Synthesis, in Vitro Evaluation, and Antileishmanial Activity of Water-Soluble Prodrugs of Buparvaquone

Abstract

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 successfull prodrug synthesis involved a strong base; e.g., sodium hydride. Buparvaquone-3-phosphate (4a) and 3-phosphonooxymethylbuparvaquone (4b) prodrugs possessed significantly higher aqueous solubilities (>3.5 mg/mL) than the parent drug (e0.03 µg/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 lowmicromolar 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.

Topical Treatment Modalities for Old World Cutaneous Leishmaniasis: A Review

“…Buparvaquone is a hydroxynaphthoquinone derivative which cannot diffuse through skin contrary to its prodrug formulation (Mantyla et al, 2004). Quite few reports of the treatment effect of this compound against leishmaniasis are available (Garnier et al, 2007).…”

Synthesis, molecular docking and antibacterial evaluation of new 1,4-naphthoquinone derivatives contains carbazole-6,11-dione moiety

“…The heterocyclic derivatives of -1,4-naphthoquinones have been identified that have potent biological activities towards viral [5], molluscidal [6], malarial [7], leishmanial [8], cancer [9], and bacterial and fungal diseases [10], due to their redox potentials [11].…”

Optimization and validation of RP‐HPLC‐UV method with solid‐phase extraction for determination of buparvaquone in human and rabbit plasma: application to pharmacokinetic study

“…These findings led to the synthesis of a number of watersoluble phosphate prodrugs such as BPQ-3-phosphate and 3-phosphonooxymethyl-BPQ, whose aqueous solubility is more than 3.5 mg/mL over the pH range of 3.0-7.4. These prodrugs are sufficiently stable in the gastrointestinal tract before their absorption and are rapidly hydrolyzed (t 1/2 = 1.2 and 3.8 min) to the parent compound in the presence of alkaline phosphatases (Mantyla et al, 2004b).…”