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Pavan FR Poelhsitz GV Barbosa MI Leite SR Batista AA Ellena J Sato LS Franzblau SG Moreno V Gambino D Leite CQ 《European journal of medicinal chemistry》2011,46(10):5099-5107
This paper describes the synthesis and characterization of four new ruthenium complexes containing 1,4 bis(diphenylphosphino)butane (dppb), 2-pyridinecarboxylic acid anion (pic) and the diimines [(2,2′-bipyridine (bipy), 4,4′-dimethyl-2,2′-bipyridine (Me-bipy), 4,4′-dichloro-2,2′-bipyridine (Cl-bipy) and 1,10-phenanthroline (phen) as ligands, with formulae [Ru(pic)(dppb)(bipy)]PF6 (SCAR01), [Ru(pic)(dppb)(Me-bipy)]PF6 (SCAR02), [Ru(pic)(dppb)(Cl-bipy)]PF6 (SCAR03) and [Ru(pic)(dppb)(phen)]PF6 (SCAR04). Additionally, the in vitro anti-Mycobacterium tuberculosis (MTB) activity, cytotoxicity and activity against in vitro infection of these complexes and two more complexes, cis-[Ru(pic)(dppe)2]PF6 (SCAR05) and cis-[RuCl2(dppb)(bipy)] (SCAR06), and their free ligands are described and discussed. All compounds showed excellent MIC against MTB, low cytotoxicity and a selectivity index higher than 10. Also, all compounds showed significant intracellular inhibition and the compound SCAR05 showed a better activity than rifampin and SQ109. This is the first report of activity against in vitro infection of ruthenium compounds. 相似文献
84.
Slepenkin A Chu H Elofsson M Keyser P Peterson EM 《The Journal of infectious diseases》2011,204(9):1313-1320
The salicylidene acylhydrazide INP0341 inhibits growth of Chlamydia in HeLa cells, has negligible cell toxicity, and does not inhibit the growth of lactobacilli. The antichlamydial activity of INP0341 was retained when tested in vaginal and semen simulants. Vaginal tissue from INP0341-treated mice appeared similar to control sham-treated mice. To determine whether INP0341 can protect mice from a vaginal challenge, C3H/HeJ mice were either sham or INP0341 treated intravaginally pre- and postinoculation with 5 × 10(2) inclusion-forming units (IFUs) of Chlamydia trachomatis serovar D. Vaginal cultures taken over a month-long period showed a significant difference in the number of control mice that were culture positive versus the number in the INP0341-treated group, 100% (25/25) and 31% (8/26), respectively (P < .05). The quantity of IFUs shed and antibody titers to Chlamydia were significantly higher for the control group (P < .05). In summary, INP0341 is a promising compound to be considered for formulation as a vaginal microbicide. 相似文献
85.
Martins FT Bonfilio R De Araújo MB Ellena J 《Journal of pharmaceutical sciences》2012,101(6):2143-2154
To optimize solubility of drugs, current strategies mainly focus on engineering and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudine--namely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a temperature of 299 ± 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solubility profiles were understood on the basis of structural and solvent-solute interaction approaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug. 相似文献
86.
Recent increases in obesity, diabetes, and hypertension, along with the aging of the US population, are driving a dramatic rise in the prevalence of chronic kidney disease (CKD). Despite this increase, the majority of Americans with early-stage CKD remain unaware of their disease. Primary care physicians are at the forefront of efforts for early recognition of CKD and management to control its progression. Patients with CKD should be referred to nephrologists no later than the point at which their estimated glomerular filtration rate reaches 30 mL/min. Nephrology evaluation at this point is essential to facilitate timely preparation for care of end-stage renal disease through preemptive transplantation or planned transition to dialysis. In addition to stringent control of underlying hypertension and/or diabetes, mineral metabolic parameters (serum parathyroid hormone, phosphorus, calcium, and bicarbonate) in patients with advancing CKD should be managed closely to avoid adverse effects on the cardiovascular and skeletal systems. 相似文献
87.
To compare the ability of a native and a recombinant preparation of the major outer membrane protein of Chlamydia trachomatis mouse pneumonitis (MoPn; Ct-nMOMP and Ct-rMOMP) to protect against an intranasal (i.n.) challenge, BALB/c mice were vaccinated by the intramuscular (i.m.) and subcutaneous (s.c.) routes using CpG-1826 and Montanide ISA 720 as adjuvants. Animals inoculated i.n. with live elementary bodies (EB) of Chlamydia served as a positive control. Negative control groups were immunized with either Neisseria gonorrhoeae recombinant porin B (Ng-rPorB) or with minimal essential medium (MEM-0). Mice immunized with Ct-rMOMP, Ct-nMOMP and EB developed a strong immune response as shown by high levels of Chlamydia specific antibodies in serum and a strong T-cell lymphoproliferative response. Following the i.n. challenge with 104 inclusion forming units (IFU) of C. trachomatis, mice immunized with Ct-nMOMP or Ct-rMOMP lost significantly less weight than the negative control animals immunized with Ng-rPorB or MEM-0 (P < 0.05). However, mice vaccinated with the Ct-nMOMP lost less weight than those immunized with the Ct-rMOMP (P < 0.05). Mice were euthanized at 10 days following the challenge, their lungs weighed and the number of IFU of Chlamydia determined. Based on the lung weight and number of IFU recovered, significant protection was observed in the groups of mice immunized with both Ct-nMOMP and the Ct-rMOMP (P < 0.05). Nevertheless, significantly better protection was achieved with the Ct-nMOMP in comparison with the Ct-rMOMP (P < 0.05). In conclusion, vaccination with a preparation of the nMOMP elicited a more robust protection than immunization with rMOMP, suggesting that the conformational structure of MOMP is critical for inducing strong protection. 相似文献
88.
A surface on the androgen receptor that allosterically regulates coactivator binding 总被引:1,自引:0,他引:1
Estébanez-Perpiñá E Arnold LA Arnold AA Nguyen P Rodrigues ED Mar E Bateman R Pallai P Shokat KM Baxter JD Guy RK Webb P Fletterick RJ 《Proceedings of the National Academy of Sciences of the United States of America》2007,104(41):16074-16079
Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target. 相似文献
89.
The classical Gram stain was originally established in 1884 by Hans Christian Gram following which numerous modifications have been developed, typically with specific sample types in mind. Gram methods such as Brown–Hopps, Brown–Brenn, and Gram–Twort have been commonly adopted for routine use in anatomical pathology laboratories, enabling the simultaneous demonstration and identification of Gram-positive and Gram-negative organisms in histological sections. The various Gram methods available to laboratories each necessitate practical and interpretative skill by laboratory staff. In addition to staff competencies, the methods require the use of appropriate control material, i.e. ideally comprising Gram-positive and Gram-negative bacteria. An integral component of laboratory annual accreditation involves the auditing of technical and procedural competency, including participation in an external quality assurance activity. In 2011 and 2016 RCPAQAP Anatomical Pathology (The Royal College of Pathologists of Australasia Quality Assurance Programs) provided its participants a Gram stain exercise, which was repeated later in the same years. This has afforded participant laboratories a valuable opportunity to review and improve on their initial performance, as resulted by the RCPAQAP Technical Module advisory committee, in conjunction with their routine protocol for that special stain. The data derived from these years have enabled a comprehensive insight of contemporary practice of Gram staining in many anatomical pathology laboratories, while also enabling an appraisal of individual and generalized laboratory performance with Gram staining. A review of contemporary Gram stain methods in use in anatomical pathology laboratories was undertaken, and performance in their execution. 相似文献
90.