Lead removal by ThioOctolig.

Octolig, a commercially available (a polyethylene diamine covalently attached to silica gel), was subjected to modifications to incorporate sulfur for enhanced removal of lead ion from aqueous solutions. The basic approach was attempted formation of "ThioOctolig" by the reaction of Octolig with thioacetamide in toluene using a shaker bath for 24 or 48 h or in the presence of 10% HCl (1 h). Our experience was that conversion was limited to about 20% based on sulfur analysis for 24 or 48 h reaction time, or in the presence of 10% HCl. In fact, with acidification, the results were poorer. Duplicate runs indicated consistent results. Literature reported that SbCl3 was an effective catalyst with a reaction time of 1 h. Use of this reagent (1-h reaction time) produced a bright orange red product, in contrast with previous yellow-colored products. A control run indicated that this reagent reacted with Octolig in toluene (in the dark) to produce a red-colored sample; thioacetamide reacted to produce a yellow sample. Use of SbCl3 (∼5 mole %) did not enhance the sulfur content of Octolig. A sample of Octolig removed 68% lead ion from a 120 ppm aqueous lead while a sample of ThioOctolig (10% S) removed 99.4% lead ions. We also investigated enhancing the sulfur incorporation upon raising the reaction temperature with thioacetamide.

Novel N-(Substituted) Thioacetamide Quinazolinone Benzenesulfonamides as Antimicrobial Agents.

AIM: With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects. MATERIALS AND METHODS: Novel quinazolinone-benzenesulfonamide derivatives 5-18 were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound 16 was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV-Visible, TEM examination, XRD patterns and DLS. Moreover, compound 16 was used to synthesize two nanoformulations: 16-CNPs by loading 16 in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against Staphylococcus aureus DNA gyrase was assayed. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of 16 was performed inside the active site of S. aureus DNA gyrase. RESULTS: Compound 16 was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25-36 mm and 0.31-5.0 µg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of 16 and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against S. aureus DNA gyrase showed IC50 ranging from 10.57 to 27.32 µM. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC50= 927, 543 and 637 µg/mL, respectively). Molecular docking of 16 inside the active site of S. aureus DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin. CONCLUSION: Compound 16 could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.

Kinetic, Thermodynamic, and Crystallographic Studies of 2-Triazolylthioacetamides as Verona Integron-Encoded Metallo-ß-Lactamase 2 (VIM-2) Inhibitor.

Inhibition of ß-lactamases presents a promising strategy to restore the ß-lactams antibacterial activity to resistant bacteria. In this work, we found that aromatic carboxyl substituted 2-triazolylthioacetamides 1a-j inhibited VIM-2, exhibiting an IC50 value in the range of 20.6-58.6 µM. The structure-activity relationship study revealed that replacing the aliphatic carboxylic acid with aromatic carboxyl improved the inhibitory activity of 2-triazolylthioacetamides against VIM-2. 1a-j (16 mg/mL) restored the antibacterial activity of cefazolin against E. coli cell expressing VIM-2, resulting in a 4-8-fold reduction in MICs. The isothermal titration calorimetry (ITC) characterization suggested that the primary binding 2-triazolylthioacetamide (1b, 1c, or 1h) to VIM-2 was a combination of entropy and enthalpy contributions. Further, the crystal structure of VIM-2 in complex with 1b was obtained by co-crystallization with a hanging-drop vapour-diffusion method. The crystal structure analysis revealed that 1b bound to two Zn(II) ions of the enzyme active sites, formed H-bound with Asn233 and structure water molecule, and interacted with the hydrophobic pocket of enzyme activity center utilizing hydrophobic moieties; especially for the phenyl of aromatic carboxyl which formed π-π stacking with active residue His263. These studies confirmed that aromatic carboxyl substituted 2-triazolylthioacetamides are the potent VIM-2 inhibitors scaffold and provided help to further optimize 2-triazolylthioacetamides as VIM-2 even or broad-spectrum MßLs inhibitors.

Discovery and Characterization of the Antimetabolite Action of Thioacetamide-Linked 1,2,3-Triazoles as Disruptors of Cysteine Biosynthesis in Gram-Negative Bacteria.

