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71.
72.
Q. van Houtum D. Welting W.J.M. Gosselink D.W.J. Klomp C.S. Arteaga de Castro W.J.M. van der Kemp 《NMR in biomedicine》2019,32(12)
Phosphorus (31P) MRSI provides opportunities to monitor potential biomarkers. However, current applications of 31P MRS are generally restricted to relatively small volumes as small coils are used. Conventional surface coils require high energy adiabatic RF pulses to achieve flip angle homogeneity, leading to high specific absorption rates (SARs), and occupy space within the MRI bore. A birdcage coil behind the bore cover can potentially reduce the SAR constraints massively by use of conventional amplitude modulated pulses without sacrificing patient space. Here, we demonstrate that the integrated 31P birdcage coil setup with a high power RF amplifier at 7 T allows for low flip angle excitations with short repetition time (TR) for fast 3D chemical shift imaging (CSI) and 3D T1‐weighted CSI as well as high flip angle multi‐refocusing pulses, enabling multi‐echo CSI that can measure metabolite T2, over a large field of view in the body. B1+ calibration showed a variation of only 30% in maximum B1 in four volunteers. High signal‐to‐noise ratio (SNR) MRSI was obtained in the gluteal muscle using two fast in vivo 3D spectroscopic imaging protocols, with low and high flip angles, and with multi‐echo MRSI without exceeding SAR levels. In addition, full liver MRSI was achieved within SAR constraints. The integrated 31P body coil allowed for fast spectroscopic imaging and successful implementation of the multi‐echo method in the body at 7 T. Moreover, no additional enclosing hardware was needed for 31P excitation, paving the way to include larger subjects and more space for receiver arrays. The increase in possible number of RF excitations per scan time, due to the improved B1+ homogeneity and low SAR, allows SNR to be exchanged for spatial resolution in CSI and/or T1 weighting by simply manipulating TR and/or flip angle to detect and quantify ratios from different molecular species. 相似文献
73.
Bhavitavya Nijampatnam Parmanand Ahirwar Piyasuda Pukkanasut Holly Womack Luke Casals Hua Zhang Xia Cai Suzanne M. Michalek Hui Wu Sadanandan E. Velu 《ACS medicinal chemistry letters》2021,12(1):48
Dental caries is a bacterial infectious disease characterized by demineralization of the tooth enamel. Treatment of this disease with conventional antibiotics is largely ineffective as the cariogenic bacteria form tenacious biofilms that are resistant to such treatments. The main etiological agent for dental caries is the bacterium Streptococcus mutans. S. mutans readily forms biofilms on the tooth surface and rapidly produces lactic acid from dietary sucrose. Glucosyl transferases (Gtfs) secreted by S. mutans are mainly responsible for the production of exopolysaccharides that are crucial for the biofilm architecture. Thus, inhibiting S. mutans’ Gtfs is an effective approach to develop selective biofilm inhibitors that do not affect the growth of oral commensals. Herein, we report a library of 90 analogs of the previously identified lead compound, G43, and exploration of its structure activity relationships (SAR). All compounds were evaluated for the inhibition of S. mutans biofilms and bacterial growth. Selected compounds from this library were further evaluated for enzyme inhibition against Gtfs using a zymogram assay and for growth inhibition against oral commensal bacterial species such as Streptococcus gordonii and Streptococcus sanguinis. This study has led to the discovery of several new biofilm inhibitors with enhanced potency and selectivity. One of the leads, IIIF1, showed marked reduction in buccal, sulcal, and proximal caries scores in a rat model of dental caries. 相似文献
74.
A numerical investigation on the effect of RF coil feed variability on global and local electromagnetic field exposure in human body models at 64 MHz
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75.
