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

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O' Neill, Paul M, Stocks, Paul A, Sabbani, Sunil, Roberts, Natalie L, Amewu, Richard K, Shore, Emma R, Aljayyoussi, Ghaith, Angulo-Barturén, Iñigo, Belén, María, Díaz, Jiménez, Bazaga, Santiago Ferrer, Martínez, María Santos, Campo, Brice, Sharma, Raman, Charman, Susan A, Ryan, Eileen, Chen, Gong, Shackleford, David M, Davies, Jill, Nixon, Gemma L, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595 and Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 (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 and Medicinal Chemistry, Vol 26, Issue 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
Subjects: WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1016/j.bmc.2018.05.006
Depositing User: Stacy Murtagh
Date Deposited: 25 May 2018 13:40
Last Modified: 17 May 2019 01:02
URI: https://archive.lstmed.ac.uk/id/eprint/8684

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