Planta Med 2013; 79 - PC8
DOI: 10.1055/s-0033-1348564

Synthesis and Antifungal Activities of Miltefosine Analogs

RR Ravu 1, YL Chen 2, MR Jacob 1, X Pan 3, AK Agarwal 1, SI Khan 1, 4, J Heitman 2, AM Clark 1, 4, XC Li 1, 4
  • 1National Center for Natural Product Research, Research Institute of Pharmaceutical Sciences, The University of Mississippi, MS 38677, USA
  • 2Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA
  • 3Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA
  • 4Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, MS 38677, USA

Miltefosine is an alkylphosphocholine that shows broad-spectrum in vitro antifungal activities and limited in vivo efficacy in mouse models of cryptococcosis. To further explore the potential of this class of compounds for the treatment of systemic mycoses, nine analogs (3a-3i) were synthesized by modifying the choline structural moiety and the alkyl chain length of miltefosine. In vitro testing of these compounds against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans revealed that 2-(benzyldimethylammonio)ethyl hexadecyl phosphate (3a), 2-(dimethyl(4-nitrobenzyl)ammonio)ethyl hexadecyl phosphate (3d), and 2-(dimethyl(4-methoxybenzyl)ammonio) ethyl hexadecyl phosphate (3e) exhibited minimum inhibitory concentrations (MIC) of 2.5-5.0 µg/mL against all tested pathogens, when compared to miltefosine with MICs of 2.5-3.3 µg/mL. Compound 3a showed low in vitro cytotoxicities against three mammalian cell lines similar to miltefosine. In vivo testing of 3a and miltefosine against C. albicans in a mouse model of systemic infection did not demonstrate efficacy. The results of this study again raise concerns for this class of compounds as drug candidates for systemic mycoses including candidiasis.