Design, synthesis and biological evaluation of novel serotonin and dopamine receptor ligands being 6-bromohexyl saccharine derivatives.

Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT1A (compound 18, Ki = 4 nM - antagonist mode) and D2 (compound 15, Ki = 7 nM - antagonist mode) receptor, and in some cases also 5-HT7 receptor (compound 17, Ki = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors.

Cocrystal Solubility Advantage Diagrams as a Means to Control Dissolution, Supersaturation, and Precipitation.

Cocrystals are often more soluble than needed and pose unnecessary risks for precipitation of less soluble forms of the drug during processing and dissolution. Such conversions lead to erratic cocrystal behavior and nullify the cocrystal solubility advantage over parent drug (SA = Scocrystal/Sdrug). This work demonstrates a quantitative method for additive selection to control cocrystal disproportionation based on cocrystal solubility advantage (SA) diagrams. The tunability of cocrystal SA is dependent on the selective drug-solubilizing power of surfactants (SPdrug = (ST/Saq)drug). This cocrystal property is used to generate SA-SP diagrams that facilitate surfactant selection and provide a framework for evaluating how SA influences drug concentration-time profiles associated with cocrystal dissolution, drug supersaturation, and precipitation (DSP). Experimental results with indomethacin-saccharin cocrystal and surfactants (sodium lauryl sulfate, Brij, and Myrj) demonstrate the log-linear relationship characteristic of SA-SP diagrams and the dependence of σmax and dissolution area under the curve (AUC) on SA with characteristic maxima at a threshold supersaturation where drug nucleation occurs. This approach is expected to streamline cocrystal formulation as it facilitates additive selection by considering the interplay between thermodynamic (SA) and kinetic (DSP) processes.

Measuring Artificial Sweeteners Toxicity Using a Bioluminescent Bacterial Panel.

Artificial sweeteners have become increasingly controversial due to their questionable influence on consumers' health. They are introduced in most foods and many consume this added ingredient without their knowledge. Currently, there is still no consensus regarding the health consequences of artificial sweeteners intake as they have not been fully investigated. Consumption of artificial sweeteners has been linked with adverse effects such as cancer, weight gain, metabolic disorders, type-2 diabetes and alteration of gut microbiota activity. Moreover, artificial sweeteners have been identified as emerging environmental pollutants, and can be found in receiving waters, i.e., surface waters, groundwater aquifers and drinking waters. In this study, the relative toxicity of six FDA-approved artificial sweeteners (aspartame, sucralose, saccharine, neotame, advantame and acesulfame potassium-k (ace-k)) and that of ten sport supplements containing these artificial sweeteners, were tested using genetically modified bioluminescent bacteria from E. coli. The bioluminescent bacteria, which luminesce when they detect toxicants, act as a sensing model representative of the complex microbial system. Both induced luminescent signals and bacterial growth were measured. Toxic effects were found when the bacteria were exposed to certain concentrations of the artificial sweeteners. In the bioluminescence activity assay, two toxicity response patterns were observed, namely, the induction and inhibition of the bioluminescent signal. An inhibition response pattern may be observed in the response of sucralose in all the tested strains: TV1061 (MLIC = 1 mg/mL), DPD2544 (MLIC = 50 mg/mL) and DPD2794 (MLIC = 100 mg/mL). It is also observed in neotame in the DPD2544 (MLIC = 2 mg/mL) strain. On the other hand, the induction response pattern may be observed in its response in saccharin in TV1061 (MLIndC = 5 mg/mL) and DPD2794 (MLIndC = 5 mg/mL) strains, aspartame in DPD2794 (MLIndC = 4 mg/mL) strain, and ace-k in DPD2794 (MLIndC = 10 mg/mL) strain. The results of this study may help in understanding the relative toxicity of artificial sweeteners on E. coli, a sensing model representative of the gut bacteria. Furthermore, the tested bioluminescent bacterial panel can potentially be used for detecting artificial sweeteners in the environment, using a specific mode-of-action pattern.

