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Sándor Kun, Éva Bokor, Ádám Sipos, Tibor Docsa, László Somsák
The aim of the present study was to broaden the structure-activity relationships of C - and N -β-d-glucopyranosyl azole type inhibitors of glycogen phosphorylase. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper catalyzed azide-alkyne cycloadditions between O -perbenzylated or O -peracetylated β-d-glucopyranosyl ethynes and aryl azides. 1-β-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O -peracetylated α-d-glucopyranosyl bromide. C -β-d-Glucopyranosyl- N -substituted-tetrazoles were synthesized by alkylation/arylation of O -perbenzoylated 5-β-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts...
March 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Yuan Zhang, Vijai Kumar Reddy Tangadanchu, Yu Cheng, Ren-Guo Yang, Jian-Mei Lin, Cheng-He Zhou
A series of isopropanol-bridged carbazole azoles as potential antimicrobial agents were designed and synthesized from commercial carbazoles. Bioassay revealed that 3,6-dichlorocarbazolyl triazole 3f could effectively inhibit the growth of E. faecalis with minimal inhibitory concentration of 2 μg/mL. The active molecule 3f showed lower propensity to trigger the development of resistance in bacteria than norfloxacin and exerted rapidly bactericidal ability. Compound 3f also exhibited low cytotoxicity to normal mammalian RAW264...
March 8, 2018: ACS Medicinal Chemistry Letters
Agustin Resendiz Sharpe, Katrien Lagrou, Jacques F Meis, Anuradha Chowdhary, Shawn R Lockhart, Paul E Verweij
Triazole resistance is an increasing concern in the opportunistic mold Aspergillus fumigatus. Resistance can develop through exposure to azole compounds during azole therapy or in the environment. Resistance mutations are commonly found in the Cyp51A-gene, although other known and unknown resistance mechanisms may be present. Surveillance studies show triazole resistance in six continents, although the presence of resistance remains unknown in many countries. In most countries, resistance mutations associated with the environment dominate, but it remains unclear if these resistance traits predominately migrate or arise locally...
April 1, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
A Skiada, C Lass-Floerl, N Klimko, A Ibrahim, E Roilides, G Petrikkos
The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common underlying disease in countries with high income and uncontrolled diabetes in developing countries. Clinical approach to diagnosis lacks sensitivity and specificity. Radiologically, multiple (≥10) nodules and pleural effusion are reportedly associated with pulmonary mucormycosis. Another finding on computerized tomography (CT) scan, which seems to indicate the presence of mucormycosis, is the reverse halo sign...
April 1, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Oriana Brea, Alberto Luna, Cristina Díaz, Ines Corral Perez
H₂ has been proposed as a long-term non-fossil fuel to be used in a future ideal carbon neutral energetic economy. However, its low volumetric energy density hinders its storage and transportation. MOFs represent very promising materials for this purpose, due to their very extended surface areas. Azolates and, in particular tetrazolates, are together with carboxylate functionalities very common organic linkers connecting metallic secondary building units in MOFs. This study addresses from a theoretical perspective the H₂ adsorptive properties of tetrazolate linkers at molecular level, following a size progressive approach...
March 14, 2018: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
H-L Lei, L-H Li, W-S Chen, W-N Song, Y He, F-Y Hu, X-J Chen, W-P Cai, X-P Tang
Talaromyces marneffei (T. marneffei) can cause talaromycosis, a fatal systemic mycosis, in patients with AIDS. With the increasing number of talaromycosis cases in Guangdong, China, we aimed to investigate the susceptibility of 189 T. marneffei clinical strains to eight antifungal agents, including three echinocandins (anidulafungin, micafungin, and caspofungin), four azoles (posaconazole, itraconazole, voriconazole, and fluconazole), and amphotericin B, with determining minimal inhibition concentrations (MIC) by Sensititre YeastOne™ YO10 assay in the yeast phase...
March 13, 2018: European Journal of Clinical Microbiology & Infectious Diseases
Royce Johnson, Jackie Ho, Pete Fowler, Arash Heidari
PURPOSE OF REVIEW: This article summarizes the diagnosis and treatment of coccidioidal meningitis (CM) and its complications. An overview of current and prospective pharmacologic treatment options and monitoring parameters is provided. A consensus has not been reached regarding universally accepted therapeutic serum levels for azoles because of insufficient evidence. We describe the preferred therapeutic drug level ranges that our institution uses to monitor azole therapy. RECENT FINDINGS: Ho et al...
