Synthesis and Structure‐Activity Relationships of a Novel Antifungal Agent, ICI 195,739

Boyle, F. Thomas; Gilman, David J.; Gravestock, Michael B.; Wardleworth, J. M.

doi:10.1111/j.1749-6632.1988.tb40391.x

Cited by 38 publications

(20 citation statements)

References 13 publications

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“…Of particular interest is the recent report of a novel bis-triazole derivative, ICI 195,739, with potent antifungal and antiprotozoal effects, particularly against T. cruzi (1,9,29). In a parallel study (32), we have shown that ICI 195,739 is 300 times more potent than ketoconazole against the epimastigote (culture) form but has comparable activity against the (intracellular) amastigote stage.…”

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confidence: 83%

Ultrastructural alterations induced by ICI 195,739, a bis-triazole derivative with strong antiproliferative action against Trypanosoma (Schizotrypanum) cruzi

Lazardi

Urbina

Souza

1991

Antimicrob Agents Chemother

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The ultrastructural alterations induced in vitro by ICI 195,739, a recently developed bis-triazole derivative with potent antiproliferative effects on Trypanosoma (Schizotrypanum) cruzi, are reported. On epimastigotes, the triazole at its minimum growth-inhibitory concentration (0.1 ,uM) produced immediately (within 24 h) gross alterations in the organization of chromatin and the appearance of large electron-dense granules; at this time, many cells were binucleated, indicating a blockade in cytokinesis. At later times (120 h), mitochondrial swelling, a characteristic effect reported previously for the dioxolane-imidazole ketoconazole when the preformed ergosterol pool is depleted, was the predominant effect and led to cell lysis. In amastigotes proliferating in Vero cells, the drug at 10 nM produced mitochondrial swelling, autophagic vacuoles, and massive alterations of the plasma membrane, leading to complete parasite destruction after 96 h of incubation of the infected monolayers with the drug. The results support previous conclusions that ICI 195,739 has a dual mechanism of action against T. cruzi, involving blockade of ergosterol biosynthesis and a direct effect on cell division which cannot be reversed by addition of exogenous ergosterol.We have recently been involved in the study of the biochemical, biophysical, and ultrastructural basis of the antiproliferative effects of ergosterol biosynthesis inhibitors on Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease (18,31,33). We have shown that ketoconazole, a dioxolane-imidazole derivative with potent antifungal and antiprotozoal activity which acts by inhibiting ergosterol biosynthesis at the level of the cytochrome P-450-dependent demethylation of lanosterol (2, 4-7, 14, 16, 18, 20, 22, 23, 25, 30-36), induces cell lysis in T. cruzi not as a consequence of accumulation of the di-and trimethylated precursors of the sterol but as a result of depletion of the preformed ergosterol pool, which leads to irreversible alteration of the plasma membrane and the kinetoplast-mitochondrion complex (19,31,33). Parallel studies with terbinafine, an allylamine derivative (24,(26)(27)(28), indicated that this drug affects the growth of T. cruzi, probably via the accumulation of a toxic metabolite, and potentiates the action of ketoconazole (19,31).Compared with the imidazole compounds, triazole derivatives such as fluconazole and itraconazole have shown superior activity against T. cruzi (13, 21) and the related protozoan parasites of the genus Leishmania (3,8,15). Of particular interest is the recent report of a novel bis-triazole derivative, ICI 195,739, with potent antifungal and antiprotozoal effects, particularly against T. cruzi (1, 9, 29). In a parallel study (32), we have shown that ICI 195,739 is 300 times more potent than ketoconazole against the epimastigote (culture) form but has comparable activity against the (intracellular) amastigote stage. We also found that the drug has a dual mechanism of action, involving blockade of ergosterol...