Increasing rates of drug-resistant Gram-negative (GN) infections, combined with a lack of new GN-effective antibiotic classes, are driving the need for the discovery of new agents. Bacterial metabolism represents an underutilized mechanism of action in current antimicrobial therapies. Therefore, we sought to identify novel antimetabolites that disrupt key metabolic pathways and explore the specific impacts of these agents on bacterial metabolism. This study describes the successful application of this approach to discover a new series of chemical probes, N-(phenyl)thioacetamide-linked 1,2,3-triazoles (TAT), that target cysteine synthase A (CysK), an enzyme unique to bacteria that is positioned at a key juncture between several fundamental pathways. The TAT class was identified using a high-throughput screen against Escherichia coli designed to identify modulators of pathways related to folate biosynthesis. TAT analog synthesis demonstrated a clear structure-activity relationship, and activity was confirmed against GN antifolate-resistant clinical isolates. Spontaneous TAT resistance mutations were tracked to CysK, and mode of action studies led to the identification of a false product formation mechanism between the CysK substrate O-acetyl-l-serine and the TATs. Global transcriptional responses to TAT treatment revealed that these antimetabolites impose substantial disruption of key metabolic networks beyond cysteine biosynthesis. This study highlights the potential of antimetabolite drug discovery as a promising approach to the discovery of novel GN antibiotics and the pharmacological promise of TAT CysK probes.

Protective effect of Moringa oleifera leaves ethanolic extract against thioacetamide-induced hepatotoxicity in rats via modulation of cellular antioxidant, apoptotic and inflammatory markers.

The current study was conducted to evaluate the ameliorative and protective potentials of Moringea oleifera leaves ethanolic extract (MOLE) against thioacetamide (TAA) toxicity. A total of 58 male albino rats were randomly assigned into six experimental groups. G1, rats received distilled water. G2, rats were injected with a single dose of TAA (200 mg/kg BW) i.p. G3, rats were given MOLE (300 mg/kg BW) orally for 26 days. G4, rats were injected TAA as in G2 and treated with MOLE as G3. G5, rats were kept for 26 days without treatment then on day 27 injected with TAA as in G2. G6, rats were given MOLE for 26 days then on day 27 injected with TAA. Phytochemical analysis of MOLE indicated the presence of kaempferol, kaempferol malonylglucoside, kaempferol hexoside, kaempferol -3-O-glucoside, kaempferol-3-O-acetyl-glucoside, cyanidin -3-O-hexoside, ellagic acid, quercetin, quercetin-3-O-glucoside, and apigenin glucoside. Intoxication of rats with TAA significantly elevated activities of serum AST, ALT, and ALP; concentrations of malondialdehyde, nitric oxide, and hepatic tissue protein expression of caspase 3 and COX2 with alteration of the histological structures of hepatic tissues, while it decreased serum levels of total protein, albumin, and hepatic tissue contents of reduced glutathione. Also, TAA intoxication resulted in 62.5% mortality in rats of G5. Treatment of TAA intoxicated rats (G4) with MOLE ameliorated the toxic effects of TAA on hepatic tissue structure and function. It decreased serum activities of AST, ALT, and ALP; enhanced hepatic GSH concentration; reduced pathological alterations and lipid peroxidation; and downregulated caspase 3 and COX2 proteins expression in hepatic tissue. In addition, MOLE protected rats of G6 from TAA-induced hepatic tissues injury and dysfunction, and increased survival rate of rats. In conclusion, MOLE had both ameliorating and protecting potentials against TAA-induced rats liver damage through regulation of antioxidant, anti-apoptotic, and inflammatory biomarkers. Graphical abstract.

Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-ß-Lactamase Inhibitors.

Metallo-ß-lactamases (MßLs) are the target enzymes of ß-lactam antibiotic resistance, and there are no effective inhibitors against MßLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MßLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC50 value range of 0.032⁻15.64 µM except 7. The chlorine substituted compounds (1, 2 and 3) inhibited NDM-1 with an IC50 value of less than 0.96 µM, and the fluorine substituted 12 and 13 inhibited VIM-2 with IC50 values of 38.9 and 2.8 µM, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that 9 and 13 are mixed inhibitors for ImiS with Ki values of 0.074 and 0.27µM using imipenem as the substrate. Docking studies showed that 1 and 9, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233.

Discovery and optimization of 3,4,5-trimethoxyphenyl substituted triazolylthioacetamides as potent tubulin polymerization inhibitors.

Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 µM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 µM, which was almost as active as that of CA-4 (IC50 = 4.2 µM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin.

Design, synthesis, docking study, α-glucosidase inhibition, and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes.

