Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity

Abstract

Novel hydroxynaphthoquinones are reported with outstanding efficacy against Plasmodium, Eimeria and Theileria species. Biochemical evidence is presented for the selective toxicity of these compounds being due to inhibition of parasite respiratory systems.

Constitutive PI3-K activity is essential for proliferation, but not survival, of Theileria parva-transformed B cells

“…The B-cell characteristics of this line grown in our laboratory have been confirmed recently (Moreau et al, 1999), and its cultivation has been described previously (Chaussepied et al, 1998). To eliminate the parasite, the hydroxynaphthoquinone derivative BW720 (Hudson et al, 1985) was added at 30 ng ml 21 . BW720c treatment was performed for 48±72 h, and cell viability was routinely tested by trypan blue exclusion (BW720c-treated cells are also referred to in this text as cured').…”

“…The macroschizont induces its host leucocyte to proliferate, and the transformation process both propagates the parasite and clonally expands the host cell population, with often fatal consequences for the infected animal (reviewed by Chaussepied and Langsley, 1996). Unusually for a transformed cell, the phenotype can be reversed as, upon drug-induced parasite death, the leucocyte either returns to a quiescent state, or dies (Hudson et al, 1985). Theileria-transformed leucocytes can be grown continuously in vitro without the addition of any exogenous growth factors, and form metastatic tumours when injected into scid mice (Fell et al, 1990).…”

<i>In-vivo</i> Therapeutic Efficacy Trial with Artemisinin Derivative, Buparvaquone and Imidocarb Dipropionate against <i>Babesia equi</i> Infection in Donkeys

“…It is difficult to explain the mechanism of this synergism (arteether and buparvaquone) in the present study. Buparvaquone acts selectively against the parasite's electron transport system at ubiquinone-cytochrome c reductase of the respiratory chain [14,11] while artemisinin-type compounds are found to block heme polymerization, causing a buildup of monomeric free heme toxic to the parasite [23]. Hence the combination might have worked well to suppress the increasing parasitaemia.…”

Parasite-mediated nuclear factor κB regulation in lymphoproliferation caused byTheileria parva infection

“…These transformed cells, primarily T cells, disseminate to lymphoid and nonlymphoid tissues, including the lung, kidney, and, intestine, where they mimic the behavior of lymphoid tumors (10,11). Remarkably unlike true lymphomas, T. parva-induced transformation can be reversed by killing the parasite (9,(10)(11)(12). This drug-induced reversal to normal lymphocyte regulation indicates that T. parva alone is sufficient and responsible for transformation.…”

“…This autocrine growth is, at least partially, attributable to parasite-induced expression of both interleukin 2 (IL-2) and the ␣-chain of the IL-2 receptor (IL-2R␣) (9,(13)(14)(15)(16). Treatment with the theilericidal drug BW720c (a protozoal-specific hydronaphthoquinone) results in down-regulation of IL-2 and IL-2R␣ expression and restoration of growth factor dependence (9,12). Both IL-2 and IL-2R␣ are transcriptionally regulated by cis-acting B enhancer elements that are, in turn, controlled by dimeric complexes of the NFB family of transcription factors (17,18).…”