Synthesis and Bioactivity of Phthalimide Analogs as Potential Drugs to Treat Schistosomiasis, a Neglected Disease of Poverty

• Main Authors: Snigdha Singh (Author), Nelly El-Sakkary (Author), Danielle E. Skinner (Author), Prem Prakash Sharma (Author), Sabine Ottilie (Author), Yevgeniya Antonova-Koch (Author), Prashant Kumar (Author), Elizabeth Winzeler (Author), Poonam (Author), Conor R. Caffrey (Author), Brijesh Rathi (Author)
• Format: Book
• Published: MDPI AG, 2020-02-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1424-8247; 10.3390/ph13020025
• Keywords: phthalimide; benzimidazole; <i>schistosoma</i>; click chemistry; anti-schistosomal activity; tropical disease; drug discovery; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 13, Iss 2, p 25 (2020)

The neglected tropical disease, schistosomiasis, is caused by trematode blood flukes of the <i>Schistosoma</i> 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 <i>Schistosoma mansoni,</i> 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 &#181;M against both somules and adults (<b>6d</b>, <b>6f</b>, <b>6i</b>&#8722;<b>6l</b>, <b>6n</b>&#8722;<b>6p</b>, <b>6s</b>, <b>6r&#8217;</b>, <b>6t&#8217;</b> and <b>6w</b>). Against somules, the majority caused degeneracy and/or death after 72 h; whereas against adult parasites, five compounds (<b>6l</b>, <b>6d</b>, <b>6f</b>, <b>6r&#8217;</b> and <b>6s</b>) elicited degeneracy, tegumental (surface) damage and/or death. Strongest potency against both developmental stages was recorded for compounds possessing <i>n</i>-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 &#8805;50 &#181;M). The data overall suggest that phthaloyl-triazole compounds are favorable synthons for additional studies as anti-schistosomals.