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

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.

SUBMITTER: Singh S

PROVIDER: S-EPMC7169845 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Singh Snigdha S El-Sakkary Nelly N Skinner Danielle E DE Sharma Prem Prakash PP Ottilie Sabine S Antonova-Koch Yevgeniya Y Kumar Prashant P Winzeler Elizabeth E Poonam Caffrey Conor R CR Rathi Brijesh B

Pharmaceuticals (Basel, Switzerland) 20200203 2

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 activ ...[more]

PMID: 32028743

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Project description:BackgroundNeglected tropical diseases affect the most vulnerable populations and cause chronic and debilitating disorders. Socioeconomic vulnerability is a well-known and important determinant of neglected tropical diseases. For example, poverty and sanitation could influence parasite transmission. Nevertheless, the quantitative impact of socioeconomic conditions on disease transmission risk remains poorly explored.MethodsThis study investigated the role of socioeconomic variables in the predictive capacity of risk models of neglected tropical zoonoses using a decade of epidemiological data (2007-2018) from Brazil. Vector-borne diseases investigated in this study included dengue, malaria, Chagas disease, leishmaniasis, and Brazilian spotted fever, while directly-transmitted zoonotic diseases included schistosomiasis, leptospirosis, and hantaviruses. Environmental and socioeconomic predictors were combined with infectious disease data to build environmental and socioenvironmental sets of ecological niche models and their performances were compared.ResultsSocioeconomic variables were found to be as important as environmental variables in influencing the estimated likelihood of disease transmission across large spatial scales. The combination of socioeconomic and environmental variables improved overall model accuracy (or predictive power) by 10% on average (P < 0.01), reaching a maximum of 18% in the case of dengue fever. Gross domestic product was the most important socioeconomic variable (37% relative variable importance, all individual models exhibited P < 0.00), showing a decreasing relationship with disease indicating poverty as a major factor for disease transmission. Loss of natural vegetation cover between 2008 and 2018 was the most important environmental variable (42% relative variable importance, P < 0.05) among environmental models, exhibiting a decreasing relationship with disease probability, showing that these diseases are especially prevalent in areas where natural ecosystem destruction is on its initial stages and lower when ecosystem destruction is on more advanced stages.ConclusionsDestruction of natural ecosystems coupled with low income explain macro-scale neglected tropical and zoonotic disease probability in Brazil. Addition of socioeconomic variables improves transmission risk forecasts on tandem with environmental variables. Our results highlight that to efficiently address neglected tropical diseases, public health strategies must target both reduction of poverty and cessation of destruction of natural forests and savannas.

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

Publications

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

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