Structural reassignment of a dibenz[b,f][1,4]oxazepin-11(10H)-one with potent antigiardial activity
Andrew G. Riches
A * , Christopher J. S. Hart B C , Matthieu Schmit A , Emmanuel A. Debele A , Snigdha Tiash B , Erin Clapper B , Tina S. Skinner-Adams B * and John H. Ryan A
A CSIRO Manufacturing, Ian Wark Laboratory, Bayview Avenue, Clayton, Vic. 3168, Australia.
B Griffith Institute for Drug Discovery, Griffith University, Nathan, Qld 4111, Australia.
C Present address: Department of Microbiology and Molecular Genetics, University of California Davis, CA 95616, USA.
Handling Editor: Craig Hutton
Australian Journal of Chemistry 75(10) 839-845 https://doi.org/10.1071/CH22184
Submitted: 23 August 2022 Accepted: 14 October 2022 Published: 10 November 2022
© 2022 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)
Abstract
A screen for compounds with antigiardial activity in the Compounds Australia Scaffolds library identified SN00797640 (supplied structure being 8-acylaminodibenzoxazepinone 1) as a hit compound with potent anti-parasitic activity (concentration for 50% growth inhibition of Giardia duodenalis, IC50 0.18 μM). To further explore the structure–activity relationships in this series, compound 1 and analogues, including its 7-acylaminodibenzoxazepinone regioisomer (2), were synthesized and assessed for anti-Giardia activity. While regioisomer 2 demonstrated antigiardial activity, resynthesized 1 and other 8-acylaminodibenzoxazepinone analogues were inactive. Comparison of spectroscopic and physical properties demonstrated the correct structure of SN00797640 to be 7-acylamino regioisomer 2. These results highlight the importance of independent synthesis in verifying the structure and activity of screening hits.
Keywords: antigiardial, dibenzoxazepinones, Giardia, giardiasis, medicinal chemistry, organic synthesis, parasite, screening, structural reassignment.
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