Thiazinoquinones as New Promising Multistage Schistosomicidal Compounds Impacting Schistosoma mansoni and Egg Viability
| Autor: | Marco Persico, Agostina Pietrantoni, Antonella Paladino, Giuliana Papoff, Lucia Bertuccini, Concetta Imperatore, Fulvio Saccoccia, Roberto Gimmelli, Giovina Ruberti, Alessandra Guidi, Marialuisa Menna, Caterina Fattorusso, Marcello Casertano, Paolo Luciano |
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| Přispěvatelé: | Roberto, Gimmelli, Persico, Marco, Imperatore, Concetta, Fulvio, Saccoccia, Guidi, Alessandra, Casertano, Marcello, Luciano, Paolo, Agostina, Pietrantoni, Lucia, Bertuccini, Antonella, Paladino, Giuliana, Papoff, Menna, Marialuisa, Fattorusso, Caterina, Giovina, Ruberti |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
schistosomiasis
chemical synthesis of nature-inspired drug leads thiazinoquinones multistage activity DFT calculations redox-active compounds Schistosomiasis Plasmodium falciparum Biology medicine.disease biology.organism_classification Microbiology Infectious Diseases Mechanism of action Parasitic disease parasitic diseases Toxicity medicine Helminths Parasite hosting Schistosoma mansoni medicine.symptom |
| Popis: | Schistosomiasis is the most significant neglected tropical parasitic disease caused by helminths in terms of morbidity and mortality caused by helminths. In this work, we present the antischistosomal activity against Schistosoma mansoni of a rationally selected small set of thiazinoquinone derivatives, some of which were previously found to be active against Plasmodium falciparum and others synthesized ad hoc. The effects on larvae, juvenile, and adult parasite viability as well as on egg production and development were investigated, resulting in the identification of new multistage antischistosomal hit compounds. The most promising compounds 6, 8, 13, and 14 with a LC50 value on schistosomula from ∼5 to ∼15 μM also induced complete death of juvenile (28 days old) and adult worm pairs (7 weeks old) and a detrimental effect on egg production and development in vitro. Structure-activity relationships (SARs) were analyzed by means of computational studies leading to the hypothesis of a redox-based mechanism of action with a one-electron reduction bioactivation step and the subsequent formation of a toxic semiquinone species, similarly to what was previously observed for the antiplasmodial activity. Our results also evidenced that the selective toxicity against mammalian cells or parasites as well as specific developmental stages of a parasite can be addressed by varying the nature of the introduced substituents. |
| Databáze: | OpenAIRE |
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