Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: Synthesis and biological properties

Ueda, Yasutsugu; Matiskella, John D.; Golik, Jerzy; Connolly, Timothy P.; Hudyma, Thomas W.; Venkatesh, Srini; Dali, Mandar; Kang, Sang-Hyuk; Barbour, Nancy P.; Tejwani, Ravi; Varia, Sailesh A.; Knipe, Jay O.; Zheng, Ming; Mathew, Marina; Mosure, Kathy; Clark, Junius M.; Lamb, Lucinda; Medin, Ivette; Gao, Qi; Huang, Stella; Chen, Chung‐Pin; Bronson, Joanne J.

doi:10.1016/j.bmcl.2003.08.029

Cited by 54 publications

(40 citation statements)

References 10 publications

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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: 74%

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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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confidence: 74%

“…[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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“…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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“…While the ultimate goal of producing phosphonooxymethyl prodrugs of ravuconazole was attained [13], several additional promising prodrugs were also developed during the course of this research. One of these studied in detail was the phosphate ester, BMS-292655 [14,15].…”

Section: Introductionmentioning

confidence: 99%

Nonclinical pharmacokinetics of BMS‐292655, a water‐soluble prodrug of the antifungal ravuconazole

Knipe¹,

Mosure²

2008

Biopharm & Drug Disp

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The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation with liver S9 preparations from all species. The major product in rat, monkey and human S9 was BMS-207147, while in dog S9, the intermediate ester, BMS-300043, predominated. BMS-300043 itself was more stable in dog S9 than in S9 preparations from the other species. Intravenous administration of BMS-292655 to rats, beagle dogs and cynomolgus monkeys indicated species differences in the extent of formation of BMS-207147 (monkeys>rats>dogs). The lower overall generation of BMS-207147 in dogs was consistent with the presence of circulating plasma levels of BMS-300043. BMS-300043 was present in monkey plasma but not detectable in rat plasma. The conversion of BMS-292655 to BMS-207147 in the presence of human S9 indicated the potential for BMS-292655 to function as a BMS-207147 prodrug in humans. The similarity in the hydrolysis of BMS-292655 when incubated with human and monkey S9 in vitro, coupled with the effective release of BMS-207147 from BMS-292655 upon i.v. administration to monkeys, is consistent with this conclusion.

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Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: Synthesis and biological properties

Cited by 54 publications

References 10 publications

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

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

Nonclinical pharmacokinetics of BMS‐292655, a water‐soluble prodrug of the antifungal ravuconazole

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