This report describes in detail a new quantitative structure-activity relational expert system (QSAR-ES) method for predicting the carcinogenic potential of pharmaceuticals and other organic chemicals in rodents, and a beta-test evaluation of its performance. The method employs an optimized, computer-automated structure evaluation (MCASE) software program and new database modules which were developed under a Cooperative Research and Development Agreement (CRADA) between FDA and Multicase, Inc. The beta-test utilized 126 compounds with carcinogenicity studies not included in control database modules and three sets of modules, including: A07-9 (Multicase, Inc.), AF1-4 (FDA-OTR/Multicase, Inc.), and AF5-8 (FDA-OTR/proprietary). The investigation demonstrated that the standard MCASE(A07-9) system which had a small data-set (n = 319), detected few structure alerts (SA) for carcinogenicity (n = 17), and had poor coverage for beta-test compounds (51%). Conversely, the new, optimized FDA-OTR/MCASE(AF5-8) system had a large data-set (n = 934), detected many SA (n = 58) and had good coverage (94%). In addition, the study showed the standard MCASE(A07-9) software had poor predictive value for carcinogens and specificity for noncarcinogens (50 and 42%), detected many false positives (58%), and exhibited poor concordance (46%). Conversely, the new, FDA-OTR/MCASE(AF5-8) system demonstrated excellent predictive value for carcinogens and specificity for non-carcinogens (97%, 98%), detected only one false positive (2%), and exhibited good concordance (75%). The dramatic improvements in the performance of the MCASE were due to numerous modifications, including: (a) enhancement of the size of the control database modules, (b) optimization of MCASE SAR assay evaluation criteria, (c) incorporation of a carcinogenic potency scale for control compound activity and MCASE biophores, (d) construction of individual rodent gender- and species-specific modules, and (e) defining assay acceptance criteria for query and control database compounds. 相似文献
76.
Taudon N Margout D Wein S Calas M Vial HJ Bressolle FM 《Journal of pharmaceutical and biomedical analysis》2008,46(1):148-156
A sensitive and selective liquid chromatography-mass spectrometry (LC-MS) method has been developed for the determination of a new antimalarial bisthiazolium salt, SAR97276, in mouse plasma and red blood cells (RBCs). A drug of the same chemical series as the test drug, T2, was used as internal standard. The method involved solid phase extraction of the compound and the internal standard from the two matrices using Oasis HLB columns. LC separation was performed on a Zorbax eclipse XDB C8 column (5 microm) with a mobile phase of acetonitrile containing trimethylamine (130 microl/l, solvent A) and 2 mM ammonium formate buffer (solvent B). MS data were acquired in single ion monitoring mode at m/z 227 for SAR97276 and m/z 326 for T2. The matrix had no influence on the detection of either SAR97276 or T2. The drug/internal standard peak area ratios were linked via quadratic relationships to plasma (1.65-1322 ng/ml) and RBC concentrations (3.31-2644 ng/ml). Precision was below 14% and accuracy was 91.4-104%. Dilution of the samples had no influence on the performance of the method. Extraction recoveries of SAR97276 were > or =90% in plasma and > or =60% in RBCs. The lower limits of quantitation were 1.65 ng/ml in plasma and 3.31 ng/ml in RBCs. Stability tests under various conditions were also investigated. The method was successfully used to determine the pharmacokinetic profile of SAR97276 in healthy mouse. 相似文献
77.
