Author
RAVU, RANGA RAO - University Of Mississippi | |
CHEN, YING-LIEN - Duke University Medical Center | |
JACOB, MELISSA - University Of Mississippi | |
PAN, XUEWEN - University Of Mississippi | |
AGARWAL, AMEETA - University Of Mississippi | |
KHAN, SHABANA - University Of Mississippi | |
HEITMAN, JOSEPH - University Of Mississippi | |
CLARK, ALICE - University Of Mississippi | |
LI, XING-CONG - University Of Mississippi |
Submitted to: Bioorganic and Medicinal Chemistry Letters
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 6/27/2013 Publication Date: 7/6/2013 Citation: Ravu, R., Chen, Y., Jacob, M.R., Pan, X., Agarwal, A.K., Khan, S.I., Heitman, J., Clark, A.M., Li, X. 2013. Synthesis and antifungal activities of miltefosine analogs. Bioorganic and Medicinal Chemistry Letters. 23:4828-4831. Interpretive Summary: This manuscript describes the synthesis and antifungal activities of alkylphosphocholine derivatives. Three compounds showed potent in vitro antifungal activities against several opportunistic fungal pathogens. Technical Abstract: Nine alkylphosphocholine derivatives (3a-3i) were prepared by modifying the choline structural moiety and the alkyl chain length of miltefosine (hexadecylphosphocholine), a broad-spectrum antifungal compound that has shown modest therapeutic efficacy in a mouse model of cryptococcosis. The synthetic compounds were tested for in vitro activities against the opportunistic fungal pathogens Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus, and Cryptococcus neoformans. Three compounds, 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) showed minimum inhibitory concentrations of 2.5 to 5.0 mcg/mL against all tested pathogens, comparable to miltefosine and amphotericin B. Despite potent in vitro activities, miltefosine and 3a did not exhibit in vivo efficacy against C. albicans in a mouse model of systemic infection. |