Synthesis and Bioactivity Evaluation of N-Arylsulfonylindole Analogs Bearing a Rhodanine Moiety as Antibacterial Agents.

Due to the rapidly growing bacterial resistance to antibiotics and the scarcity of novel agents under development, bacterial infections are still a pressing global problem, making new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, urgently needed. In this paper, seven series of N-arylsulfonylindole analogs 5-11 bearing rhodanine moieties were synthesized, characterized, and evaluated for antibacterial activity. According to the in vitro antimicrobial results, half of the synthesized compounds showed potent inhibition against four Gram-positive bacteria, with MIC values in the range of 0.5-8 µg/mL. For multidrug-resistant strains, compounds 6a and 6c were the most potent, with MIC values of 0.5 µg/mL, having comparable activity to gatifloxacin, moxiflocaxin and norfloxacin and being 128-fold more potent than oxacillin (MIC = 64 µg/mL) and 64-fold more active than penicillin (MIC = 32 µg/mL) against Staphylococcus aureusATCC 43300.

LTP-1, a novel antimitotic agent and Stat3 inhibitor, inhibits human pancreatic carcinomas in vitro and in vivo.

Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a novel antimitotic and Stat3 inhibitor, LTP-1, on human pancreatic cancer in vitro and in vivo. We found that LTP-1 inhibited pancreatic cancer cell growth and viability with significant G2/M arrest and disruption of microtubule dynamics. LTP-1 also caused G2/M arrest-independent Stat3 dephosphorylation along with ERK activation, which indicated the possible dual function of LTP-1. Long-term treatment of LTP-1 also induced polyploidy, activated caspases, induced subG1 cell population, and therefore, triggered pancreatic cancer cell apoptosis. Finally, we used an in vivo xenograft model to demonstrate that LTP-1 suppressed the growth of pancreatic adenocarcinoma. In summary, our data suggest that LTP-1 may alter microtubule dynamics, which ultimately causes polyploidy and apoptosis, thereby inhibiting pancreatic cancer growth in vitro and in vivo. This study provides evidence that LTP-1 could be a potential therapeutic agent for further development of pancreatic cancer treatment.

Syntheses, biological activities and SAR studies of novel carboxamide compounds containing piperazine and arylsulfonyl moieties.

A series of novel carboxamide compounds 19a-19j, 20a-20j and 22a-22d containing piperazine and arylsulfonyl moieties have been synthesized. The bioassay results showed that some compounds exhibited favorable herbicidal activities against dicotyledonous plants and many of them possessed excellent antifungal activities. Among 24 novel compounds, some showed superiority over the commercial fungicides Chlorothalonil, Dimethomorph, Thiophanate-methyl, Iprodione, and Zhongshengmycin at 500 mg/L concentration. Some compounds also exhibited high KARI inhibitory activity at 100 µg/mL concentration and could be used as new KARI lead inhibitors for further studies. Moreover, SAR of these new compounds were comprehensively investigated using different computational methods in which 3D-QSAR model obtained provided useful information for further structural optimization for the discovery of new fungicides. The results of this research will contribute to explore comprehensive biological activities of piperazine-containing compounds in different areas of chemistry.

Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1).

The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.

Identification of arylsulfonamides as Aquaporin 4 inhibitors.

Carbonic anhydrase inhibitors AZA, EZA, and 4-acetamidobenzsulfonamide were found to inhibit human AQP4-M23 mediated water transport by 80%, 68%, and 23%, respectively, at 20 microM in an in vitro functional assay. AZA was found to have an IC50 against AQP4 of 0.9 microM. Phloretin was inactive under the same conditions.

Determination and distribution of alkyl ethoxysulfates and linear alkylbenzene sulfonates in coastal marine sediments from the Bay of Cadiz (southwest of Spain).

The distribution of the two main anionic surfactants manufactured and used in the world, alkyl ethoxysulfates (AES) and linear alkylbenzene sulfonates (LAS), has been studied in sediments from a salt marsh and an estuary of the Bay of Cadiz (southwest of Spain). The identification and quantification of AES and LAS was carried out after automated Soxhlet extraction with methanol, followed by solid-phase extraction and liquid chromatography coupled to electrospray mass spectrometry. The latter procedure permitted the unequivocal identification of every LAS homologue as well as the AES homologues of up to 16 carbon atoms in their alkyl chain and of up to 12 ethylene oxide groups. Recoveries were in the range of 51% to 84% and limits of detection from 1 to 5 microg/kg. We have focused our attention particularly on AES because, in spite of their great use, these compounds have received less attention than LAS and their occurrence has not been described in marine environmental samples. Alkyl ethoxysulfates concentration values range between 100 and 400 microg/kg in the topmost layer of sediments at the sampling areas. The relative distribution of AES homologues shows higher percentages for the longer alkyl chain homologues in sediments as well as for the shorter ethoxymers. A decrease in LAS concentrations has been found relative to past studies in one of the sampling areas as a consequence of the reduction of urban wastewater discharges.

