Synthesis of Partially Fluorinated Alkyl Triflates by Electrochemical Fluorination (Simons Process).

A scalable straightforward synthesis of monofluoro- and difluoromethyl triflate CF3 SO2 OCH2 F (MH2F ) and CF3 SO2 OCHF2 (MHF2 ) through electrochemical fluorination (ECF, Simons process) of methyl triflate MH3 in anhydrous hydrogen fluoride at nickel anodes is presented. The ECF method is also feasible for the preparation of the deuterated analogues CF3 SO2 OCD2 F (MD2F ) and CF3 SO2 OCDF2 (MD2F ). Surprisingly, no H/D exchange occurs during ECF of CF3 SO2 OCD3 (MD3 ); this provides further evidence for a NiF3 /NiF4 -mediated ECF mechanism. The ECF of selected partially fluorinated ethyl triflates is described, and electrochemical fluorination of CF3 SO2 OCH2 CF3 (EH2F3 ) leads to the until now unknown chiral CF3 SO2 OCHFCF3 (EHFF3 ). The analogous fluoromethyl and fluoroethyl nonaflates are also accessible by ECF. This study contains detailed spectroscopic, structural, and thermal data on (fluoro)methyl and fluoro(ethyl) triflates.

In silico elucidation of plausible anti-obesity activity by Withaferin-A compound targeting alpha-amylase.

OBJECTIVE: The study aimed to evaluate the Withaferin-A against the drug target α-amylase, revealing its plausible mode of action and molecular-level interactions essential for this specific target inhibitory potential computational approach. MATERIALS AND METHODS: In this scenario, we used computational methods, including docking, molecular dynamics simulation, and model-building simulations, to elucidate the atomic-level details responsible for the inhibitory potential of Withaferin-A derived from W. somnifera. The studio visualizer software was used for the visualization of ligands, structures of the receptor, bond length, and rendering of the image. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics of phytochemicals were investigated. Crystal structure of protein receptors and ligands were generated. Semi-flexible docking was done using Autodock software. Docking was performed using the Lamarckian Genetic Algorithm (LGA). Molecular descriptors were evaluated, and the pharmacological properties of the phytochemicals were explored. Molecular dynamic simulations were analyzed at the atomic level. All the simulations were conducted under the same temperature, pressure, and volume circumstances over the simulated time scale. RESULTS: Withaferin-A has shown a strong binding affinity towards α-amylase as demonstrated with -9.79 Kcal/mol with 66.61 estimated nanomolecular IC50 value for plausible anti-obesity activity. Molecular-level relationships and knowledge obtained from this study indicate solid interactions with TYR59, ASP197, and HIS299 residues which are of high importance for future works related to computational screening of target-specific α-amylase inhibitors. The results from the analysis have revealed potential molecular-level interactions useful for further designing/discovering novel α-amylase inhibitors. CONCLUSIONS: The framework of the studied phytochemicals enables the rapid development of subsequent modifications that could result in more lead-like compounds with better inhibitory efficacy and selectivity for α-amylase.

Insights into structure-property relationships in ionic liquids using cyclic perfluoroalkylsulfonylimides.

Room temperature ionic liquids of cyclic sulfonimide anions ncPFSI (ring size: n = 4-6) with the cations [EMIm]+ (1-ethyl-3-methylimidazolium), [BMIm]+ (1-butyl-3-methylimidazolium) and [BMPL]+ (BMPL = 1-butyl-1-methylpyrrolidinium) have been synthesized. Their solid-state structures have been elucidated by single-crystal X-ray diffraction and their physicochemical properties (thermal behaviour and stability, dynamic viscosity and specific conductivity) have been assessed. In addition, the ion diffusion was studied by pulsed field gradient stimulated echo (PFGSTE) NMR spectroscopy. The decisive influence of the ring size of the cyclic sulfonimide anions on the physicochemical properties of the ILs has been revealed. All ILs show different properties compared to those of the non-cyclic TFSI anion. While these differences are especially distinct for ILs with the very rigid 6cPFSI anion, the 5-membered ring anion 5cPFSI was found to result in ILs with relatively similar properties. The difference between the properties of the TFSI anion and the cyclic sulfonimide anions has been rationalized by the rigidity (conformational lock) of the cyclic sulfonimide anions. The comparison of selected IL properties was augmented by MD simulations. These highlight the importance of π+-π+ interactions between pairs of [EMIm]+ cations in the liquid phase. The π+-π+ interactions are evident for the solid state from the molecular structures of the [EMIm]+-ILs with the three cyclic imide anions determined by single-crystal X-ray diffraction.

Significance of Orlistat in management of dyslipidemia, systolic blood pressure and body mass index.

OBJECTIVE: The current study intends to find out the efficacy of Orlistat in the management of hyperlipidemia, Systolic Blood Pressure (SBP) and Body Mass Index (BMI). MATERIALS AND METHODS: This retrospective study has evaluated the lipid profiles of the patients, who have been using metformin therapy for Type 2 diabetes. The study has obtained data regarding the parameters like triglyceride, Total cholesterol (TC), LDL cholesterol, HDL cholesterol and LDL/HDL ratio, systolic blood pressure and Body Mass Index (BMI). Random distribution of patients was done into placebo and Orlistat groups. The placebo group received only metformin, and patients in the Orlistat group received Orlistat along with metformin. After 24 weeks, the follow-up study was done, and statistical analysis was conducted. RESULTS: The study found that the Orlistat group has significant improvement (p<0.05) more improvement in LDL cholesterol, HDL cholesterol, Total cholesterol, LDL/HDL Ratio and Triglycerides, while BMI and systolic blood pressure did not show a significant difference between placebo and Orlistat group. CONCLUSIONS: This study has concluded that Orlistat can be used for significant improvement in lipid profile. The study also found that Orlistat may not have a significant effect on reducing BMI and blood pressure without adequate lifestyle modification.

