The schistosome enzyme that activates oxamniquine has the characteristics of a sulfotransferase

Pica‐Mattoccia, Livia; Carlini, Daniele; Гуиди, Алессандра; Cimica, Velasco; Vigorosi, Fabio; Cioli, Donato

doi:10.1590/s0074-02762006000900048

Cited by 43 publications

(45 citation statements)

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“…Als Oxamniquin-aktivierendes Enzym wurde eine schistosomale Sulfotransferase identifiziert. [133,134] Hycanthon und Lucanthon interkalieren in die DNABasenpaare, was ihre Mutagenität erklärt. Oxamniquin hingegen fehlt das Dreiringsystem und interkaliert deshalb nicht.…”

Section: Myrazid Benzodiazepine Cyclosporin a Uswunclassified

Chemotherapie gegen Schistosomiasis

et al. 2013

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Schistosomiasis (Bilharziose) ist nach Malaria die zweithäufigste Krankheit in Afrika. Schätzungsweise 600 Millionen Menschen in über 70 Ländern in den Tropen und Subtropen haben ein hohes Ansteckungsrisiko mit mindestens 200 000 Todesfällen aus 200 Millionen Infizierten pro Jahr. Der Übertragungsweg sämtlicher Schistosoma‐Arten ist der direkte Kontakt mit der in Süßwasser frei schwimmenden Form des Parasiten, den in Schnecken heranwachsenden Zerkarien. In den Blutgefäßen des Wirts versorgen sich die Schistosoma‐Larven und adulte Schistosomen durch den Verdau von roten Blutkörperchen mit Aminosäuren. Impfungen gegen Schistosomiasis waren bislang nicht erfolgreich, und zur Eindämmung der Krankheit existiert zurzeit nur ein einziger Arzneistoff, das seit über 35 Jahren im Einsatz befindliche Praziquantel. Neuerdings kommen zudem Bedenken über ein mögliches Nachlassen der Wirksamkeit der Substanz auf. Deshalb müssen unbedingt neue und sichere antischistosomale Arzneistoffe entwickelt werden, die in Zweifachtherapien zusammen mit Praziquantel eingesetzt werden.

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Section: Myrazid Benzodiazepine Cyclosporin a Uswunclassified

Chemotherapie gegen Schistosomiasis

et al. 2013

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“…It has been suggested that the drug is activated through esterification by a schistosome enzyme, and then the ester dissociates spontaneously while the resulting electrophilic reactant ion is capable of alkylation of the schistosome DNA (Cioli et al 1995). Pica-Mattoccia et al (2006) reported that oxamniquine has to be activated by a parasite enzyme with sulfotransferase characteristics, and that resistant strains lack the enzyme. In experimental animal models, it was found that oxamniquine causes a shift of the worms from the mesenteric veins to the liver where the male and the female decouple.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Current chemotherapy arsenal for schistosomiasis mansoni: alternatives and challenges

et al. 2009

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Schistosomiasis still represents a major health problem in many tropical and subtropical countries despite continuing control efforts. Due to the unavailability of a vaccine that is practically applicable to humans, the use of chemotherapy is the mainstay of schistosomiasis-associated morbidity control. This paper attempts to review the antischistosomal drugs currently used in the treatment of intestinal schistosomiasis caused by Schistosoma mansoni. Their antischistosomal properties, advantages, and disadvantages as well as issues regarding the evidence for drug resistance and combination studies are reviewed in a simple manner. The recent trends towards the identification of specific chemotherapeutic targets for the treatment of schistosomes are also discussed briefly.

