A comparative study on the genetic effects of hycanthone and oxamniquine

Ray, Verne A.; Holden, Henry E.; Ellis, J.; Hyneck, Martha L.

doi:10.1080/15287397509529323

Cited by 27 publications

(4 citation statements)

References 26 publications

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“…Furthermore, the alterations of the NDI observed to the compounds 8 and 12 showed that the human cells used responded to the damages induced by the compounds, probably arresting the cell cycle to promote the DNA repair. Unlike these compounds, studies indicate that the oxamniquine has low mutagenic potential (Ray et al 1975), although there are reports of its mutagenic effect when tested on Salmonella typhimurium strain TA100 (Batzinger, Bueding, 1977;Dayan, Deguingand, Truzman, 1985).…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Lopes

Suzuki

Pereira

et al. 2018

Braz. J. Pharm. Sci.

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“…Only weak embryotoxicity was detected after applying high oral doses . Studies of mutagenicity were mostly negative, occasionally weakly positive . Side effects were often described to be mild and of short duration.…”

Section: Anthelmintic Drug Therapymentioning

confidence: 99%

“…[100] Studies of mutagenicityw ere mostly negative, occasionally weakly positive. [101][102][103] Side effects were often described to be mild and of short duration.N ausea, dizziness, drowsiness, headache, abdominald iscomfort, vomiting, and diarrhea were most commonly observed. Hallucinations or seizures rarely occurred.…”

Section: Oxamniquinementioning

confidence: 99%

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

et al. 2018

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Chemotherapy based on repeated doses of praziquantel remains the most effective control strategy against schistosomiasis, a neglected tropical disease caused by platyhelminths of the genus Schistosoma spp. Its long-term use, however, raises serious concerns about drug resistance against praziquantel. Therefore, it is generally acknowledged that alternative treatment options are urgently needed. This Review summarizes data on relinquished drugs as well as recent advances in the area of antischistosomal compounds from a medicinal chemistry point of view. Furthermore, insights into the structure-activity relationships of each class of compounds are presented including in vitro and in vivo data, if available. Although many compounds have demonstrated good antischistosomal activity in vitro, they offer little promise to replace praziquantel. Nevertheless, the race to develop novel antischistosomal agents is ongoing.

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“…More than 3 million people have been treated with OX (Dr. T. Nash, National Institutes of Health; personal communication). It is positive in the Salmonella mutation assay , but it is negative in mammalian cells for SCE induction and chromosomal aberration (Ray et al, 1975), and is noncarcinogenic in animals (Haese and Bueding, 1976).…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Ames assay and the induction of sister chromatid exchanges: Results with ten pharmaceuticals and five selected agents

1986

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Seven antischistosomal drugs, two antimalarial drugs, and one antiamoebic drug were tested in all five Ames strains for induction of mutation, as well as for induction of cytotoxicity, inhibition of cellular progression, and the induction of sister chromatid exchanges in two cultured mammalian cell lines. We found that two agents shown to be negative in the Ames test were positive for sister chromatid exchange induction. Based on qualitative and quantitative evaluation, we find that all but three of the pharmaceuticals should be considered to be potential human carcinogens.

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A comparative study on the genetic effects of hycanthone and oxamniquine

Cited by 27 publications

References 26 publications

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Chemotherapy for Fighting Schistosomiasis: Past, Present and Future

Comparison of the Ames assay and the induction of sister chromatid exchanges: Results with ten pharmaceuticals and five selected agents

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