Studies on Parasitologic and Haematologic Activities of an Enaminone Derivative of 4-Hydroxyquinolin-2(1H)-one Against Murine Schistosomiasis Mansoni

Amal M. El–Shennawy, MD; Amira H. Mohamed, MD; Mohamed Abass, MD

Disclosures
In This Article

Introduction

It is estimated that about 200 million people worldwide are currently affected by schistosomiasis, a disease caused by flatworms belonging to the genus Schistosoma. The disease is usually chronic and debilitating, with severe consequences to the urinary tract when S hematobium is the organism involved and major damage to the liver and intestine when S mansoni or S japoniciun is involved. Only 3 drugs are in current use (metrifonate, oxamniquine, and praziquantel [PZQ]), and PZQ may be the only one destined to remain on the market. To be left with only 1 drug easily available against schistosomiasis is clearly a very dangerous situation, especially in view of the very recent report on PZQ–resistant schistosomes. This would not be surprising in countries like Egypt, where the drug has been used aggressively for more than 10 years. In addition, PZQ does not prevent reinfection and sometimes even enhances the rate of reinfection, especially in young adults.[1] Moreover, PZQ is not ovicidal, nor is it effective against young stages of the parasite.[2] Because of phenomena such as the development of resistance, it remains an urgent necessity to find new compounds that show particularly good efficacy against schistosomiasis.

Th cell subsets originate from CD4+ T cell precursors and are defined by the cytokines they produce.[3] These subsets have been shown to play a central role in the control and regulation of many immune responses, including those directed against parasitic infections such as Leishmania major and Schistosoma mansoni. In murine models of S mansoni infection, a well–defined Th subset dichotomy has been reported in which T helper 1 (Th1) produces interferon gamma (IFN–gamma) and tumor necrosis factor–alpha (TNF–alpha), which activate macrophages as part of a delayed type hypersensitivity reaction. The reaction was reported to provide protection against S mansoni infection in mice.[4] Th2 lymphocytes are known to produce IL–4, IL–5, IL–10, and IL–13, which are essential for the production by B cells of IgE, IgG1, IgA, and IgM antibody isotypes and eosinophil and mast cell activation. Th2–type cells are believed to be essential in human protection against schistosome infections but have been shown to play a role in pathology, which accompanies the deposition of eggs in the tissues of S mansoni–infected mice.[5] A series of immunoepidemiologic studies involving the follow–up of drug–cured S mansoni and S haematobium patients who subsequently became reinfected has shown that a proportion of these subjects acquire partial immunity to reinfection, and that this immunity appears to be dependent upon specific IgE antibodies.[6]

Recently, a series of novel synthesized enaminones, derived from 3–(un)substituted 4–hydroxyquinolin–2(1H)–ones, were assayed for their molluscicidal activities against Biomphalaria alexandrina and Lymnaea natalensis snails. From this series, 1–butyl–3–[2 ethyl–3–(dimethylamino) propyl–2–enoyl]–4–hydroxyquinolin–2(1H)–one (BDHQ) showed more potency against hatchability of B alexandrina egg masses, the infection rate, and the prepatent period of the snails. In addition, this derivative revealed potential larvicidal effects (100% mortality) on both miracidia and cercariae of S mansoni with reduced exposure time. This active derivative was also examined against Daphnia magna, and their nontoxic effect at LD/50 suggests that this compound is environmentally safe and can play important roles as molluscicides and larvicides.[7] BDHQ can thus be considered to exhibit unique antischistosomal activity.

In the present study, we used electron microscopy and parasitologic study to screen the novel enaminone derivative of 4–hydroxyquinolinone, BDHQ, for its potential activity against murine schistosomiasis and correlate this study with serum levels of IFN–gamma and IgE.

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