Design, in silico study, synthesis and in vitro evaluation of some N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives as potential pancreatic lipase inhibitors for anti-obesity activity.

OBJECTIVE: The aim of the study is to design N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives and evaluate its anti-obesity activity. MATERIALS AND METHODS: A few pyrazole-fused benzimidazole derivatives were designed as potential Pancreatic Lipase (PL) inhibitors. The designed N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives have been screened using the Lipinski rule of five, ADMET analysis, acute toxicity prediction, and molecular docking. Later on, the derivatives which possess the most drug-likeness properties and displayed the most potent inhibition of the enzyme in molecular docking were synthesized. Then, in vitro enzyme assay was performed. RESULTS: Orlistat used as the standard exhibited 91±1.68% inhibition of the enzyme, displayed binding affinity (BA) of only -4.5 kcal/mol with Pancreatic Lipase (PL), and made only one salt bridge attractive charge and carbon-hydrogen bond with ASP79 and TRP252, respectively. Compound 9 displayed the most potent activity (93±1.12% inhibition of P.L. and -9.5 kcal/mol BA). It has formed five conventional H- bonds with GLU253, ILE78, ASP79, PHE258, and one Pi-donor H- bond with ILE78. From the present investigation, we hereby reported (E)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine as most potent PL inhibitor for the treatment of obesity, which can be further optimized by undergoing more studies using in vivo and in vitro models. CONCLUSIONS: (E)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine as most potent PL inhibitor for the treatment of obesity which can be further optimized better using more in vivo and in vitro models. PL plays a critical role in digesting dietary fat. Therefore, PL inhibitors are verified as a potential therapy for treating obesity.

Regional and hemispheric susceptibility of the temporal lobe to FTLD-TDP type C pathology.

Post-mortem studies show that focal anterior temporal lobe (ATL) neurodegeneration is most often caused by frontotemporal lobar degeneration TDP-43 type C pathology. Clinically, these patients are described with different terms, such as semantic variant primary progressive aphasia (svPPA), semantic dementia (SD), or right temporal variant frontotemporal dementia (FTD) depending on whether the predominant symptoms affect language, semantic knowledge for object or people, or socio-emotional behaviors. ATL atrophy presents with various degrees of lateralization, with right-sided cases considered rarer even though estimation of their prevalence is hampered by the paucity of studies on well-characterized, pathology-proven cohorts. Moreover, it is not clear whether left and right variants show a similar distribution of atrophy within the ATL cross-sectionally and longitudinally. Here we study the largest cohort to-date of pathology-proven TDP-43-C cases diagnosed during life as svPPA, SD or right temporal variant FTD. We analyzed clinical, cognitive, and neuroimaging data from 30 cases, a subset of which was followed longitudinally. Guided by recent structural and functional parcellation studies, we constructed four bilateral ATL regions of interest (ROIs). The computation of an atrophy lateralization index allowed the comparison of atrophy patterns between the two hemispheres. This led to an automatic, imaging-based classification of the cases as left-predominant or right-predominant. We then compared the two groups in terms of regional atrophy patterns within the ATL ROIs (cross-sectionally) and atrophy progression (longitudinally). Results showed that 40% of pathology proven cases of TDP-43-C diagnosed with a temporal variant presented with right-lateralized atrophy. Moreover, the findings of our ATL ROI analysis indicated that, irrespective of atrophy lateralization, atrophy distribution within both ATLs follows a medial-to-lateral gradient. Finally, in both left and right cases, atrophy appeared to progress to the contralateral ATL, and from the anterior temporal pole to posterior temporal and orbitofrontal regions. Taken together, our findings indicate that incipient right predominant ATL atrophy is common in TDP-43-C pathology, and that distribution of damage within the ATLs appears to be the same in left- and right- sided variants. Thus, regardless of differences in clinical phenotype and atrophy lateralization, both temporal variants of FTD should be viewed as a spectrum presentation of the same disease.

Bidentate Boron Lewis Acids: Selectivity in Host-Guest Complex Formation.

Bidentate boron Lewis acids based on 1,8-diethynylanthracene were synthesised in two steps by initial stannylation of the terminal alkynes and subsequent tin-boron exchange with different chloroboranes. The reactions were very selective, and the target compounds were obtained in high purity and good to excellent yields. Complexation experiments of 1,8-bis[(diphenylboranyl)ethynyl]anthracene with nitrogen bases (pyridine, pyrimidine, TMEDA) afforded three stable adducts, which were structurally characterised by X-ray diffraction. Competition experiments demonstrated the selective exchange of guests, and quantum-chemical calculations provided information on their energetics. NMR experiments at low temperature gave insight into the dynamic behaviour of the TMEDA adduct.