DSC, FTIR and Raman Spectroscopy Coupled with Multivariate Analysis in a Study of Co-Crystals of Pharmaceutical Interest.

Co-crystals have garnered increasing interest in recent years as a beneficial approach to improving the solubility of poorly water soluble active pharmaceutical ingredients (APIs). However, their preparation is a challenge that requires a simple approach towards co-crystal detection. The objective of this work was, therefore, to verify to what extent a multivariate statistical approach such as principal component analysis (PCA) and cluster analysis (CA) can be used as a supporting tool for detecting co-crystal formation. As model samples, physical mixtures and co-crystals of indomethacin with saccharin and furosemide with p-aminobenzoic acid were prepared at API/co-former molar ratios 1:1, 2:1 and 1:2. Data acquired from DSC curves and FTIR and Raman spectroscopies were used for CA and PCA calculations. The results obtained revealed that the application of physical mixtures as reference samples allows a deeper insight into co-crystallization than is possible with the use of API and co-former or API and co-former with physical mixtures. Thus, multivariate matrix for PCA and CA calculations consisting of physical mixtures and potential co-crystals could be considered as the most profitable and reliable way to reflect changes in samples after co-crystallization. Moreover, complementary interpretation of results obtained using DSC, FTIR and Raman techniques is most beneficial.

Removal and attenuation of sewage effluent combined tracer signals of phosphorus, caffeine and saccharin in soil.

Contaminants in septic tank effluent (STE) are expected to be removed by the soil system before discharging to the environment. However, potential contaminants such as phosphorus (P), caffeine and artificial sweeteners do find their way to watercourses impacting aquatic eco systems. In this study, the attenuation of STE P, caffeine and saccharin were investigated in untreated soil and in soil with reduced microbial activity, in aqueous solutions and in the complex matrix of STE. Time series sorption and desorption experiments using batch equilibrium and a column experiment of STE P attenuation were conducted. The results revealed that the soil distribution coefficients (Kd) were: P 81.57 > caffeine 22.16 > saccharin 5.98 cm3/g, suggesting greater soil affinity to P adsorption. The data revealed that 80% of saccharin and 33% of caffeine attenuation was associated with microbial activities rather than adsorption processes. However, a complete removal of saccharin and caffeine did not occur during the equilibration period, suggesting their leaching potential. The dominant mechanism of P attenuation was adsorption (chemical and physical), yielding P retention of >73% and 35% for P in aqueous solution and in STE matrix, respectively, for batch equilibrium. The soil in the column acted as effluent P sink retaining 125 µg P/g soil of effluent P. The attenuation of P, caffeine and saccharin in the aqueous solution was greater than in STE, suggesting that the complex composition of STE reduced soil adsorption ability, and that other substances present in STE may be competing for soil binding sites. The data revealed that caffeine and P had similarities in the interaction with soils and thus caffeine may be considered as a STE tracer of anthropogenic source of P in receiving waters.

Influence of Package Visual Cues of Sweeteners on the Sensory-Emotional Profiles of Their Products.

Substantial evidence suggests influence of color, physical state, and other extrinsic features on consumer perception and acceptability of food products. In this study, 560 subjects evaluated liking and emotional responses associated with 5 sweeteners (sucralose, stevia, saccharin, aspartame, and sucrose) under 2 eliciting conditions: control (brand name only) and informed (brand name/packet image), to assess impact of the packet color. For a given condition, 5 identical tea samples each labeled with a sweetener type were rated for sweetness and overall liking (9-point) and emotions (5-point). Nonsignificant interactions between eliciting condition and sweetener type were found for liking attributes and emotions (except peaceful), indicating their independent effects. However, overall differences existed among sweetener types and eliciting conditions based on both hedonic and emotional responses (MANOVA, P < 0.05), suggesting modulating effects of packet color on sweetener type in the sensory-emotion space. The sensory-emotion profile for sucrose was separate from that of nonnutritive sweeteners, with statistically significant Mahalanobis distances among sample centroids. Increases in positive emotion intensities contrasted with a decrease in negative emotion intensities were observed for some sweeteners moving from the control to informed condition. Sweetness liking was strongly correlated with the emotion satisfied (sucralose, saccharin) only in the control condition, whereas it was strongly correlated with the emotions pleased and satisfied (stevia), disgusted (aspartame), and satisfied (sucrose) only in the informed condition. Overall, results suggested that sensory liking and emotions during the consumption experience are related not entirely to the type of sweetener, but also the color of the packet.

