Synthesis and antifungal activities of miltefosine analogs

Abstract

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 N-benzyl-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3a), N,N-dimethyl-N-(4-nitrobenzyl)-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (3d), and N-(4-methoxybenzyl)-N,N-dimethyl-2-{[(hexadecyloxy)hydroxyphosphinyl]oxy}ethanaminium inner salt (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 cytotoxicity 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 indicate that further investigation will be required to determine the potential usefulness of the alkylphosphocholines in the treatment of invasive fungal infections.

Miltefosine is active against Sporothrix brasiliensis isolates with in vitro low susceptibility to amphotericin B or itraconazole

“…A larger spectrum of MIC values (0.5-4 mg ml 21 ) was reported by Brilhante et al (2014) for the treatment of the mycelial form of S. brasiliensis. The MIC values for miltefosine reported here are in line with the 2 mg ml 21 value reported for the treatment of Candida albicans, Candida glabrata, Candida krusei, Crytococcus gatti, Crytococcus neoformans, Aspergillus fumigatus and Trichophyton mentagrophytes with this drug (Widmer et al, 2006;Tong et al, 2007;Ravu et al, 2013).…”

“…and Aspergillus sp. (Widmer et al, 2006;Ravu et al, 2013), and also for the mycelial form of S. schenckii complex species (Brilhante et al, 2014).…”

In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis

“…However, Wiederhold et al found that, for cryptococcal meningitis and disseminated cryptococcosis models, doses up to 45 mg/kg/day of miltefosine did not improve the survival or reduce the infectious process (48). Similarly, intraperitoneal treatment with doses up to 10 mg/kg/day of miltefosine was not effective in a murine model of disseminated candidiasis (49). These negative results may be associated with the high binding of miltefosine to plasma proteins (up to 95%) (25), reducing their systemic activity and its penetration across the blood-brain barrier.…”

In Vitro Combination of Voriconazole and Miltefosine against Clinically Relevant Molds

“…Miltefosine has been used successfully in a combination therapy with voriconazole and terbinafine against Scedosporium prolificans (13) and in a case of S. prolificans mediastinitis (14). In animal models against disseminated cryptococcosis or candidiasis, some authors found that miltefosine was effective (9), whereas others reported that it provided only limited effectiveness (15,16). The drug's potential effect against molds, either alone or in combination, has not yet been tested.…”