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James M Apgar, Robert R Wilkening, Mark L Greenlee, James M Balkovec, Amy M Flattery, George K Abruzzo, Andrew M Galgoci, Robert A Giacobbe, Charles J Gill, Ming Jo Hsu, Paul Liberator, Andrew S Misura, Mary Motyl, Jennifer Nielsen Kahn, Maryann Powles, Fred Racine, Jasminka Dragovic, Bahanu Habulihaz, Weiming Fan, Robin Kirwan, Shu Lee, Hao Liu, Ahmed Mamai, Kingsley Nelson, Michael Peel
The clinical success of the echinocandins, which can only be administered parentally, has validated β-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency...
December 15, 2015: Bioorganic & Medicinal Chemistry Letters
Alexander J Lepak, Karen Marchillo, David R Andes
Echinocandins inhibit the synthesis of β-1,3-D-glucan in Candida and are the first-line therapy in numerous clinical settings. Their use is limited by poor oral bioavailability, and they are available only as intravenous therapies. Derivatives of enfumafungin are novel orally bioavailable glucan synthase inhibitors. We performed an in vivo pharmacodynamic (PD) evaluation with a novel enfumafungin derivative, SCY-078 (formerly MK-3118), in a well-established neutropenic murine model of invasive candidiasis against C...
February 2015: Antimicrobial Agents and Chemotherapy
Russell E Lewis, Guangling Liao, Katherine Young, Cameron Douglas, Dimitrios P Kontoyiannis
Antifungal exposure can elicit immunological effects that contribute to activity in vivo, but this activity is rarely screened in vitro in a fashion analogous to MIC testing. We used RAW 264.7 murine macrophages that express a secreted embryonic alkaline phosphatase (SEAP) gene induced by transcriptional activation of NF-κB and activator protein 1 (AP-1) to develop a screen for immunopharmacological activity of cell wall-active antifungal agents. Isolates of Candida albicans and Aspergillus fumigatus that conditionally express genes involved in cell wall synthesis were also tested with the reporter macrophages...
2014: Antimicrobial Agents and Chemotherapy
Cristina Jiménez-Ortigosa, Padmaja Paderu, Mary R Motyl, David S Perlin
MK-3118 is as an orally active new antifungal in the early stage of clinical development that inhibits the biosynthesis of β-(1,3)-glucan. We evaluated the in vitro activity of this compound against wild-type and echinocandin-resistant (ER) isolates containing mutations in the FKS gene(s) of Candida spp. and Aspergillus spp. MK-3118 demonstrated enhanced efficacy for most C. albicans and C. glabrata ER isolates relative to caspofungin, with decreased MICs and half-maximal inhibitory concentrations (IC50s).
2014: Antimicrobial Agents and Chemotherapy
Michael A Pfaller, Shawn A Messer, Mary R Motyl, Ronald N Jones, Mariana Castanheira
MK-3118, a glucan synthase inhibitor derived from enfumafungin, and comparator agents were tested against 71 Aspergillus spp., including itraconazole-resistant strains (MIC, ≥ 4 μg/ml), using CLSI and EUCAST reference broth microdilution methods. The CLSI 90% minimum effective concentration (MEC(90))/MIC(90) values (μg/ml) for MK-3118, amphotericin B, and caspofungin, respectively, were as follows: 0.12, 2, and 0.03 for Aspergillus flavus species complex (SC); 0.25, 2, and 0.06 for Aspergillus fumigatus SC; 0...
February 2013: Antimicrobial Agents and Chemotherapy
Michael A Pfaller, Shawn A Messer, Mary R Motyl, Ronald N Jones, Mariana Castanheira
OBJECTIVES: To evaluate the activity of the orally bioavailable enfumafungin derivative MK-3118 and comparator antifungal agents tested against a collection of 113 clinical isolates of Candida spp. using CLSI and EUCAST broth microdilution (BMD) methods. METHODS: Candida spp. isolates (n=113) were tested by CLSI and EUCAST methods. The collection contained 29 Candida albicans, 29 Candida glabrata, 21 Candida tropicalis, 15 Candida parapsilosis and 19 Candida krusei, including azole- and echinocandin-resistant isolates...
April 2013: Journal of Antimicrobial Chemotherapy
Brian H Heasley, Gregory J Pacofsky, Ahmed Mamai, Hao Liu, Kingsley Nelson, Ghjuvanni Coti, Michael R Peel, James M Balkovec, Mark L Greenlee, Paul Liberator, Dongfang Meng, Dann L Parker, Robert R Wilkening, James M Apgar, F Racine, Ming Jo Hsu, Robert A Giacobbe, Jennifer Nielsen Kahn
Orally bioavailable inhibitors of β-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation...
