Synthesis, in vitro evaluation, and antileishmanial activity of water-soluble prodrugs of buparvaquone.
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.
Mäntylä
Antti
A
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box, 1627, FIN-70211 Kuopio, Finland. Antti.Mantyla@uku.fi
Garnier
Tracy
T
Rautio
Jarkko
J
Nevalainen
Tapio
T
Vepsälainen
Jouko
J
Koskinen
Ari
A
Croft
Simon L
SL
Järvinen
Tomi
T
D000284:Administration, Oral; D000287:Administration, Topical; D000469:Alkaline Phosphatase / Q000737:chemistry; D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D005260:Female; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007891:Leishmania / Q000187:drug effects* / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000469:parasitology; D007898:Leishmaniasis, Visceral / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012867:Skin / Q000378:metabolism; D012995:Solubility; D014867:Water
C481786:3-phosphonooxymethylbuparvaquone; D000981:Antiprotozoal Agents; D009285:Naphthoquinones; D010755:Organophosphates; D011355:Prodrugs; C481785:buparvaquone-3-phosphate; C046326:buparvaquone; D014867:Water; D000469:Alkaline Phosphatase