Characterization of the solubility and solid-state properties of saccharin salts of fluoroquinolones.

Saccharinates salts of the fluoroquinolone antibiotics norfloxacin, ciprofloxacin, ofloxacin, and enrofloxacin were obtained as pure crystalline anhydrous solids with sweet taste. The products were characterized by one- ((13)C) and two-dimensional ((1)H-(13)C) dimensions solid state Nuclear Magnetic Resonance and infrared spectroscopy showing ionic interactions between the saccharine amide and the fluoroquinolone piperazine. Several intermolecular bindings were also identified. Thermal behavior and powder X-ray diffraction provided complementary evidences of salt formation. The series of products showed improved properties with respect to water solubility. A solubility model was developed. These salts would be a good way forward to developing more suitable formulations of these APIs.

Effects of an artificial sweetener on health, performance, and dietary preference of feedlot cattle.

Two experiments examined the effects of a saccharin-based artificial sweetener (Sucram) on health, performance, and dietary preference of feedlot cattle. In Exp. 1, 200 steer calves (initial BW = 190.4 +/- 1.47 kg) were fed a 65% concentrate diet supplemented with or without 200 mg of Sucram/kg (DM basis) during a 56-d receiving-growing period. Feeding Sucram did not affect overall (P = 0.19) DMI; however, from d 29 to 56, there was a trend (P = 0.10) for increased DMI with Sucram (5.71 vs. 6.02 kg/d, respectively). From d 0 to 28 and d 0 to 56, there were trends (P = 0.11 and 0.12, respectively) for increased ADG and for increased d-56 BW (P = 0.07) for calves fed Sucram. No differences were detected (P = 0.82) for receiving (REC) period morbidity. During the finishing (FIN) period, 180 steers from the REC period were assigned (9 pens/treatment in a 2 x 2 factorial design) to the following treatments: 1) control REC/control FIN; 2) control REC/Sucram FIN; 3) Sucram REC/control FIN; and 4) Sucram REC/ Sucram FIN. Over the FIN period, ADG tended (P = 0.12) to be greater for Sucram; however, carcass-adjusted ADG did not differ among treatments. Daily DMI was affected by a REC x FIN interaction (P = 0.08), which was the result of greater DMI by cattle in the Sucram REC/Sucram FIN treatment and decreased DMI by cattle in the Sucram REC/control FIN treatment. In general, changes in carcass characteristics were minor. In Exp. 2, 12 steers (initial BW = 395.6 +/- 6.17 kg) were used in a simultaneously replicated 3 x 3 Latin square preference test. Each square consisted of 3 pens, with 2 steers/pen, and 3 time periods. Bunks had dividers at their midpoint, and equal quantities of diet (as-fed basis) were delivered randomly on either side of the divider daily. Treatments were: 1) control; 2) Sucram = basal diet supplemented with 200 mg of Sucram/kg of DM; and 3) choice = control and Sucram on separate sides of the divider. Dietary preference differed on d 1 (P = 0.01) and d 3 (P = 0.02) for control vs. choice and Sucram vs. choice, with the choice group consuming 0.49 and 1.72 kg of DM more of the Sucram diet than the control diet, respectively. This effect, however, was not consistent across days, and average DMI did not differ (P = 0.81) among treatments. Addition of Sucram to the diet of newly received cattle tended to increase receiving period ADG; however, its effects on morbidity, finishing performance, and dietary preference were limited.