Water-soluble
phosphate prodrugs of
buparvaquone (1), containing a hydroxynaphthoquinone structure, were synthesized and evaluated in vitro for improved topical and oral
drug delivery against cutaneous and
visceral leishmaniasis. The successful
prodrug synthesis involved a strong base; e.g.,
sodium hydride.
Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethyl-buparvaquone (4b)
prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent
drug (</=0.03 microg/mL) over a pH range of 3.0-7.4. Moreover, 4a and 4b maintained adequate lipophilicity as indicated by distribution coefficients (log D) between 0.5 and 3.0 over this pH range. Both 4a and 4b were also shown to be substrates for
alkaline phosphatase in vitro and thus are promising bioreversible
prodrugs for the improved topical and oral bioavailability of 1.
Buparvaquone and its
prodrugs showed nanomolar or low-micromolar ED(50) activity values against species that cause
cutaneous leishmaniasis, e.g., L. major, L. amazonensis, L. aethiopica, L. mexicana, and L. panamensis and also L. donovani, which is the causative agent of
visceral leishmaniasis. From these results, the human skin permeation of the
prodrugs 4a and 4b were studied in vitro. While no
buparvaquone permeated across post mortem skin in vitro during 72 h of experiments, both
prodrugs 4a and 4b permeated readily through the skin. In addition, 4b easily released the parent
drug in human skin homogenate and, therefore, is a promising
prodrug candidate to deliver
buparvaquone through the skin for the treatment of
cutaneous leishmaniasis.