November 15, 2012: Bioorganic & Medicinal Chemistry Letters
Yong-Li Zhong, Donald R Gauthier, Yao-Jun Shi, Mark McLaughlin, John Y L Chung, Philippe Dagneau, Benjamin Marcune, Shane W Krska, Richard G Ball, Robert A Reamer, Nobuyoshi Yasuda
An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively...
April 6, 2012: Journal of Organic Chemistry
Richard F Hector, Donald E Bierer
INTRODUCTION: New classes of synthetic and semi-synthetic β-glucan inhibitors have recently emerged, providing analogs that, in some cases, have been proven to have a high degree of activity against fungi, offering the prospect of alternatives to the commercially available lipopeptide/echinocandin agents caspofungin, micafungin and anidulafungin. AREA COVERED: This review covers applications disclosing compound classes that include synthetic pyridazinone analogs, bicyclic heteroaryl ring compounds, aniline derivates, and semi-synthetic echinocandin and enfumafungin derivatives...
October 2011: Expert Opinion on Therapeutic Patents
Ivone M Martins, Juan C G Cortés, Javier Muñoz, M Belén Moreno, Mariona Ramos, José A Clemente-Ramos, Angel Durán, Juan C Ribas
Three specific β(1,3)glucan synthase (GS) inhibitor families, papulacandins, acidic terpenoids, and echinocandins, have been analyzed in Schizosaccharomyces pombe wild-type and papulacandin-resistant cells and GS activities. Papulacandin and enfumafungin produced similar in vivo effects, different from that of echinocandins. Also, papulacandin was the strongest in vitro GS inhibitor (IC(50) 10(3)-10(4)-fold lower than with enfumafungin or pneumocandin), but caspofungin was by far the most efficient antifungal because of the following...
February 4, 2011: Journal of Biological Chemistry
Andrea Escalante, Martha Gattuso, Pilar Pérez, Susana Zacchino
Phytolaccoside B (1), an antifungal monodesmoside triterpenoid glycoside isolated from berries of Phytolacca tetramera Hauman (Phytolaccaceae), alters the morphology of yeasts and molds. The malformations were similar to those produced by enfumafungin, a known inhibitor of (1-->3)-beta-D-glucan synthase, an enzyme that catalyzes the synthesis of (1-->3)-beta-D-glucan, one of the major polymers of the fungal cell wall. However, enzymatic assays revealed that 1 did not inhibit (1-->3)-beta-D-glucan synthase, but it did produce a notable enhancement of the chitin synthase 1 activity and, concomitantly, a rise in chitin, another important polymer of the fungal cell walls...
October 2008: Journal of Natural Products
F Peláez, A Cabello, G Platas, M T Díez, A González del Val, A Basilio, I Martán, F Vicente, G E Bills, R A Giacobbe, R E Schwartz, J C Onish, M S Meinz, G K Abruzzo, A M Flattery, L Kong, M B Kurtz
In a screening of natural products with antifungal activity derived from endophytic fungi, we detected a potent activity in a culture belonging to the form-genus Hormonema, isolated from leaves of Juniperus communis. The compound is a new triterpene glycoside, showing an antifungal activity highly potent in vitro against Candida and Aspergillus and with moderate efficacy in an in vivo mouse model of disseminated candidiasis. The agent is especially interesting since its antifungal spectrum and its effect on morphology of Aspergillus fumigatus is comparable to that of the glucan synthase inhibitor pneumocandin B,,, the natural precursor of the clinical candidate MK-0991 (caspofungin acetate)...
October 2000: Systematic and Applied Microbiology
J Onishi, M Meinz, J Thompson, J Curotto, S Dreikorn, M Rosenbach, C Douglas, G Abruzzo, A Flattery, L Kong, A Cabello, F Vicente, F Pelaez, M T Diez, I Martin, G Bills, R Giacobbe, A Dombrowski, R Schwartz, S Morris, G Harris, A Tsipouras, K Wilson, M B Kurtz
The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Natural-product inhibitors of cell wall (1,3)-beta-D-glucan synthase such as lipopeptide pneumocandins and echinocandins as well as the glycolipid papulacandins have been evaluated as potential therapeutics for the last two decades. As a result, MK-0991 (caspofungin acetate; Cancidas), a semisynthetic analogue of pneumocandin B(o), is being developed as a broad-spectrum parenteral agent for the treatment of aspergillosis and candidiasis...
February 2000: Antimicrobial Agents and Chemotherapy
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