March 13, 2018: Current Neurology and Neuroscience Reports
Barbara Birk, Alexander Stähle, Mathias Meier, Markus Palm, Dorothee Funk-Weyer, Gerhard Breves, Harald Seulberger
The approving agencies for plant protection agents request xenobiotic metabolism and residue studies in rats, farm animals and plants (e.g. EU regulation 1107/2009) according to OECD guidelines. The specific intestinal physiology of ruminants might lead to specific residues, which should be investigated very carefully. Specific aspects of xenobiotic metabolism in ruminants may arise, which are investigated by performing additional in vivo studies. The aim of the present work is to asses a modified rumen simulation system (RUSITEC) for such studies in vitro...
March 12, 2018: ALTEX
Ilias Kounatidis, Lauren Ames, Rupal Mistry, Hsueh-Lui Ho, Ken Haynes, Petros Ligoxygakis
Candida glabrata ( C. glabrata ) forms part of the normal human gut microbiota but can cause life-threatening invasive infections in immune-compromised individuals. C. glabrata displays high resistance to common azole antifungals, which necessitates new treatments. In this investigation, we identified five C. glabrata deletion mutants ( Δada2 , Δbas1 , Δhir3, Δino2 and Δmet31 ) from a library of 196 transcription factor mutants that were unable to grow and activate an immune response in Drosophila larvae...
March 13, 2018: G3: Genes—Genomes—Genetics
Stephen R Brand, Thorsten P Degenhardt, Karen Person, Jack D Sobel, Paul Nyirjesy, Robert J Schotzinger, Amir Tavakkol
BACKGROUND: Lanosterol demethylase (CYP51), is an enzyme essential for fungal growth, and catalyzes an early step in the biosynthetic pathway of ergosterol, a sterol required for fungal cell membrane formation and integrity. CYP51 is the molecular target of the class of drugs referred to as 'azole antifungals.' VT-1161 is a novel, oral, selective inhibitor of fungal CYP51, and is being developed for the treatment of recurrent vulvovaginal candidiasis. OBJECTIVE: We evaluated the efficacy and safety of 4 dosing regimens of oral VT-1161 compared to placebo in women with recurrent vulvovaginal candidiasis, defined as at least 3 symptomatic episodes of acute vulvovaginal candidiasis within a 12-month period...
March 10, 2018: American Journal of Obstetrics and Gynecology
J Denis, M-P Ledoux, Y Nivoix, R Herbrecht
Triazoles compounds are first-line agents for the treatment of invasive fungal diseases. Isavuconazole is the most recent triazole compound, approved in 2015 by the FDA and the EMA to treat invasive aspergillosis and mucormycosis. We reviewed here the in vitro activity of isavuconazole against a vast spectrum of species. Isavuconazole MICs were evaluated using CLSI, EUCAST or Etest methods, with no significant differences between the technics. Low MIC50 and MIC90 (<1μg/mL) were described for isavuconazole against the majority of Candida spp...
March 10, 2018: Journal de Mycologie Médicale
Sergio Álvarez-Pérez, Marta E García, José L Blanco
Combination therapy has become popular in clinical practice, but limited data on the effects of combinations of antifungal agents is still available for most fungal pathogens. We studied the in vitro response of 30 genetically diverse clinical strains of the basidiomycetous lipophilic yeast Malassezia pachydermatis obtained from cases of canine otitis to several amphotericin B (AMB)-azole combinations. Broth microdilution checkerboard tests revealed that AMB antagonized the effects of itraconazole (ITC) and voriconazole (VRC) in 50% and 6...
March 8, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Qingdi Quentin Li, Huei-Fung Tsai, Ajeet Mandal, Bryan A Walker, Jason A Noble, Yuichi Fukuda, John E Bennett
Pathogenic fungi, including Candida glabrata, develop strategies to grow and survive both in vitro and in vivo under azole stress. However, the mechanisms by which yeast cells counteract the inhibitory effects of azoles are not completely understood. In the current study, it was demonstrated that the expression of the ergosterol biosynthetic genes ERG2, ERG3, ERG4, ERG10, and ERG11 was significantly upregulated in C. glabrata following fluconazole treatment. Inhibiting ergosterol biosynthesis using fluconazole also increased the expression of the sterol influx transporter AUS1 and the sterol metabolism regulators SUT1 and UPC2 in fungal cells...
