Anti-Schistosomal Activity and ADMET Properties of 1,2,5-Oxadiazinane-Containing Compound Synthesized by Visible-Light Photoredox Catalysis

15 July 2024, Version 1

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.

Keywords

Bioisostere
Schistosomiasis
Praziquantel
Photocycloaddition
α-Aminoalkyl radical

Supplementary materials

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Supplementary Material for the Research Article
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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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Compound4_10μM_Day5
Description
This video demonstrates the worm movement assay for compound 4 against Schistosoma mansoni.
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PZQ_10μM_Day5
Description
This video demonstrates the worm movement assay for PZQ against Schistosoma mansoni.
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DMSO_Day5
Description
This video demonstrates the worm movement assay for DMSO against Schistosoma mansoni.
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