde and glutathione (GSH).     

Inhibitory effects in vitro of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-glutathione,a proposed metabolite of l-histidine,on γ-glutamyltransferase activity

A transfer of the γ-glutamyl moiety of S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]glutathione (I), an adduct of glutathione and l-histidine metabolite urocanic acid, has been investigated by using γ-glutamyltransferase preparation from bovine kidney. When an equimolar mixture of two diastereomers of compound I in a phosphate buffer was allowed to react with glycylglycine in the presence of the transferase, two diastereomers of N-{S-[2-carboxy-1-(1H-imidazol-4-yl)ethyl]-l-cysteinyl}glycine (II) were formed in the same yield with each other and this was accompanied by a formation of γ-glutamylglycylglycine. Kinetics of compound I with the transferase indicated high affinity between the two materials, while the maximal reaction velocity of the γ-glutamyl transfer was low. Effects of compound I in vitro on the transfer of γ-glutamyl moiety of γ-glutamyl-p-nitroanilide to glycylglycine with the transferase were also studied, and the results indicated that the transfer was suppressed by compound I based on its competitive and non-competitive inhibitions. These results suggest that little variation in reactivities of two diastereomers of compound I as the substrate is given by the difference in stereomerism of their asymmetric carbon atoms and that inhibitory effects of compound I on the catalytic action of the transferase is of sufficient physiological importance to decrease the degradation of natural γ-glutamyl compounds, such as glutathione and its analogs.     

Synthesis,Biological Evaluation and in Silico Studies of 3-Hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide Derivatives

In the present study, a series of 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were synthesized, characterized and evaluated for theirin vitroactivity, i. e., antimicrobial, antioxidant and anti-inflammatory. The target compounds were synthesized by condensation reaction of 3-hydroxy-2-naphthoic acid hydrazide with substituted benzaldehydes which were subjected to cyclization reaction with thioglycolic acid and ZnCl₂ to get target compounds. The synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives were examined for their antimicrobial activity and 3-hydroxy-N-(4-oxo-2-(3,4,5-trimethoxyphenyl)thiazolidin-3-yl)-2-naphthamide ( S20 ) exhibited the highest antimicrobial potential. The N′-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide ( S5 ) displayed good antifungal potential against Rhizopus oryzae, whereas N′-(2,3-dichlorobenzylidene)-3-hydroxy-2-naphthohydrazide ( S20 ) showed the highest antioxidant potential and N-(2-(2,6-dichlorophenyl)-4-oxothiazolidin-3-yl)-3-hydroxy-2-naphthamide ( S16 ) displayed the highest anti-inflammatory activity. The results of molecular docking studies revealed that existence of hydrogen bonding and hydrophobic interactions with their respective proteins. In silico ADMET studies were carried out by Molinspiration, Pre-ADMET and OSIRIS property explorer to predict the pharmacokinetic behaviour of synthesized 3-hydroxy-N-(2-(substituted phenyl)-4-oxothiazolidin-3-yl)-2-napthamide derivatives.     

2(S),3(S)-3-hydroxy-4-methyleneglutamic Acid from Gleditsia caspica

A new natural product, 2(S),3(S)-3-hydroxy-4-methyleneglutamic acid (G3) has been isolated from seeds of Gleditsia caspica. The structure has been established by chemical and spectroscopic methods. Catalytic reduction of G3 yields 2(S),4(S)-4-methylglutamic acid and a new amino acid, 2(S),3(S),4(S)-3-hydroxy-4-methylglutamic acid. Ozonolysis of G3 followed by oxidation gives 2(S),3(R)-3-hydroxyaspartic acid. The S- (or l-) configurations at C₂ in G3 and in 2(S),3(S),4(S)-3-hydroxy-4-methyglutamic acid and the S-configurations at C₃ for G3 and 2(S),3(S),4(S)-3-hydroxy-4-methylglutamic acid and at C₄ for 2(S),3(S),4(S)-3-hydroxy-4-methylglutamic acid are inferred from the configurations at C₂ in 2(_S),4(_S)-4-methylglutamic acid and at C₂ and C₃ in 2(S),3(R)-3-hydroxyaspartic acid. The seeds also contain appreciable quantities of 2(S),3(S),4(R)-3-hydroxy-4-methylglutami c acid (G1) and 2(S),4(R)-4-methylglutamic acid.     