March 9, 2018: Molecular Medicine Reports
Saori Tanii, Mieko Arisawa, Takaya Tougo, Masahiko Yamaguchi
C-N-linked bi(heteroaryl)s are synthesized by a rhodium-catalyzed N-heteroarylation reaction of N-benzoyl heteroarenes including azoles/azolones, pyridones, cyclic ureas, and cyclic imides using heteroaryl aryl ethers. The reaction involves the covalent bond-exchange reaction of N-CO and HetAr-O bonds without using metal bases and exhibits a broad applicability, giving diverse C-N-linked bi(heteroaryl)s containing five- and six-membered heteroarenes. The N-heteroarylation of N-H azoles/azolones and pyridone proceeds at higher reaction temperatures...
March 12, 2018: Organic Letters
Zafer Sahin, Merve Ertas, Barkın Berk, Sevde Nur Biltekin, Leyla Yurttas, Seref Demirayak
Steroidal and non-steroidal aromatase inhibitors target the suppression of estrogen biosynthesis in the treatment of breast cancer. Researchers have increasingly focused on developing non-steroidal derivatives for their potential clinical use avoiding steroidal side-effects. Non-steroidal derivatives generally have planar aromatic structures attached to the azole ring system. One part of this ring system comprises functional groups that inhibit aromatization through the coordination of the haem group of the aromatase enzyme...
February 27, 2018: Bioorganic & Medicinal Chemistry
Kristina Beijer, Maria Jönsson, Siraz Shaik, Daphné Behrens, Björn Brunström, Ingvar Brandt
Antifungal azoles are widely used in medicine, agriculture, and material protection and several antifungal azoles have been found in environmental samples. Although these compounds were designed to inhibit fungal enzymes such as lanosterol-14-demethylase (cytochrome P450 (CYP) 51), it is well established that the inhibitory actions of azoles are not specific for fungal CYP isozymes. We refined a gill filament assay to determine the inhibition of CYP1, measured as reduced 7-ethoxyresorufin-O-deethylase (EROD) activity, in rainbow trout (Oncorhynchus mykiss) gill tissue ex vivo...
February 21, 2018: Aquatic Toxicology
Raimunda Sâmia Nogueira Brilhante, Edmilson Emanuel Monteiro Correia, Glaucia Morgana de Melo Guedes, Jonathas Sales de Oliveira, Débora de Souza Collares Maia Castelo-Branco, Rossana de Aguiar Cordeiro, Adriana de Queiroz Pinheiro, Lúcio Jackson Queiroz Chaves, Waldemiro de Aquino Pereira Neto, José Júlio Costa Sidrim, Marcos Fábio Gadelha Rocha
BACKGROUND: As shown by recent researches, most of the clinically relevant fungi, including dermatophytes, form biofilms in vitro and in vivo, which may present antimicrobial tolerance favoring recurrent infections. OBJECTIVES: The aim of this study was to determine the minimum inhibitory concentrations (MICs) of itraconazole (ITC), voriconazole (VCZ) and griseofulvin (GRI) against Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Microsporum canis and Microsporum gypseum, in planktonic and biofilm growth...
March 8, 2018: Mycoses
Quan-Zhen Lv, Yu-Lin Qin, Lan Yan, Liang Wang, Chuyue Zhang, Yuan-Ying Jiang
Antifungal azole drugs inhibit the synthesis of ergosterol and cause the accumulation of sterols containing a 14α-methyl group, which is related to the properties of cell membrane. Due to the frequent recurrence of fungal infections and clinical long-term prophylaxis, azole resistance is increasing rapidly. In our research, Nsg2p, encoded by the ORF19.273 in Candida albicans , is found to be involved in the inhibition of 14α-methylated sterols and resistance to azoles. Under the action of fluconazole, nsg2 Δ/Δ mutants are seriously damaged in the integrity and functions of cell membranes with a decrease of ergosterol ratio and an increase of both obtusifoliol and 14α-methylfecosterol ratio...
2018: Frontiers in Microbiology
Jianjun Qiao, Yi Sun, Lujuan Gao, Chengyan He, Wenqian Zheng
No abstract text is available yet for this article.
March 5, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Galen M Kabulski, Shawn H MacVane
Previous studies of patients with cystic fibrosis (CF) treated with azole antifungals have shown altered pharmacokinetics relative to healthy patients. Data regarding the pharmacokinetic profile of isavuconazole in patients with CF undergoing lung transplantation is currently not available. Serum trough concentrations assessed in a single CF patient following transplant revealed significantly lower values relative to available literature. Larger studies are required to validate CF population pharmacokinetics of isavuconazole...
March 7, 2018: Transplant Infectious Disease: An Official Journal of the Transplantation Society
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