Carboxylic acid and phosphate ester derivatives of fluconazole: Synthesis and antifungal activities

Nguyen Hai Nam, Soroush Sardari, Meredith Selecky, Keykavous Parang

Research output: Contribution to journalArticle

Abstract

Carboxylic acid and phosphate ester derivatives of fluconazole were synthesized and evaluated in vitro against Cryptococcus neoformans, Candida albicans, and Aspergillus niger. Two classes of fluconazole derivatives, (a) carboxylic acid esters and (b) fatty alcohol and carbohydrate phosphate esters, were synthesized and evaluated in vitro against Cryptococcus neoformans, Candida albicans, and Aspergillus niger. All carboxylic acid ester derivatives of fluconazole (1a-l), such as O-2-bromooctanoylfluconazole (1g, MIC = 111 μg/mL) and O-11-bromoundecanoylfluconazole (1j, MIC = 198 μg/mL), exhibited higher antifungal activity than fluconazole (MIC ≥ 4444 μg/mL) against C. albicans ATCC 14053 in SDB medium. Several fatty alcohol phosphate triester derivatives of fluconazole, such as 2a, 2b, 2f, 2g, and 2h, exhibited enhanced antifungal activities against C. albicans and/or A. niger compared to fluconazole in SDB medium. For example, 2-cyanoethyl-ω-undecylenyl fluconazole phosphate (2b) with MIC value of 122 μg/mL had at least 36 times greater antifungal activity than fluconazole against C. albicans in SDB medium. Methyl-undecanyl fluconazole phosphate (2f) with a MIC value of 190 μg/mL was at least 3-fold more potent than fluconazole against A. niger ATCC 16404. All compounds had higher estimated lipophilicity and dermal permeability than those for fluconazole. These results demonstrate the potential of these antifungal agents for further development as sustained-release topical antifungal chemotherapeutic agents.

Original languageEnglish (US)
Pages (from-to)6255-6269
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number23
DOIs
Publication statusPublished - Dec 1 2004
Externally publishedYes

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Keywords

  • Antifungal activity
  • Carboxylic acid esters
  • Phosphate esters
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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