Browsing by Author "Campo, B."
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Item Plasmodium malariae and Plasmodium falciparum comparative susceptibility to antimalarial drugs in Mali(Journal of Antimicrobial Chemotherapy, 2021) Dembele, L.; Aniweh, Y.; Diallo, N.; Sogore, F.; Sangare, C.P.O; Haidara, A.S.; Traore, A.; Diakite´, S.A.S.; Diakite, M.; Campo, B.; Awandare, G.A.; Djimde, A.A.Objectives: To evaluate Plasmodium malariae susceptibility to current and lead candidate antimalarial drugs. Methods: We conducted cross-sectional screening and detection of all Plasmodium species malaria cases, which were nested within a longitudinal prospective study, and an ex vivo assessment of efficacy of a panel of antimalarials against P. malariae and Plasmodium falciparum, both PCR-confirmed mono-infections. Reference compounds tested included chloroquine, lumefantrine, artemether and piperaquine, while candidate antimalarials included the imidazolopiperazine GNF179, a close analogue of KAF156, and the Plasmodium phosphatidylinositol- 4-OH kinase (PI4K)-specific inhibitor KDU691. Results: We report a high frequency (3%–15%) of P. malariae infections with a significant reduction in ex vivo susceptibility to chloroquine, lumefantrine and artemether, which are the current frontline drugs against P. malariae infections. Unlike these compounds, potent inhibition of P. malariae and P. falciparum was observed with piperaquine exposure. Furthermore, we evaluated advanced lead antimalarial compounds. In this regard, we identified strong inhibition of P. malariae using GNF179, a close analogue of KAF156 imidazolopiperazines, which is a novel class of antimalarial drug currently in clinical Phase IIb testing. Finally, in addition to GNF179, we demonstrated that the Plasmodium PI4K-specific inhibitor KDU691 is highly inhibitory against P. malariae and P. falciparum. Conclusions: Our data indicated that chloroquine, lumefantrine and artemether may not be suitable for the treatment of P. malariae infections and the potential of piperaquine, as well as new antimalarials imidazolopiperazines and PI4K-specific inhibitor, for P. malariae cure.Item 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).