Exploring 5-nitrofuran derivatives against nosocomial pathogens: Synthesis,antimicrobial activity and chemometric analysis

The burden of nosocomial or health care-associated infection (HCAI) is increasing worldwide. According to the World Health Organization (WHO), it is several fold higher in low- and middle-income countries. Considering the multidrug-resistant infections, the development of new and more effective drugs is crucial. Herein, two series (I and II) of 5-nitrofuran derivatives were designed, synthesized and assayed against microorganisms, including Gram-positive and -negative bacteria, and fungi. The pathogens screened was directly related to either the most currently relevant HCAI, or to multidrug-resistant infection caused by MRSA/VRSA strains, for instance. The sets I and II were composed by substituted-[N′-(5-nitrofuran-2-yl)methylene]benzhydrazide and 3-acetyl-5-(substituted-phenyl)-2-(5-nitro-furan-2-yl)-2,3-dihydro-1,3,4-oxadiazole compounds, respectively. The selection of the substituent groups was based upon physicochemical properties, such as hydrophobicity and electronic effect. The compounds have showed better activity against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis. The findings from S. aureus strain, which was more susceptible, were used to investigate the intersamples and intervariables relationships by applying chemometric methods. It is noteworthy that the compound 4-butyl-[N′-(5-nitrofuran-2-yl)methylene]benzhydrazide has showed similar MIC value to vancomycin, which is the reference drug for multidrug-resistant S. aureus infections. Taken the findings together, the 5-nitrofuran derivatives might be indeed considered as promising hits to develop novel antimicrobial drugs to fight against nosocomial infection.     

Neuroprotective Activity of (+)-(S)-2-[(1S,5R)-(3,7-Dioxo-2,4,6,8-Tetraazabicyclo[3.3.0]oct-2-yl)]-4-methylthiobutanoic acid

A study of the neurotropic, neuroprotective, and antioxidant action of the enantiomers and racemate of 2-[(3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-4-methylthiobutanoic acid synthesized in a stereoselective reaction of (R)-, (S)-, or (R,S)-N-carbamoylmethionine with 4,5-dihydroxyimidazolidine-2-one showed that only (+)-(S)-2-[(1S,5R)-(3,7-dioxo-2,4,6,8-tetraazabicyclo[3.3.0]oct-2-yl)]-4-methylthiobutanoic acid had neuroprotective properties. X-ray structure analysis showed that the predominating racemate of glycolurils is crystallized from aqueous solutions as a conglomerate. Antioxidant activity was not detected.     

The synthesis of arginine derivatives of chromone and azauracil

The coupling of N-succinimide esters of 3-[7-hydroxy-3-(4-methyl-1,3-thiazol-2-yl)-6-ethyl-4-oxo-4H-chromen-2-yl]propanoic acid and 5-carboxymethyl-6-azauracil with free arginine yielded the corresponding arginine derivatives, which were purified by crystallization. The structures of the compounds were confirmed by ¹H NMR spectroscopy     

Comparative mutagenesis by aminofluorene derivatives A possible effect of DNA configuration

The mutagenicity of N-acetoxy-N-2-acetylaminofluorene-(N-acetoxy-2AAF) for Salmonella typhimuricum TA98 is greatly reduced when compared to that of N-hydroxy-2-aminofluorene. This decrease in mutagenic response is accompanied by the formation of a deoxyguanosine-2-acetylaminofluorene adduct. The deoxyguanosine-2-aminofluorene adduct, characteristic of cells exposed to N-hydroxy-2-aminofluorene, was not detected in N-acetoxy-2AAF-treated cells. Enzymic deacetylation of N-acetoxy-2AAF results in restoration of potent mutagenicity. N-Acetoxy-2-acetylamino-7-iodofluorene is also more mutagenic than N-acetoxy-2AAF. Because the acetylated and unacetylated guanine induce greatly different configurational changes, the results may be indicative that the introduction of the syn configuration and a possible shift to the Z-conformation at the mutational hot spot of Salmonella typhimurium TA98 [(dG-dC)₈] results in reduced mutagenic potency.     

N-acetoxy-N-acetylaminoarenes and nitrosoarenes one-electron non-enzymatic and enzymatic oxidation products of various carcinogenic aromatic acethydroxamic acids

A number of carcinogenic aromatic acethydroxamic acids (e.g.N-hydroxy-N-acetyl derivatives of 2-aminofluorene, 3-aminofluorene, 4-aminostilbene, 1-aminonaphthalene, 2-aminonaphthalene, 2-aminophenanthrene, and 4-aminobiphenyl) are readily oxidized by alkaline Fe(CN)₆³⁻ or Ag₂O. The free nitroxide radicals thus formed dismutate in organic solution according to second order kinetics to yield the corresponding N-acetoxy-N-acetylaminoarenes and nitrosoarenes. The structures of the latter products were established by mass and infrared spectrum analyses. Evicence was obtained for a similar one-electron oxidation of these acethydroxamic acids with horseradish peroxidase and H₂O₂ at pH 7. One-electron oxidation of N-hydroxy-2-acetylaminofluorene was also demonstrated with lactoperoxidase and human myeloperoxidase. The possible relevance of a similar peroxidative attack in vivo to the carcinogenic activities of some aromatic amines and amides is discussed.     

Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I₂₀ as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I₂₀ also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I₂₀ promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I₂₀ and tubulin Arg β369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.     

Synthesis and cholinesterase inhibitory activity of new 2-benzofuran carboxamide-benzylpyridinum salts

A series of benzofuran-2-carboxamide-N-benzyl pyridinium halide derivatives (6a-o) are synthesized as new cholinesterase inhibitors. The synthetic pathway involves the reaction of salicylaldehyde derivatives and ethyl bromoacetate, followed by hydrolysis and amidation with 3- and 4-picolyl amine. Subsequently, N-((pyridin-4-yl) methyl) benzofuran-2-carboxamide and substituted N-((pyridin-3-yl) methyl) benzofuran-2-carboxamides reacts with benzyl halides to afford target compounds (6a-o). The chemical structures of all derivatives were confirmed by spectroscopic methods. The studies reveal that some of the synthesized compounds are potent butyrylcholinesterase inhibitors with IC₅₀ values in the range of 0.054–2.7 µM. In addition, good inhibitory effects on Aβ self-aggregation are observed for 6h and 6k (33.1 and 46.4% at 100 µM, respectively).     

Synthesis,isomerism, and hypotensive activity of thiethane-containing hydrazones of uracilylacetic acid

By the reaction of 2-[6-methyl-1-(thiethane-3-yl)uracil-3-yl]acetic acid hydrazide with aryl aldehydes and acetophenone derivatives, acylhydrazones have been obtained, which exist in DMSO solutions as a mixture of two stereoisomers of an E _C=N-isomer, due to the hindered internal rotation around the hydrazide bond. It has been found that the compounds synthesized exhibit a hypotensive activity.     

Squarate-based carbocyclic nucleosides: Syntheses,computational analyses and anticancer/antiviral evaluation

Squaric acid and its derivatives are versatile synthons and have demonstrated applications in medicinal chemistry, notably as non-classical bioisosteric replacements for functional groups such as carboxylic acids, alpha-amino acids, urea, guanidine, peptide bonds and phosphate/pyrophosphate linkages. Surprisingly, no reports have appeared concerning its possible application as a nucleobase substitute in nucleosides. A preliminary investigation of such an application is reported herein. 3-Amino-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione, 3-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-4-methoxycyclobut-3-ene-1,2-dione, and 3-hydroxy-4-((1R,4S)-4-(hydroxymethyl)cyclopent-2-en-1-yl)amino-cyclobut-3-ene-1,2-dione sodium salt were synthesized. Computational analyses of their structures and preliminary antitumor and antiviral screening results are reported.     

Highly stereoselective synthesis of C-vinyl furanosides through acid-catalyzed S(N)2 inversion at the C-3 position of 1,2-dideoxy-hept-1-enitols

A highly stereoselective synthesis of C-vinyl furanosides through the S_N2 inversion at the C-3 position of the 1,2-dideoxy-hept-1-enitols is disclosed. Treatment of the 1,2-dideoxy-hept-1-enitols with diphenylammonium trifluoromethanesulfonate as the acid catalyst produced the C-vinyl furanosides (3,6-anhydro-1,2-dideoxy-hept-1-enitol derivatives) via a subsequent S_N2 intramolecular debenzyloxyation-cycloetherification reaction at the C-3 position.     

Synthesis and bioactivity of novel methyl 6-deoxy-6-(N'-alkyl/aryl-N'-benzothiazol-2-yl)guanidino-alpha-D-glucopyranosides

A series of new methyl 6-deoxy-6-[N′-alkyl/aryl-N″-(benzothiazol-2-yl)]guanidino-α-d-glucopyranosides were obtained from the reaction of an alkyl/aryl amine in the presence of HgCl₂ and sugar-thiourea derivatives, followed by the removal of protecting groups. The sugar-thiourea derivatives were obtained from the treatment of 2-aminobenzothiazole derivatives with methyl 2,3,4-tri-O-acetyl-6-deoxy-6-isothiocyanato-α-d-glucopyranoside in dry pyridine. Some of the synthesized guanidines displayed anti-influenza activity.     