Synthesis and antiviral/antitumor evaluation of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes and related compounds as a new class of diarylsulfones.

Based on general SARs previously described for anti-HIV-1 diarylsulfone derivatives, a series of 2-amino- and 2-carboxamido-3-arylsulfonylthiophenes has been prepared and evaluated as potential antiviral and antitumor agents. In cell culture, some of the 2-aminothiophenes exhibited moderate and selective activity against HIV-1, with 2-amino-3-(2-nitrophenylsulfonyl)thiophene (7e) being most attractive (EC(50)=3.8 microg/mL, CC(50)=>100 microg/mL). In broad-spectrum antiviral assays, the 3-arylsulfonyl-2-(trifluoroacetamido)thiophenes (8c-g) and 2-acetamido-3-arylsulfonyl-5-nitrothiophenes (9f-g) proved considerably active (IC(50)=0.1-10 microg/mL) against human cytomegalovirus (CMV) and/or varicella zoster virus (VZV). Based on the activity of the trifluoroacetamides, ring-modified furan, N-(substituted)pyrrole, phenyl, and 3,4-thiophene analogues were prepared, and these compounds were also active against CMV and/or VZV, with the notable exception of the 3,4-thiophene derivative. In contrast to other amines, the 2-aminopyrrole precursors (13a-d) also exhibited potent activity against CMV. Unfortunately, most of these compounds displayed significant cytotoxicity against human fibroblasts, the cells supporting CMV and VZV replication, and thus selectivity indices were low. The most notable exception to this was the naphthyl-substituted aminopyrrole 13d, which exhibited both potent (IC(50)=0.3 microg/mL) and selective (CC(50)=>50 microg/mL) activity against CMV. Finally, thiophene aryl amides 8i-k displayed moderate in vitro activity against certain leukemia, breast, and colon cancer cell lines.

Determination of sulfophenylcarboxylic acids in marine samples by solid-phase extraction then high-performance liquid chromatography.

An analytical method is presented for the determination of sulfophenylcarboxylic acids (SPC) produced by the biodegradation of linear alkylbenzene sulfonates (LAS) in marine samples. Isolation and concentration of the compounds was by solid-phase extraction. The different factors affecting extraction efficiency packing composition, pH, clean-up, ionic strength, and elution solvents--were studied and optimized. With the proposed method C4-C13SPC and C10-C13 LAS recoveries varied between 65% and 105%, with standard deviations between 0.1 and 5, respectively, for 100-mL samples and 100 microg L(-1) concentrations of each homolog. Detection limits within the range 0.5 g L(-1) (for C4SPC) to 1.0 g L(-1) (for C12SPC) were obtained by liquid chromatography with fluorescence detection. This method is the first to be proposed that enables the simultaneous determination of monocarboxylic SPC (C>3) and LAS homologs in marine samples by a simple, sensitive, and specific method giving high recoveries and reproducibility. SPC with from three to twelve carbon atoms in the carboxyl chain have been found in marine water samples.

Handling of marine and estuarine samples for the determination of linear alkylbenzene sulfonates and sulfophenylcarboxylic acids.

Due to the physicochemical properties of linear alkylbenzene sulfonates (LAS), an anionic surfactant, it is difficult to obtain representative samples from sampling sites. Further, the high biodegradability of these compounds makes it necessary to study their biodegradation intermediates, sulfophenylcarboxylic acids (SPC) that do not have a surfactant character and show a different behavior. A procedure for determining and quantifying LAS and SPC in different environmental matrices by Soxhlet and solid-phase extractions and high-performance liquid chromatography is presented. The recoveries varied in the range from 85 to 102% for the water samples, and from 75 to 105% for sediment samples, with a standard deviation of between 1 and 7, and 2 and 11, respectively. Detection limits obtained were in the range from 5 to 10 microg kg(-1) for sediment samples (10 g) and from 0.2 to 0.4 microg l(-1) for water samples (250 ml). The method was applied to the simultaneous determination of LAS (C10-C13) and SPC (C4-C13) homologues in water, sediment and interstitial water collected from different areas of Spain.

On the mechanism of bilitranslocase transport inactivation by phenylmethylsulphonyl fluoride.

