Abstract
The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the Schistosoma genus and infects approximately 200 million people worldwide. With just one partially effective drug available for disease treatment, new drugs are urgently needed. Herein, a series of 47 phthalimide (Pht) analogues possessing high-value bioactive scaffolds (i.e., benzimidazole and 1,2,3,-triazoles) was synthesized by click-chemistry. Compounds were evaluated for anti-schistosomal activity in culture against somules (post-infective larvae) and adults of Schistosoma mansoni, their predicted ADME (absorption, distribution, metabolism, and excretion) properties, and toxicity vs. HepG2 cells. The majority showed favorable parameters for surface area, lipophilicity, bioavailability and Lipinski score. Thirteen compounds were active at 10 µM against both somules and adults (6d, 6f, 6i–6l, 6n–6p, 6s, 6r’, 6t’ and 6w). Against somules, the majority caused degeneracy and/or death after 72 h; whereas against adult parasites, five compounds (6l, 6d, 6f, 6r’ and 6s) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing n-butyl or isobutyl as a linker, and a pentafluorophenyl group on triazole. Apart from five compounds for which anti-parasite activity tracked with toxicity to HepG2 cells, there was apparently no toxicity to HepG2 cells (EC50 values ≥50 µM). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals.
Highlights
Schistosomiasis, known as bilharzia, is a parasitic disease that infects approximately 200 million people and is caused by trematode flatworms of the genus Schistosoma [1]
We have shown that Pht analogues embedded with benzimidazole and flexible triazoles are potent agents against Plasmodium falciparum (Pf 3D7) and Pf W2 malaria strains with 50% inhibitory concentration (IC50 ) values of ~0.7 μM [34]
The approach was inspired by our recent results that describe a synergistic association of Pht, benzimidazole and triazoles with antiplasmodial activity at submicromolar concentrations [34]
Summary
Schistosomiasis, known as bilharzia, is a parasitic disease that infects approximately 200 million people and is caused by trematode flatworms of the genus Schistosoma [1]. The hundreds of eggs produced daily by mated pairs elicit a chronic and morbid immuno-inflammatory and fibrotic pathogenesis that can result in pain, malaise and a decreased ability to work [2,3,4,5,6,7]. There are two main forms of schistosomiasis, urinary schistosomiasis [12,13,14] and intestinal schistosomiasis [15,16,17,18] The former (caused by S. haematobium) mainly affects the bladder, kidneys and urogenital system, whereas the latter (due to S. mansoni and S. japonicum) causes intestinal damage, and hypertension of the abdominal blood vessels, spleen and liver [5,19]
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