Design, synthesis and antifungal activity of a novel water soluble prodrug of antifungal triazole

Ohwada, Jun; Tsukazaki, Masao; Hayase, Tadakatsu; Oikawa, Nobuhiro; Isshiki, Yoshiaki; Fukuda, Hiroshi; Mizuguchi, Eisaku; Sakaitani, Masahiro; Shiratori, Yasuhiko; Yamazaki, Toshikazu; Ichihara, Shigeyasu; Umeda, Isao; Shimma, Nobuo

doi:10.1016/s0960-894x(02)00892-2

Cited by 69 publications

(41 citation statements)

References 8 publications

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“…The results of in vitro and animal model studies have shown that isavuconazole is active against Candida spp. (both fluconazole-sensitive and fluconazole-resistant strains), Aspergillus spp., Cryptococcus spp., and other molds, including the Mucorales and Scedosporium species (21)(22)(23)(24)(25)(26)(27)(28).…”

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confidence: 99%

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Cornely

Böhme²,

Schmitt‐Hoffmann

et al. 2015

Antimicrob Agents Chemother

103

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Isavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n ‫؍‬ 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n ‫؍‬ 12). The mean ؎ standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ؎ 22.3 g · h/ml and 113.1 ؎ 19.6 g · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n ‫؍‬ 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.) I nvasive fungal infections (IFIs) are associated with significant morbidity, mortality, and health care costs in patients with hematologic malignancies (1, 2). Allogeneic hematopoietic stem cell transplantation and chemotherapy-associated neutropenia place patients with acute myeloid leukemia (AML) at risk of developing an IFI (3). Aspergillus spp. and Candida spp. are the predominant IFI pathogens in patients with acute leukemia (1, 3, 4). However, other molds, such as the Mucorales, Scedosporium spp., and Fusarium spp., are emerging as pathogens in this setting and are associated with high mortality rates (1).Because IFIs are often difficult to diagnose, and delays in treatment can significantly increase the risk of mortality (5, 6), antifungal prophylaxis has become a commonly used strategy in patients at high risk of IFIs (7, 8). Fluconazole, itraconazole, posaconazole, voriconazole, and micafungin are recommended for prophylactic use in patients with hematologic malignancies (9, 10). Although the results of randomized clinical trials support the prophylactic benefits of these agents (7,8,11), each may be limited in their use: fluconazole has no activity against molds (12); posaconazole demonstrates broad-spectrum activity against both yeasts and mo...

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confidence: 99%

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Cornely

Böhme²,

Schmitt‐Hoffmann

et al. 2015

Antimicrob Agents Chemother

103

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“…It is known that water-soluble prodrugs can be readily accessed by alkylating a triazole ring with halomethyl acetate derivatives to give a quaternary ammonium salt prodrug. 12,14,18) Phosphonooxymethy ether of ravuconazole has also been reported 13) (Fig. 1).…”

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confidence: 73%

“…[7][8][9][10] There have been some efforts to overcome this problem by using a prodrug approach. [11][12][13][14] Previously, we identified CS-758 [15][16][17] which has a broad antifungal spectrum covering Aspergillus spp., FLCZ-resistant Candida spp. and has a good safety profile, including low drug-drug interaction.…”

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confidence: 99%

Design, Synthesis and Antifungal Activity of the Novel Water-Soluble Prodrug of Antifungal Triazole CS-758

et al. 2010

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CS-758 was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, phosphoryl ester prodrugs were designed. In this study, the synthesis and evaluation of these injectable prodrugs are described. Phosphoryl ester 17h was soluble in water, and was stable in both water and in a solid state. 17h was converted to CS-758 in human liver microsome and was also converted to CS-758 in rats after intravenous (i.v.) administration with good conversion speed and efficiency. 17h (i.v.) reduced the viable cell counts in kidneys in a murine hematogenous Candida albicans infection model and in lungs in a murine pulmonary Aspergillus fumigatus infection model, wherein the effects were comparable to or slightly superior to that of CS-758 (per os).

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“…So far, however, triazolium derivatives as antimicrobial agents have been reported rather seldom. Some reports in literature showed that the introduction of a positive charge group in the triazole derivatives is helpful to increase the water solubility and membrane permeability [13,14], which could result in the enhancement of biological activities. Very recently, it was reported in the literature that 2-hydroxyphenacyl triazolium derivatives (2a -2f, Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antibacterial and Antifungal Activities of Novel 1,2,4‐Triazolium Derivatives

Luo

Gan

et al. 2009

Archiv der Pharmazie

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A series of novel 1,2,4-triazolium derivatives was synthesized starting from commercially available 1H-1,2,4-triazole, 2,4-dichlorobenzyl chloride, or 2,4-difluorobenzyl bromide. Their antibacterial and antifungal activities were evaluated against Staphylococcus aureus ATCC 29213, Escherichia coli ATCC 25922, Bacillus proteus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans ATCC 76615, and Aspergillus fumigatus. All structures of the new compounds were confirmed by NMR, IR, and MS spectra, and elemental analyses. The antimicrobial tests showed that most of synthesized triazolium derivatives exhibit significant antibacterial and antifungal activities in vitro. 1-(2,4-Difluorobenzyl)-4-dodecyl-1H-1,2,4-triazol-4-ium bromide and 1-(2,4-Dichlorobenzyl)-4-dodecyl-1H-1,2,4- triazol-4-ium bromide were the most potent compounds against all tested strains with the MIC values ranging from 1.05 to 8.38 microM. They exhibited much stronger activities than the standard drugs chloramphenicol and fluconazole which are in clinical use. The results also showed that the antimicrobial activities of triazolium derivatives depend upon the type of substituent, the length of the alkyl chain, and the number of triazolium rings.

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Design, synthesis and antifungal activity of a novel water soluble prodrug of antifungal triazole

Cited by 69 publications

References 8 publications

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Safety and Pharmacokinetics of Isavuconazole as Antifungal Prophylaxis in Acute Myeloid Leukemia Patients with Neutropenia: Results of a Phase 2, Dose Escalation Study

Design, Synthesis and Antifungal Activity of the Novel Water-Soluble Prodrug of Antifungal Triazole CS-758

Synthesis, Antibacterial and Antifungal Activities of Novel 1,2,4‐Triazolium Derivatives

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