Abstract
The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the anti-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of anti-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with N,N,N',N'-tetraalkyldiaminomethane in the presence of an IrIII complex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3+3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent anti-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ.
Supplementary materials
Title
Supplementary Material for the Research Article
Description
This is the supplementary material for the research article titled 'Anti-Schistosomal Activity and ADMET Properties of a 1,2,5-Oxadiazinane-Containing Compound Synthesized by Visible-Light Photoredox Catalysis.' The data supporting the findings of this study are included in this supplementary material.
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Title
Compound4_10μM_Day5
Description
This video demonstrates the worm movement assay for compound 4 against Schistosoma mansoni.
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Title
PZQ_10μM_Day5
Description
This video demonstrates the worm movement assay for PZQ against Schistosoma mansoni.
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Title
DMSO_Day5
Description
This video demonstrates the worm movement assay for DMSO against Schistosoma mansoni.
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