A novel series of acridine linked to thioacetamides 9a-o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC50 = 80.0 ±â€¯2.0-383.1 ±â€¯2.0 µM against yeast α-glucosidase, when compared to the standard drug acarbose (IC50 = 750.0 ±â€¯1.5 µM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC50 = 80.0 ±â€¯2.0 µM). The in vitro cytotoxic assay of compounds 9a-o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a Ki of 85 µM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.

Azolylthioacetamides as a potent scaffold for the development of metallo-ß-lactamase inhibitors.

In an effort to develop new inhibitors of metallo-ß-lactamases (MßLs), twenty-eight azolylthioacetamides were synthesized and assayed against MßLs. The obtained benzimidazolyl and benzioxazolyl substituted 1-19 specifically inhibited the enzyme ImiS, and 10 was found to be the most potent inhibitor of ImiS with an IC50 value of 15 nM. The nitrobenzimidazolyl substituted 20-28 specifically inhibited NDM-1, with 27 being the most potent inhibitor with an IC50 value of 170 nM. Further studies with 10, 11, and 27 revealed a mixed inhibition mode with competitive and uncompetitive inhibition constants in a similar range as the IC50 values. These inhibitors resulted in a 2-4-fold decrease in imipenem MIC values using E. coli cells producing ImiS or NDM-1. While the source of uncompetitive (possibly allosteric) inhibition remains unclear, docking studies indicate that 10 and 11 may interact orthosterically with Zn2 in the active site of CphA, while 27 could bridge the two Zn(II) ions in the active site of NDM-1 via its nitro group.

Phase-contrast MR flow imaging: A tool to determine hepatic hemodynamics in rats with a healthy, fibrotic, or cirrhotic liver.

PURPOSE: To test a magnetic resonance (MR) scanning protocol as a noninvasive tool to determine hepatic hemodynamics and to assess the degree of liver fibrosis in an animal model of liver fibrosis and cirrhosis. MATERIALS AND METHODS: Fifty-four male Wistar rats were studied. Thirty-nine received thioacetamide (TAA) in their drinking water for either 12 or 16 weeks. MR measurements were performed using flow-sensitive 2D phase-contrast MRI and a 9.4T preclinical scanner. The following hemodynamic parameters were investigated: portal cross-sectional area, mean portal flow velocity, and portal and aortic flow volume rate. Therefore, rats (n = 46) were divided into three groups: CON (control, n = 13), FIB (fibrosis, n = 25), and CIR (cirrhosis, n = 8). Furthermore, the degree of liver fibrosis was assessed by a self-established MR score and verified by a standardized histological score (n = 48). RESULTS: Portal and aortic flow parameters could be reliably detected. A significant decrease in portal flow velocity was found in FIB (FIB vs. CON: -21%, P = 0.006 and CIR vs. CON: -17%, P = 0.105) and in portal flow volume rate in FIB and CIR (FIB vs. CON: -20%, P = 0.009 and CIR vs. CON: -25%, P = 0.024). If the histological score is taken as standard, the self-established MR score enabled discrimination between healthy and diseased livers (sensitivity to identify diseased livers: 89% and specificity to identify healthy livers: 100%). CONCLUSION: This MR scanning protocol presents a noninvasive tool to determine hepatic hemodynamics in healthy and diseased rats. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1526-1534.

The structure of the metallo-ß-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor.

The increasing number of pathogens expressing metallo-ß-lactamases (MBLs), and in this way achieving resistance to ß-lactam antibiotics, is a significant threat to global public health. A promising strategy to treat such resistant pathogens is the co-administration of MBL inhibitors together with ß-lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified. Verona integron-encoded metallo-ß-lactamase 2 (VIM-2) is a widespread MBL with a broad substrate spectrum and hence is an interesting drug target for the treatment of ß-lactam-resistant infections. In this study, three triazolylthioacetamides were tested as inhibitors of VIM-2. One of the tested compounds showed clear inhibition of VIM-2, with an IC50 of 20 µM. The crystal structure of the inhibitor in complex with VIM-2 was obtained by DMSO-free co-crystallization and was solved at a resolution of 1.50 Å. To our knowledge, this is the first structure of a triazolylthioacetamide inhibitor in complex with an MBL. Analysis of the structure shows that the inhibitor binds to the two zinc ions in the active site of VIM-2 and revealed detailed information on the interactions involved. Furthermore, the crystal structure showed that binding of the inhibitor induced a conformational change of the conserved residue Trp87.

