Ortho-nitrobenzyl derivatives as potential anti-schistosomal agents

Abstract

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...

Druggable Hot Spots in the Schistosomiasis Cathepsin B1 Target Identified by Functional and Binding Mode Analysis of Potent Vinyl Sulfone Inhibitors

“…SmCB1 is a critical digestive peptidase in the gut of the flatworm parasite S. mansoni ,, and a target for antischistosomal drugs. , Peptidomimetic protease inhibitors with a vinyl sulfone warhead are potent SmCB1 binders and antischistosomals with superior functional properties compared to other tested inhibitor chemotypes. , In this study, we provide the first structural characterization of inhibitors effective against SmCB1 in a subnanomolar range and identify the hot spots underpinning that potency.…”