In vitro antileishmanial properties of tri- and pentavalent antimonial preparations

TLDR

To better understand the antileishmanial effects of antimonial agents, we synthesized complexes of tri‑ and pentavalent antimony with mannan. The study measured IC₅₀ values of these complexes and reference antimonials against promastigotes and intramacrophage amastigotes. Trivalent antimonials were markedly more potent than pentavalent ones, with IC₅₀s 60‑to‑600‑fold higher for promastigotes than amastigotes, yet intracellular antimony levels were comparable; macrophages accumulated and retained antimony, acting as a reservoir that increased parasite exposure over time, while N‑acetylcysteine antagonized the effects of the trivalent and pentavalent complexes but not sodium stibogluconate.

Abstract

To better understand the antileishmanial effects of antimonial agents we synthesized complexes of tri- and pentavalent antimony with mannan. The 50% inhibitory concentrations (IC50s) of these agents, along with those of potassium antimony tartrate [Sb(III)] and sodium stibogluconate [Sb(V)], were determined for promastigotes and intramacrophage amastigotes. The trivalent antimonial agents were more potent than the pentavalent agents. Although the IC50s were 60- to more-than-600-fold higher for promastigotes than for amastigotes, similar intracellular antimony concentrations in both life forms were measured after incubation with all four drugs at their respective IC50s. Macrophages accumulated antimony during a 4-h exposure that was retained intracellularly for at least 3 days. Amastigotes inside macrophages had a higher antimony content 6 days after a single 4-h treatment than they did immediately after treatment, suggesting that macrophages serve as a reservoir for antimonial agents and prolong parasite exposure. Macrophages concentrated antimony from the medium with potassium antimony tartrate, trivalent antimony-mannan, and pentavalent antimony-mannan treatments. N-Acetylcysteine antagonized the antileishmanial effects of these three drugs against intracellular amastigotes; in contrast, it had minimal effects on the action of sodium stibogluconate.