Synthesis and biological evaluation of esterified and acylated derivatives of NH2-(AEEA)5-amphotericin B

Based on NH 2 -(AEEA) 5 -amphotericin B ( DMR005 ; AEEA is 8-amino-3,6-dioxaoctanoic acid), a series of novel esterified and acylated derivatives of DMR005 were synthesized. These derivatives were evaluated for their antifungal activities using the broth dilution method, for their hemolytic toxicity with sterile defibrinated sheep blood, and for their self-association through UV–visible spectroscopy. The preliminary screening tests indicated that NH 2 -(AEEA) 5 -amphotericin B methyl ester ( DMR031 ) was an ideal compound. The results of minimum inhibitory concentration and time-kill assays showed that antifungal activities of DMR031 (4 μg ml −1 ) against Candida albicans ATCC10231 and ATCC90028 were reduced by four times compared to these of amphotericin B (AmB) (1 μg ml −1 ). DMR031 (142 ± 1 mg ml −1 ) significantly improved the water solubility of AmB as DMR005 did. Preliminary safety assessments of DMR031 were carried out via cell toxicity assay of HEK293T in vitro, which turned out to be much better than AmB. AmB had good efficacy in vivo at a dose of 1 mg ml −1 . However, DMR031 still had no efficacy in vivo even at a dose of 16 mg ml −1 , merely prolonged the survival time of mice.