SCY-078 Is Fungicidal against Candida Species in Time-Kill Studies.

SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpene antifungals in clinical development for treating candidemia and invasive candidiasis. susceptibilities by broth microdilution, antifungal carryover, and time-kill dynamics were determined for three reference (ATCC) strains ( 90028, 90018, and 750), a quality-control (QC) strain ( 6258), and four other strains ( MYA-2732, 64124, and 76485 and 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators.

The cyclophilin inhibitor SCY-635 suppresses viral replication and induces endogenous interferons in patients with chronic HCV genotype 1 infection.

Background & Aims: SCY-635 is a non-immunosuppressive analog of cyclosporin A that inhibits cyclophilins A and B and hepatitis C virus (HCV) replication in vitro. In a phase 1b multi-dose escalation study, we evaluated the safety, plasma pharmacokinetics, and antiviral activity of 15 days of monotherapy with SCY-635 in adults with chronic genotype 1 HCV infection.

Methods: Twenty adults with chronic HCV genotype 1 were randomized to SCY-635 oral doses of 100, 200, or 300 mg three times daily for 15 days.

SCY-635, a novel nonimmunosuppressive analog of cyclosporine that exhibits potent inhibition of hepatitis C virus RNA replication in vitro.

SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 microM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4.

Antimalarial activity of N-alkyl amine, carboxamide, sulfonamide, and urea derivatives of a dispiro-1,2,4-trioxolane piperidine.

With an aim to identify a dispiro-1,2,4-trioxolane with high oral activity and good physicochemical properties, 27 derivatives of an achiral piperidine trioxolane were synthesized; most were potent antimalarial peroxides with IC(50)s ranging from 0.20 to 7.0 ng/mL.

Effect of functional group polarity on the antimalarial activity of spiro and dispiro-1,2,4-trioxolanes.

Based on the structures of several lipophilic trioxolane antimalarial prototypes, we set out to determine which functional groups were associated with good antimalarial profiles and identify more polar (lower LogP/LogD) lead compounds with good physicochemical properties. More lipophilic trioxolanes tended to have better oral activities than their more polar counterparts. Trioxolanes with a wide range of neutral and basic, but not acidic, functional groups had good antimalarial profiles.

Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: charting a workable structure-activity relationship using simple prototypes.

This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane.

Identification of an antimalarial synthetic trioxolane drug development candidate.

The discovery of artemisinin more than 30 years ago provided a completely new antimalarial structural prototype; that is, a molecule with a pharmacophoric peroxide bond in a unique 1,2,4-trioxane heterocycle. Available evidence suggests that artemisinin and related peroxidic antimalarial drugs exert their parasiticidal activity subsequent to reductive activation by haem, released as a result of haemoglobin digestion by the malaria-causing parasite. This irreversible redox reaction produces carbon-centred free radicals, leading to alkylation of haem and proteins (enzymes), one of which--the sarcoplasmic-endoplasmic reticulum ATPase PfATP6 (ref.

Carbon isosteres of the 4-aminopyridine substructure of chloroquine: effects on pK(a), hematin binding, inhibition of hemozoin formation, and parasite growth.

Unlike diprotic chloroquine (CQ), its two 4-aminoquinoline carbon isosteres (1, 2) are monoprotic at physiological pH. Compared to CQ, hematin binding affinity of 1 decreased 6.4-fold, and there was no measurable binding for 2.

Schistosoma japonicum: In vitro effects of artemether combined with haemin depend on cultivation media and appraisal of artemether products appearing in the media.

We recently found that the exposure of schistosomes in vitro to artemether plus haemin can lead to parasite death, while exposure to each compound singly had no effect. Since these observations might be relevant to understanding the mechanism of action of artemether against schistosomes, we conducted additional experiments. First, we performed a comparative appraisal of Schistosoma japonicum survival after incubation in two media, namely Hanks' balanced salt solution (HBSS) and RPMI 1640, supplemented with inactivated calf serum, antibiotics and different concentrations of artemether and/or haemin.

Intracellular accumulation, subcellular distribution, and efflux of tilmicosin in bovine mammary, blood, and lung cells.