Indole derivatives as dual-effective agents for the treatment of neurodegenerative diseases: Synthesis,biological evaluation,and molecular modeling studies

Several indole derivatives, that were highly potent ligands of GluN2B-subunit-containing N-methyl-d-aspartate (NMDA) receptor, also demonstrated antioxidant properties in ABTS method. In particular, the 2-(4-benzylpiperidin-1-yl)-1-(5-hydroxy-1H-indol-3-yl)ethanone (1) proved to be a dual-effective neuroprotective agent. With the aim to increase the antioxidant properties we added a catechol moiety onto piperidine moiety. The designed hybrid derivative 3,4-dihydroxy-N-[1-[2-(5-hydroxy-1H-indol-3-yl)-2-oxoethyl]piperidin-4-yl]benzamide (10) was the most effective antioxidant agent (>94.1 ± 0.1% of inhibition at 17 μM) and showed GluN2B/NMDA receptor affinity at low micromolar concentration (IC₅₀ 0.66 μM). By means of computational studies we explored the effect of the presence of this antioxidant fragment during the recognition process to binding pocket.     

On the metabolic activation of the carcinogen N-hydroxy-N-2-acetylaminofluorene : III. Oxidation with horseradish peroxidase to yield 2-nitrosofluorene and N-acetoxy-N-2-acetylaminofluorene

Previous studies have shown that the carcinogen N-hydroxy-2-acetylaminofluorene is converted by one-electron oxidants to a free nitroxide radical which dismutates to N-acetoxy-2-acetylaminofluorene and 2-nitrosofluorene. The present study shows that the same oxidation can be achieved with horseradish peroxidase and H₂O₂. The free radical intermediate was detected by its ESR signal, and the yields of N-acetoxy-2-acetylaminofluorene and of 2-nitrosofluorene were determined under a number of conditions. Addition of tRNA to the reaction mixture containing N-acetoxy-N-2-acetyl[2′-³H]aminofluorene yielded tRNA-bound radioactivity; addition of guanosine yielded a reaction product which appears to be N-guanosin-8-yl)-2-acetylaminofluorene. The latter compound has previously been identified as a reaction product of N-acetoxy-2-acetylaminofluorene and guanosine. Preliminary attempts to demonstrate the formation of a nitroxide free radical or its dismutation products with rat liver mixed function oxidase systems were not successful.     

Ligand chirality-controlled selective formation of mono- and dinuclear copper complexes

Reaction of copper(II) acetate with the (S)-enantiomer of a tridentate binaphthyl Schiff base ligand, 2-(3,5-dichloro-2-hydroxybenzylideneamino)-2′-hydroxy-1,1′-binaphthyl (H₂L), in methanol afforded mononuclear copper(II) complex [Cu^II(HL)₂] ((S,S)-1) in 52% isolated yield. The same reaction gave dinuclear copper(II) complex [Cu^II₂(L)₂] ((R,S)-2) in 73% isolated yield when racemic-H₂L was used instead of (S)-H₂L. Both complexes (S,S)-1 and (R,S)-2 were characterized by elemental analysis, mass spectrometry, and X-ray crystallography. The present work highlights the functioning of ligand chirality as a ‘switch’ for selective formation of mono- and dinuclear metal complexes.     

A non-symmetrical compartmental ligand derived from acetazolamide and its mononuclear cobalt(III) complex with an empty outer compartment

The Schiff base, non-symmetrical, compartmental ligand N-[5-(2-{[2-hydroxy-3-methoxy-phenyl-methylidene]-amino}-phenyl-sulfamoyl)-[1,3,4]thiadiazol-2-yl]-acetamide (H₃L) has been prepared by condensation of the acetazolamide derivative N-[5-(2-amino-phenylsulfamoyl)-[1,3,4]thiadiazol-2-yl]-acetamide (3) with 2-hydroxy-3-methoxy-benzaldehyde. The complexation of H₃L with cobalt(II) chloride in pyridine under aerobic conditions yielded [Co^III(HL)(py)₂][Co^II(py)Cl₃] · CH₃CH₂OH (4). The single crystal X-ray structures of H₃L and 4 are reported. In the mononuclear cation [Co^III(HL)(py)₂]⁺ of 4 the octahedral cobalt(III) ion is bound at the inner, metal ion binding site, and the larger, empty, outer metal binding site is partly occupied by the hydrogen-bonded ethanol molecule of crystallisation.