Synthesis and evaluation of the anti parasitic activity of aromatic nitro compounds

Lopes, Marcela Silva; Pietra, Renata Celi Carvalho de Souza; Borgati, Tatiane Freitas; Romeiro, Carla F.D.; Júnior, Policarpo Ademar Sales; Romanha, Álvaro J.; Alves, Ricardo José; Souza-Fagundes, Elaine M.; Fernandes, Ana Paula; Oliveira, Renata Barbosa de

doi:10.1016/j.ejmech.2011.09.002

Cited by 17 publications

(10 citation statements)

References 14 publications

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“…This method is considered the in vitro method of choice in screening drugs for activity against T. cruzi because it mimics the lifecycle of the parasite [38,39].…”

Section: Anti-t Cruzi Activity Against Amastigote and Trypomastigotementioning

confidence: 99%

Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain

Espíndola

Cardoso

Filho

et al. 2015

European Journal of Medicinal Chemistry

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The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones.

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“…This method is considered the in vitro method of choice in screening drugs for activity against T. cruzi because it mimics the lifecycle of the parasite [38,39].…”

Section: Anti-t Cruzi Activity Against Amastigote and Trypomastigotementioning

confidence: 99%

Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain

Espíndola

Cardoso

Filho

et al. 2015

European Journal of Medicinal Chemistry

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“…Starting materials 3, 4 and 7 were not commercially available and were synthesized according to reported procedures (Vlahakis et al, 2013;Soares et al, 2010;Lopes et al, 2011). Compounds 15a-c, e were prepared by a base-catalyzed hydrolysis with lithium hydroxide of the correspondent methyl ester derivatives 14a-c, e.…”

Section: Chemistrymentioning

confidence: 99%

In silico structure-based design and synthesis of novel anti-RSV compounds

et al. 2015

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Respiratory syncytial virus (RSV) is the major cause for respiratory tract disease in infants and young children. Currently, no licensed vaccine or a selective antiviral drug against RSV infections are available. Here, we describe a structure-based drug design approach that led to the synthesis of a novel series of zinc-ejecting compounds active against RSV replication. 30 compounds, sharing a common dithiocarbamate moiety, were designed and prepared to target the zinc finger motif of the M2-1 protein. A library of ∼ 12,000 small fragments was docked to explore the area surrounding the zinc ion. Among these, seven ligands were selected and used for the preparation of the new derivatives. The results reported here may help the development of a lead compound for the treatment of RSV infections.

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Section: Introductionmentioning

confidence: 99%

“…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.…”

mentioning

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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Synthesis and evaluation of the anti parasitic activity of aromatic nitro compounds

Cited by 17 publications

References 14 publications

Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain

Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain

In silico structure-based design and synthesis of novel anti-RSV compounds

Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

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