Tilmicosin is a semisynthetic macrolide antibiotic currently approved for veterinary use in cattle and swine to combat respiratory disease. Because the concentrations of tilmicosin are generally low in bovine serum, the interaction of tilmicosin with three types of bovine phagocytes (monocyte-macrophages, macrophages, and neutrophils from blood, lungs, and mammary gland, respectively) and mammary gland epithelial cells was evaluated to provide an understanding of potential clinical efficacy. After incubation with radiolabeled tilmicosin, uptake was determined and expressed as the ratio of the intracellular to the extracellular drug concentration.

Mechanism of the intracellular killing and modulation of antibiotic susceptibility of Listeria monocytogenes in THP-1 macrophages activated by gamma interferon.

Listeria monocytogenes, a facultative intracellular pathogen, readily enters cells and multiplies in the cytosol after escaping from phagosomal vacuoles. Macrophages exposed to gamma interferon, one of the main cellular host defenses against Listeria, become nonpermissive for bacterial growth while containing Listeria in the phagosomes. Using the human myelomonocytic cell line THP-1, we show that the combination of L-monomethyl arginine and catalase restores bacterial growth without affecting the phagosomal containment of Listeria.

The determination of the cellular volume of avian, porcine and bovine phagocytes and bovine mammary epithelial cells and its relationship to uptake of tilmicosin.

In order to compare the intracellular concentration of antimicrobial agents in phagocytic and nonphagocytic cells, the knowledge of their cell volume is essential. For the first time, the determination of the avian, porcine, and bovine polymorphonuclear neutrophils (PMN), monocyte-derived macrophages, macrophages, and bovine mammary epithelial cell volume was performed using [3H]-water and [14C]-carboxyinulin. The comparison of all the cells showed that the PMN have a size range between 3.

Intracellular accumulation, subcellular distribution, and efflux of tilmicosin in chicken phagocytes.

Tilmicosin is a semi-synthetic macrolide antibiotic, currently approved for veterinary use in cattle and swine respiratory disease, and is in development for use in poultry mycoplasma air sacculitis. In order to provide an understanding of clinical efficacy, the in vitro interaction of tilmicosin with three types of chicken phagocytes (MQ-NCSU macrophages, monocyte-macrophages, and heterophils) was evaluated. After incubation with radiolabeled tilmicosin, uptake was determined and expressed as the ratio of the cellular (Cc) to the extracellular (Ce) drug concentration (Cc:Ce).

Intracellular accumulation, subcellular distribution and efflux of tilmicosin in swine phagocytes.

Tilmicosin is a semi-synthetic macrolide antibiotic, currently approved for veterinary use in cattle and swine respiratory disease. As the concentrations of tilmicosin are generally low in swine lung tissue, the interaction of tilmicosin with three types of swine phagocytes (monocyte-macrophages, alveolar macrophages, and neutrophils) was evaluated to provide an understanding of clinical efficacy. After incubation with radiolabelled tilmicosin, uptake was determined and expressed as the ratio of the intracellular (Ci) to the extracellular (Ce) drug concentration (Ci/Ce).

Effect of recombinant human gamma interferon on intracellular activities of antibiotics against Listeria monocytogenes in the human macrophage cell line THP-1.

Listeria monocytogenes is a facultative intracellular pathogen which enters cells by endocytosis and reaches phagolysosomes from where it escapes and multiplies in the cytosol of untreated cells. Exposure of macrophages to gamma interferon (IFN-gamma) restricts L. monocytogenes to phagosomes and prevents its intracellular multiplication.

Cellular uptake, localization and activity of fluoroquinolones in uninfected and infected macrophages.

Pefloxacin, like other fluoroquinolones, accumulates in macrophages and several other types of nucleated cells (but not in erythrocytes). Upon fractionation of macrophage homogenates by isopycnic centrifugation in sucrose gradients, fluoroquinolones are not found associated with any specific cellular structure. We have compared the activities of pefloxacin and roxithromycin against intracellular Staphylococcus aureus in mouse J774 macrophages.

In vitro susceptibility of Campylobacter jejuni to 27 antimicrobial agents and various combinations of beta-lactams with clavulanic acid or sulbactam.

The in vitro susceptibility of human isolates of Campylobacter jejuni was investigated with 27 antibiotics and 8 combinations of beta-lactams with clavulanic acid or sulbactam. Ansamycin, the new quinolines, erythromycin, and cefpirome were the most active drugs against C. jejuni; amoxicillin, ampicillin, cefotaxime, and ceftazidime 90% of the isolates, greater than or equal to 50 mg/liter).