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confidence: 83%

Ultrastructural alterations induced by ICI 195,739, a bis-triazole derivative with strong antiproliferative action against Trypanosoma (Schizotrypanum) cruzi

Lazardi

Urbina

Souza

1991

Antimicrob Agents Chemother

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“…D0870 ( Fig. 1) is the R-enantiomer of IC1195,739, which has excellent in vitro and in vivo antifungal activities (4,16). In this study, we found that the potent activity of ICI195,739 is attributable to D0870 and evaluated in vitro and in vivo activities of D0870 in comparison with those of FCZ and other antifungal agents.…”

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confidence: 91%

“…D0870 (Fig. 1) is the R-enantiomer of IC1195,739, which has excellent in vitro and in vivo antifungal activities (4,16 In vitro antifungal activity. MICs and minimum antibiotic concentrations (MACs) were determined by the twofold agar dilution method with synthetic amino acid medium (fungal) …”

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confidence: 99%

In vitro and in vivo antifungal activities of D0870, a new triazole agent

Yamada

Tsuda

Watanabe

et al. 1993

Antimicrob Agents Chemother

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In vitro and in vivo antifungal activities of D0870 were evaluated in comparison with those of fluconazole. D0870, which is the R-enantiomer of IC1195,739, was found to be the mycologically active enantiomer by comparing the activities of D0870 with those of M16355 (S-enantiomer of IC1195,739). D0870 showed a broad spectrum of antifungal activity and MICs and minimum antibiotic concentrations 4-to 2,000-fold lower in synthetic amino acid medium (fungal) agar than those of fluconazole for various fungi. Although MICs of D0870 were affected by variation of the test conditions, such as type of medium, inoculum size of fungi, supplementation with fetal bovine serum, and pH of medium, they were consistently much lower than those of fluconazole under any condition. In vivo activities of D0870 in the systemic infection models with Candida albicans, Cryptococcus neoformans, and Aspergillus fiumigatus in normal mice and in the mice immunosuppressed with cyclophosphamide or cortisone acetate were 2-to 7-fold and 3-to 89-fold greater than those of fluconazole, respectively. In these infection models in immunosuppressed mice, the therapeutic efficacy of D0870 was almost equivalent to that in normal mice, whereas the efficacy of fluconazole was 2-to 50-fold lower than that in normal mice.It has been reported that the recent rise in the number of patients with systemic fungal infections closely relates to therapy using immunosuppressive or anticancer agents (6, 7). These kinds of agents reportedly cause the destruction of the cellular or humoral host defense system, and that destruction inevitably raises the frequency of opportunistic infections caused by fungi such as Candida, Aspergillus, or Cryptococcus species. Under these circumstances, the need for potent systemic antifungal agents has been increasing recently. Six systemic antifungal agents, amphotericin B (AMPH), flucytosine, miconazole (MCZ), ketoconazole, fluconazole (FCZ), and itraconazole, have been developed so far for clinical use. However, the clinical values of these agents have been limited primarily by their relatively high risks of toxicity, emergence of drug resistance, pharmacokinetic deficiencies, and/or insufficiency of their antifungal activities (7,8,14). Thus, much effort still has been made to develop novel potent antifungal agents which are safe and systemically effective against various deep-seated mycoses. D0870 (Fig. 1) is the R-enantiomer of IC1195,739, which has excellent in vitro and in vivo antifungal activities (4,16 In vitro antifungal activity. MICs and minimum antibiotic concentrations (MACs) were determined by the twofold agar dilution method with synthetic amino acid medium (fungal)

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“…In the past few years, SAR of antifungal triazoles has been extensively studied [26,27]. Therefore, current research efforts are mainly focused on optimisation of the side chain attached to the pharmacophore.…”

Section: Pharmacological Significance Of Triazole Scaffoldmentioning

confidence: 99%

“…Recently, Lindstedt et al studied the therapeutic effects of 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1-H-1,2,4-triazole (ST1959) (27) in the treatment of autoimmune diseases. The evidence obtained in this study indicates that the beneficial effects exerted by (ST1959) rely upon a decrease in human T cell proliferation and inhibition of cytokine expression at the transcriptional level.…”

Section: Immunomodulatory Activitymentioning

confidence: 99%