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“…Oxamniquine is a pro-drug that is activated by a Schistosoma sulfotransferase enzyme (Pica-Mattoccia et al, 2006). It is only clinically useful against S. mansoni infections (Caffrey, 2007;Axton, Garnett, 1976).…”

Section: Introductionmentioning

confidence: 99%

“…These compounds would be active per se, without the requirement for sulfotransferase activation, as proposed in Figure 4. Evidence suggests that oxamniquine-resistant schistosomes do not express the enzyme sulfotransferase and therefore cannot convert the oxamniquine into its active form (Valentim et al, 2013;Pica-Mattoccia et al, 2006). Therefore, compounds that are active per se could be an alternative in the treatment of oxamniquineresistant S. mansoni infections.…”

Section: Introductionmentioning

confidence: 99%

“…It is active against all schistosome species and is safe and inexpensive. However, concerns over the possible development of resistance to praziquantel due to its large-scale use, motivates the search of new anti-schistosomal agents (Wang, Wang, Liang, 2012;Caffrey, 2015).Oxamniquine is a pro-drug that is activated by a Schistosoma sulfotransferase enzyme (Pica-Mattoccia et al, 2006). It is only clinically useful against S. mansoni infections (Caffrey, 2007;Axton, Garnett, 1976).…”

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Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Lopes

Suzuki

Pereira

et al. 2018

Braz. J. Pharm. Sci.

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In the search for new anti-schistosomal agents, a series of fifteen ortho-nitrobenzyl derivatives was assayed in vitro against both the schistosomulum (somule) and adult forms of Schistosoma mansoni. Compounds 8 and 12 showed significant activity against somules at low micromolar concentrations, but none was active against adults. The SAR demonstrated that the compounds most active against the parasite were mutagenic to the human cell line RKO-AS45-1 only at concentrations 10-to 40-fold higher than the worm-killing dose. Given their electrophilicity, compounds were also screened as inhibitors of the S. mansoni cysteine protease (cathepsin B1) in vitro. Amides 5 and 15 exhibited a modest inhibition activity with values of 55.7 and 50.6 % at 100 µM, respectively. The nitrobenzyl compounds evaluated in this work can be regarded as hits in the search for more active and safe anti-schistosomal agents.Keywords: Nitro-aromatic. Schistosoma mansoni/ anti-schistosomal activity. Cathepsin B1. Mutagenicity INTRODUCTIONSchistosomiasis is a neglected tropical disease caused by a flatworm of the genus Schistosoma. The major species involved are S. haematobium, which causes the urogenital form of the disease, and S. mansoni and S. japonicum, which are responsible for the intestinal disease (Colley et al., 2014). An estimated 240 million people worldwide are infected by Schistosoma parasites and more than 700 million live in endemic areas (WHO, 2016a).Praziquantel, a pyrazino-isoquinoline derivative (Figure 1), is registered as an essential medicine by the World Health Organization (WHO, 2016b) and is the first choice therapy for schistosomiasis. It is active against all schistosome species and is safe and inexpensive. However, concerns over the possible development of resistance to praziquantel due to its large-scale use, motivates the search of new anti-schistosomal agents (Wang, Wang, Liang, 2012;Caffrey, 2015).Oxamniquine is a pro-drug that is activated by a Schistosoma sulfotransferase enzyme (Pica-Mattoccia et al., 2006). It is only clinically useful against S. mansoni infections (Caffrey, 2007;Axton, Garnett, 1976). The activated derivative is a nitro-aromatic compound that displays a good leaving group (sulfate) at the benzylic position. This product dissociates forming an electrophilic agent, which alkylates the parasite DNA (Abdul-Ghani et al., 2009) (Figure 2). Nitro-aromatic compounds, such as fexinidazole, benznidazole, and niclosamide, (Figure 3) are known for their pharmacological potential and our group has investigated the biological activities of a series of orthonitrobenzyl derivatives that act as alkylating agents (Lopes et al., 2015;Lopes et al., 2011;Soares et al., 2010).Based on the need for new anti-schistosomal agents, we evaluated the schistosomicidal activity of nitro-aromatic compounds, analogs of "activated" oxamniquine, against S. mansoni in vitro. These compounds would be active per se, without the requirement for sulfotransferase activation, as proposed in Figure 4. Evidence suggests that oxamni...

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The schistosome enzyme that activates oxamniquine has the characteristics of a sulfotransferase

Cited by 43 publications

References 20 publications

Chemotherapie gegen Schistosomiasis

Chemotherapie gegen Schistosomiasis

Current chemotherapy arsenal for schistosomiasis mansoni: alternatives and challenges

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

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