Long MC Shaddix SC Moukha-Chafiq O Maddry JA Nagy L Parker WB 《Biochemical pharmacology》2008,75(8):1588-1600
Adenosine kinase (Ado kinase) from Mycobacterium tuberculosis is structurally and biochemically unique from other known Ado kinases. This purine salvage enzyme catalyzes the first step in the conversion of the adenosine analog, 2-methyl-Ado (methyl-Ado), into a metabolite with antitubercular activity. Methyl-Ado has provided proof of concept that the purine salvage pathway from M. tuberculosis may be utilized for the development of antitubercular compounds with novel mechanisms of action. In order to utilize this enzyme, it is necessary to understand the topography of the active site to rationally design compounds that are more potent and selective substrates for Ado kinase. A previous structure-activity relationship identified modifications to the base moiety of adenosine (Ado) that result in substrate and inhibitor activity. In an extension of that work, 62 Ado analogs with modifications to the ribofuranosyl moiety, modifications to the base and ribofuranosyl moiety, or modifications to the glycosidic bond position have been analyzed as substrates and inhibitors of M. tuberculosis Ado kinase. A subset of these compounds was further analyzed in human Ado kinase for the sake of comparison. Although no modifications to the ribose moiety resulted in compounds as active as Ado, the best substrates identified were carbocyclic-Ado, 8-aza-carbocyclic-Ado, and 9-[alpha-l-lyxofuranosyl]-adenine with 38%, 4.3%, and 3.8% of the activity of Ado, respectively. The most potent inhibitor identified, 5'-amino-5'-deoxy-Ado, had a K(i)=0.8muM and a competitive mode of inhibition. MIC studies demonstrated that poor substrates could still have potent antitubercular activity. 相似文献
78.
New alkenyl derivative from Piper malacophyllum and analogues: Antiparasitic activity against Trypanosoma cruzi and Leishmania infantum
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Marina T. Varela Marta L. Lima Mariana K. Galuppo Andre G. Tempone Alberto de Oliveira João Henrique G. Lago João Paulo S. Fernandes 《Chemical biology & drug design》2017,90(5):1007-1011
Alkylphenols isolated from Piper malacophyllum (Piperaceae), gibbilimbols A and B, showed interesting activity against the parasites Trypanosoma cruzi and Leishmania infantum. In continuation to our previous work, a new natural product from the essential oil of the leaves of P. malacophyllum was isolated, the 5‐[(3E)‐oct‐3‐en‐1‐il]‐1,3‐benzodioxole, and also a new set of five compounds was prepared. The antiparasitic activity of the natural product was evaluated in vitro against these parasites, indicating potential against the promastigote/trypomastigote/amastigote forms (IC50 32–83 μm ) of the parasites and low toxicity (CC50 > 200 μm ) to mammalian cells. The results obtained to the synthetic compounds indicated that the new derivatives maintained the promising antiparasitic activity, but the cytotoxicity was considerably lowered. The amine derivative LINS03011 displayed the most potent IC50 values (13.3 and 16.7 μm ) against amastigotes of T. cruzi and L. infantum, respectively, indicating comparable activity to the phenolic prototype LINS03003, with threefold decreased (CC50 73.5 μm ) cytotoxicity, leading the selectivity index (SI) towards the parasites up to 24.5. In counterpart, LINS03011 has not shown membrane disruptor activity in SYTOX Green model. In summary, this new set showed the hydroxyl is not essential for the antiparasitic activity, and its substitution could decrease the toxicity to mammalian cells. 相似文献
79.
A field‐based disparity analysis of new 1,2,5‐oxadiazole derivatives endowed with antiproliferative activity
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Federica Porta Arianna Gelain Daniela Barlocco Nicola Ferri Silvia Marchianò Valentina Cappello Livia Basile Salvatore Guccione Fiorella Meneghetti Stefania Villa 《Chemical biology & drug design》2017,90(5):820-839
A series of 1,2,5‐oxadiazoles were synthesized as new potential antiproliferative agents. The in vitro cytotoxic activity evaluation of title compounds through MTT assay revealed that some of them showed significant activity against the HCT‐116 cancer cell line. The field‐based disparity analysis provided indications about the electrostatic, hydrophobic, and shape features underlying the cytotoxicity, suggesting that increasing the negative electrostatic field on the heterocyclic core of the structure has positive effects on the activity. The structure–activity relationships (SAR) around a particular compound can be explained allowing for a structural rationale for the differences in activity. The SAR provided by this series of compounds can be exploited to carry out further lead optimization. 相似文献
80.