Browsing by Author "Shore, E.R."
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Item Optimisation of the synthesis of second generation 1,2,4,5 tetraoxane antimalarials(Elsevier Ltd, 2016) O' Neill, P.M.; Sabbani, S.; Nixon, G.L.; Schnaderbeck, M.; Roberts, N.L.; Shore, E.R.; Riley, C.; Murphy, B.; McGillan, P.; Ward, S.A.; Davies, J.; Amewu, R.K.An efficient route to the synthesis of potent antimalarial aryloxy 1,2,4,5-tetraoxanes is described that permits parallel synthesis for Structure–Activity Relationship (SAR) investigations. Brief details of the in vitro and in vivo antimalarial evaluation are included which enables identification of antimalarial leads for further development. Also described is an improved approach to the synthesis of a selected late-lead compound in just four or five synthetic steps from commercially available starting materials. © 2016Item Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria(Elsevier Ltd, 2018) O’ Neill, P.M.; Stocks, P.A.; Sabbani, S.; Roberts, N.L.; Amewu, R.K.; Shore, E.R.; Aljayyoussi, G.; Angulo-Barturén, I.; Belén, M.; Jiménez-Díaz; Bazaga, S.F.; Martínez, M.S.; Campo, B.; Sharma, R.; Charman, S.A.; Ryan, E.; Chen, G.; Shackleford, D.M.; Davies, J.; Nixon, G.L.; Biagini, G.A.; Ward, S.A.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. © 2018Item A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance(Nature Communications, 2017) O'Neill, P.M.; Amewu, R.K.; Charman, S.A.; Sabbani, S.; Gnädig, N.F.; Straimer, J.; Fidock, D.A.; Shore, E.R.; Roberts, N.L.; Wong, M.H.-L.; Hong, W.D.; Pidathala, C.; Riley, C.; Murphy, B.; Aljayyoussi, G.; Gamo, F.J.; Sanz, L.; Rodrigues, J.; Cortes, C.G.; Herreros, E.; Angulo-Barturén, I.; Jiménez-Díaz, M.B.; Bazaga, S.F.; Martínez-Martíne, M.S.; Campo, B.; Sharma, R.; Ryan, E.; Shackleford, D.M.; Campbell, S.; Smith, D.A.; Wirjanata, G.; Noviyanti, R.; Price, R.N.; Marfurt, J.; Palmer, M.J.; Copple, I.M.; Mercer, A.E.; Ruecker, A.; Delves, M.J.; Sinden, R.E.; Siegl, P.; Davies, J.; Rochford, R.; Kocken, C.H.M.; Zeeman, A.-M.; Nixon, G.L.; Biagini, G.A.; Ward, S.A.K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives. © 2017 The Author(s).