Synthesis of carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives as new potential PET tracers for imaging of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1).

The target tracer carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives, N-(3-[(11)C]methoxy-4-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (3-[(11)C]4a) and N-(4-[(11)C]methoxy-3-methoxyphenyl)-2-((5-methoxy-3H-imidazo[4,5-b]pyridin-2-yl)thio)acetamide (4-[(11)C]4a); 2-((6-amino-9H-purin-8-yl)thio)-N-(3-[(11)C]methoxy-4-methoxyphenyl)acetamide (3-[(11)C]8a) and 2-((6-amino-9H-purin-8-yl)thio)-N-(4-[(11)C]methoxy-3-methoxyphenyl)acetamide (4-[(11)C]8a), were prepared by O-[(11)C]methylation of their corresponding precursors with [(11)C]CH3OTf under basic condition (2N NaOH) and isolated by a simplified solid-phase extraction (SPE) method in 50-60% radiochemical yields based on [(11)C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-555GBq/µmol.

Fabrication of CdMoO4@CdS core-shell hollow superstructures as high performance visible-light driven photocatalysts.

CdMoO4@CdS core-shell hollow microspheres with the diameter of 2-3 µm were synthesized through a simple ion exchange hydrothermal method by using CdMoO4 solid microspheres as the sacrificial template in the presence of thioacetamide (TAA). Based on the detailed investigation it was found that the concentration of TAA in the starting solution affects the size of the CdS nanosheets and the hollowing process. At the TAA concentration of 0.1 M, CdMoO4@CdS core-shell hollow spheres with a CdS nanosheet thickness of 50-100 nm were obtained. The formed CdS nanosheets have a hexagonal wurtzite structure and exhibit good size uniformity and regularity. Furthermore, the photocatalytic activity of the as-prepared samples was evaluated towards degradation of Rhodomine B (RhB) aqueous dye solution under visible-light. Compared to CdMoO4 microspheres, CdMoO4@CdS core-shell hollow microspheres show enhanced photocatalytic activity. The observed photocatalytic performance was attributed to the synergetic effects of composite morphology, pore structure, and exposed two-dimensional (2D) CdS nanosheets with dominant 001 facets in CdMoO4@CdS core-shell hollow microspheres. Furthermore, the growth mechanism of CdMoO4@CdS hollow microspheres was discussed in detail.

Excited state proton transfer dynamics of thioacetamide in S2(ππ*) state: resonance Raman spectroscopic and quantum mechanical calculations study.

The photophysics and photochemistry of thioacetamide (CH3CSNH2) after excitation to the S2 electronic state were investigated by using resonance Raman spectroscopy in conjunction with the complete active space self-consistent field (CASSCF) method and density functional theory (DFT) calculations. The A-band resonance Raman spectra in acetonitrile, methanol, and water were obtained at 299.1, 282.4, 266.0, 252.7, and 245.9 nm excitation wavelengths to probe the structural dynamics of thioacetamide in the S2 state. CASSCF calculations were done to determine the transition energies and structures of the lower-lying excited states, the conical intersection points CI(S2/S1) and CI(S1/S0), and intersystem crossing points. The structural dynamics of thioacetamide in the S2 state was revealed to be along eight Franck-Condon active vibrational modes ν15, ν11, ν14, ν10, ν8, ν12, ν18, and ν19, mostly in the CC/CS/CN stretches and the CNH8,9/CCH5,6,7/CCN/CCS in-plane bends as indicated by the corresponding normal mode descriptions. The S2 → S1 decay process via the S2/S1 conical intersection point as the major channel were excluded. The thione-thiol photoisomerization reaction mechanism of thioacetamide via the S2,FC → S'1,min excited state proton transfer (ESPT) reaction channel was proposed.

Synthesis and characterization of new 2-cyano-2-(p-tolyl-hydrazono)-thioacetamide metal complexes and a study on their antimicrobial activities.

