Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria


O' Neill, Paul M, Stocks, Paul A, Sabbani, Sunil, Roberts, Natalie L, Amewu, Richard K ORCID: 0000-0002-4676-436X, Shore, Emma R, Aljayyoussi, Ghaith, Angulo-Barturen, Inigo, Belen, Maria, Jimenez-Diaz, et al (show 12 more authors) (2018) Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria. BIOORGANIC & MEDICINAL CHEMISTRY, 26 (11). pp. 2996-3005.

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Abstract

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.

Item Type: Article
Uncontrolled Keywords: Animals, Humans, Mice, Rats, Plasmodium falciparum, Malaria, Disease Models, Animal, Tetraoxanes, Morpholines, Antimalarials, Administration, Oral, Drug Stability, Inhibitory Concentration 50
Depositing User: Symplectic Admin
Date Deposited: 30 May 2018 09:14
Last Modified: 21 Jun 2023 01:44
DOI: 10.1016/j.bmc.2018.05.006
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3021909
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