Thiazinoquinones as New Promising Multistage Schistosomicidal Compounds Impacting Schistosoma mansoni and Egg Viability (6 views)
Acs Infect Dis (ISSN: 2373-8227linking), 2020 Jan 10; 6 (1 ): 124-137.
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Paper type: Journal Article , Research Support, Non-U. S. Gov'T
Impact factor: 0, 5-year impact factor: 0
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Keywords: Animals , Female , Larva Drug Effects , Life Cycle Stages Drug Effects , Ovum Drug Effects Physiology , Quinones Chemistry Pharmacology , Schistosoma Mansoni Drug Effects Physiology , Schistosomicides Pharmacology , Structure-Activity Relationship , Dft Calculations , Chemical Synthesis Of Nature-Inspired Drug Leads , Multistage Activity , Redox-Active Compounds , Schistosomiasis , Thiazinoquinones
Affiliations:
*** IBB - CNR ***
Institute of Biochemistry and Cell Biology , National Research Council , Campus A. Buzzati-Traverso, Via E. Ramarini 32 , 00015 Monterotondo (Rome) , Italy.
The NeaNat Group, Department of Pharmacy , University of Naples "Federico II" , Via D. Montesano 49 , 80131 Napoli , Italy.
Centro Interuniversitario di Ricerca sulla Malaria/Italian Malaria Network , 06126 Perugia , Italy.
Core Facilities , Italian National Institute of Health , Viale Regina Elena 299 , 00161 Rome , Italy.
Institute of Chemistry of Molecular Recognition , National Research Council , Via M. Bianco 9 , 20131 Milano , Italy.
References:
Not available.
Acs Infect Dis (ISSN: 2373-8227linking), 2020 Jan 10; 6 (1 ): 124-137.
Export to BibTeX Export to EndNote
Paper type: Journal Article , Research Support, Non-U. S. Gov'T
Impact factor: 0, 5-year impact factor: 0
Url: Not available.
Keywords: Animals , Female , Larva Drug Effects , Life Cycle Stages Drug Effects , Ovum Drug Effects Physiology , Quinones Chemistry Pharmacology , Schistosoma Mansoni Drug Effects Physiology , Schistosomicides Pharmacology , Structure-Activity Relationship , Dft Calculations , Chemical Synthesis Of Nature-Inspired Drug Leads , Multistage Activity , Redox-Active Compounds , Schistosomiasis , Thiazinoquinones
Affiliations:
*** IBB - CNR ***
Institute of Biochemistry and Cell Biology , National Research Council , Campus A. Buzzati-Traverso, Via E. Ramarini 32 , 00015 Monterotondo (Rome) , Italy.
The NeaNat Group, Department of Pharmacy , University of Naples "Federico II" , Via D. Montesano 49 , 80131 Napoli , Italy.
Centro Interuniversitario di Ricerca sulla Malaria/Italian Malaria Network , 06126 Perugia , Italy.
Core Facilities , Italian National Institute of Health , Viale Regina Elena 299 , 00161 Rome , Italy.
Institute of Chemistry of Molecular Recognition , National Research Council , Via M. Bianco 9 , 20131 Milano , Italy.
References:
Not available.
Thiazinoquinones as New Promising Multistage Schistosomicidal Compounds Impacting Schistosoma mansoni and Egg Viability
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 LC(50) 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.
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 LC(50) 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.
Thiazinoquinones as New Promising Multistage Schistosomicidal Compounds Impacting Schistosoma mansoni and Egg Viability
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