2-Cyano-2-(p-tolyl-hydrazono)-thioacetamide (Cthta) reacted with V(IV), Zr(IV), Pd(II), Pt(IV), Ce(IV) and U(VI) in acetone as a solvent at room temperature to form a solid complexes with characteristic color for metal ion. The molar ratio for all synthesized complexes is M:Cthta=1:2 which was established from the results of chemical analysis. The isolated complexes have been characterized with their melting points, elemental analysis, magnetic properties, conductance measurements, mass, IR, UV-Vis. and (1)H NMR spectroscopic methods and thermal analyses. The results supported the formation of the complexes and indicated that the Cthta reacts as a bidentate ligand. The thermogravimetric and infrared spectroscopic data confirmed the presence of water in the composition of the complexes. The molar conductance values of all complexes in (DMSO) were found in the range 150.71-328.85S cm(2) mol(-1) at room temperature. The magnetic moments of the complexes were measured at room temperature. The kinetic parameters of thermogravimetric and its differential have been evaluated by using Coats Redfern (CR) and Horowitz-Metzeger (HM) methods. The ligand as well as their metal complexes were also evaluated for their antibacterial and antifungal activities.

Pre-treatment for ultrafiltration: effect of pre-chlorination on membrane fouling.

Microbial effects are believed to be a major contributor to membrane fouling in drinking water treatment. Sodium hypochlorite (NaClO) is commonly applied in membrane cleaning, but its potential use as a pretreatment for controlling operational fouling has received little attention. In this study, the effect of adding a continuous low dose of NaClO (1 mg/l as active Cl) in combination with alum, before ultrafiltration, was compared with only alum as pretreatment. The results showed that the addition of NaClO substantially reduced membrane fouling both in terms of the rate of TMP development and the properties of the membrane cake layer. Although the size of nano-scale primary coagulant flocs changed little by the addition of NaClO, the cake layer on the membrane had a greater porosity and a substantially reduced thickness. NaClO was found to inactivate bacteria in the influent flow, which reduced both microbial proliferation and the production of proteins and polysaccharides in the cake layer and contributed significantly to improving the overall ultrafiltration performance. NaClO dosing had no adverse impact on the formation of currently regulated disinfection by-product compounds (THMs and HAAs).

Molecular basis for the antiparasitic activity of a mercaptoacetamide derivative that inhibits histone deacetylase 8 (HDAC8) from the human pathogen schistosoma mansoni.

Schistosomiasis, caused by the parasitic flatworm Schistosoma mansoni and related species, is a tropical disease that affects over 200 million people worldwide. A new approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during the life cycle of the parasite. Recently, we identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for antiparasitic therapy. Here, we present results on the investigations of a focused set of HDAC (histone deacetylase) inhibitors on smHDAC8. Besides several active hydroxamates, we identified a thiol-based inhibitor that inhibited smHDAC8 activity in the micromolar range with unexpected selectivity over the human isotype, which has not been observed so far. The crystal structure of smHDAC8 complexed with the thiol derivative revealed that the inhibitor is accommodated in the catalytic pocket, where it interacts with both the catalytic zinc ion and the essential catalytic tyrosine (Y341) residue via its mercaptoacetamide warhead. To our knowledge, this is the first complex crystal structure of any HDAC inhibited by a mercaptoacetamide inhibitor, and therefore, this finding offers a rationale for further improvement. Finally, an ester prodrug of the thiol HDAC inhibitor exhibited antiparasitic activity on cultured schistosomes in a dose-dependent manner.

Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues.

2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (±)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (±)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (±)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT.

Influence of the polyvinyl pyrrolidone concentration on particle size and dispersion of ZnS nanoparticles sythesized by mcrowave iradiation.

Zinc sulfide semiconductor nanoparticles were synthesized in an aqueous solution of polyvinyl pyrrolidone via a simple microwave irradiation method. The effect of the polymer concentration and the type of sulfur source on the particle size and dispersion of the final ZnS nanoparticle product was carefully examined. Microwave heating generally occurs by two main mechanisms: dipolar polarization of water and ionic conduction of precursors. The introduction of the polymer affects the heating rate by restriction of the rotational motion of dipole molecules and immobilization of ions. Consequently, our results show that the presence of the polymer strongly affects the nucleation and growth rates of the ZnS nanoparticles and therefore determines the average particle size and the dispersion. Moreover, we found that PVP adsorbed on the surface of the ZnS nanoparticles by interaction of the C-N and C=O with the nanoparticle's surface, thereby affording protection from agglomeration by steric hindrance. Generally, with increasing PVP concentration, mono-dispersed colloidal solutions were obtained and at the optimal PVP concentration (5%), sufficiently small size and narrow size distributions were obtained from both sodium sulfide and thioacetamide sulfur sources. Finally, the sulfur source directly influences the reaction mechanism and the final particle morphology, as well as the average size.