TY - JOUR
T1 - Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria.
AU - O’ Neill, Paul M.
AU - Stocks, Paul A.
AU - Sabbani, Sunil
AU - Roberts, Natalie L.
AU - Amewu, Richard K.
AU - Shore, Emma R.
AU - Aljayyoussi, Ghaith
AU - Angulo-Barturén, Iñigo
AU - Belén, María
AU - Jiménez-Díaz, null
AU - Bazaga, Santiago Ferrer
AU - Martínez, María Santos
AU - Campo, Brice
AU - Sharma, Raman
AU - Charman, Susan A.
AU - Ryan, Eileen
AU - Chen, Gong
AU - Shackleford, David M.
AU - Davies, Jill
AU - Nixon, Gemma L.
AU - Biagini, Giancarlo
AU - Ward, Steve
PY - 2018/7/15
Y1 - 2018/7/15
N2 - 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.
AB - 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.
U2 - 10.1016/j.bmc.2018.05.006
DO - 10.1016/j.bmc.2018.05.006
M3 - Article
SN - 0968-0896
VL - 26
SP - 2996
EP - 3005
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 11
ER -