Bilitranslocase is a plasma membrane carrier involved in the uptake of bilirubin and other organic anions from the blood into the liver cell. In the membrane, the carrier occurs as two interchangeable metastable forms, with high and low affinity for the substrates, respectively. The latter form can be specifically produced by either cysteine- or arginine modification. In liver plasma membrane vesicles, the serine-specific reagent phenylmethylsulphonyl fluoride is a partial inhibitor of bilitranslocase-mediated BSP transport rate. In this work, phenylmethyl-sulphonyl fluoride is shown to reduce the carrier maximal transport rate, without affecting its affinity for that substrate. In addition, it is found that the chemical modification caused by this reagent neither influences the equilibrium between the high- and the low-affinity forms nor prevents their free interconversion. From the effects of combined derivatizations of cysteine(s), arginine(s) and serine(s), it is concluded that the functionally relevant aminoacid residues lie in a close spatial arrangement. Also, in this study, the PMSF-modified serine(s) is shown to be involved in bilirubin binding by bilitranslocase.

8-(Sulfostyryl)xanthines: water-soluble A2A-selective adenosine receptor antagonists.

8-(Sulfostyryl)xanthine derivatives were synthesized as water-soluble A2A-selective adenosine receptor (AR) antagonists. meta- and para-sulfostyryl-DMPX (3,7-dimethyl-1-propargylxanthine) derivatives 11a and 11b exhibited high affinity to rat A2A-AR in submicromolar concentrations, and were 20- to 30-fold selective versus rat A1-AR. Styryl-DMPX derivatives were inactive at human A2B- and A3-AR. 1,3-Dipropyl-8-p-sulfostyrylxanthine (13) or only a 7-methyl derivative (14) showed similar (13) or higher (14) A2A affinity than 11a and 11b but showed no (13) or only a low degree (14) of selectivity versus A1-, A2B-, and A3-AR. The A2A-selective sulfostyryl-DMPX derivatives exhibit high water-solubility and may be useful research tools for in vivo studies.

New efficient sulfurizing reagents for the preparation of oligodeoxyribonucleotide phosphorothioate analogues.

A set of new sulfurizing agents representing disulfides of arylsulfonic acids has been developed for the automated synthesis of phosphorothioate oligonucleotide analogues via the phosphoramidite method. These reagents, such as bis(benzenesulfonyl)disulfide, bis(p-toluenesulfonyl)disulfide, bis(p-methoxybenzensulfonyl)disulfide, and bis (p-chlorobenzenesulfonyl) disulfide, are easily prepared crystalline solid compounds. They are relatively inexpensive, easy to handle, and efficiently convert internucleotide cyanoethyl phosphite to the phosphorothioate triester within 1-2 min. The efficiency of phosphorothioate oligonucleotide synthesis with the use of these reagents is comparable to that of phosphodiester oligonucleotides.

Appearance of chemically treated root canal walls in the scanning electron microscope.

The dissolving effects of seven endodontic solutions on unprepared root canal walls of young intact human premolars were evaluated with the scanning electron microscopy. After incubation at 37 degrees C in distilled water or isotonic saline for 10 min the predentinal surfaces showed no changes as compared with untreated controls. The demineralizers Decal and Largal Ultra had little effect on the organic tissues but caused some decalification where mineralized dentin was exposed. Nelex caused concentration-dependent coagulation of the residual pulp tissue, making typical ring structures on the surfaces. Sodium hypochlorite at 2.5% and 5.0% dissolved most of the predentin, exposing the globular appearance of the mineralizing front. Salvizol produced small globules on otherwise intact surfaces. Dissolution of both the organic and inorganic tissue of the root canal wall would require the combined use of two of the solutions studied.

Appearance of chemically treated root canal walls in the scanning electron microscope.

The dissolving effects of seven endodontic solutions on unprepared root canal walls of young intact human premolars were evaluated with the scanning electron microscope. After incubation at 37 degrees C in distilled water or isotonic saline for 10 min the predentinal surfaces showed no changes as compared with untreated controls. The demineralizers Decal and Largal Ultra had little effect on the organic tissues but caused some decalcification where mineralized dentin was exposed. Nelex caused concentration-dependent coagulation of the residual pulp tissue, making typical ring structures on the surfaces. Sodium hypochlorite at 2.5% and 5.0% dissolved most of the predentin, exposing the globular appearance of the mineralizing front. Salvizol produced small globules on otherwise intact surfaces. Dissolution of both the organic and inorganic tissue of the root canal wall would require the combined use of two of the solutions studied.

Dissolution of bovine pulp tissue by endodontic solutions.

Pulpal tissue was incubated at 37 degrees C for 10 min with various solutions used for root canal therapy. The dissolved material was assayed for hydroxyproline (HYP) and total phosphate, and the insoluble residue for HYP and dry weight. Sodium hypochlorite (NaOCl) at 5% and diluted to 2.5% showed the strongest solvent capacity measured as loss of HYP and weight from the tissue. Dilution to 0.5% significantly decreased the effectiveness of NaOCl. The absence of HYP from the NaOCl extracts suggested decomposition of this amino acid. The other solutions tested were far inferior in their ability to dissolve pulpal tissue. The demineralizing solutions tested were poor solubilizers of soft tissue; however, they caused a considerable increase in the amount of phosphate released.