Spiroindolones, a Potent Compound Class for the Treatment of Malaria
Matthias Rottmann,Matthias Rottmann,Case W. McNamara,Bryan K. S. Yeung,Marcus C. S. Lee,Bin Zou,Bruce Russell,Bruce Russell,Patrick Seitz,Patrick Seitz,David Plouffe,Neekesh V. Dharia,Jocelyn Tan,Steven Cohen,Kathryn S. R. Spencer,Gonzalo E. González-Páez,Suresh B. Lakshminarayana,Anne Goh,Rossarin Suwanarusk,Timothy Jegla,Esther K. Schmitt,Hans-Peter Beck,Hans-Peter Beck,Reto Brun,Reto Brun,François Nosten,François Nosten,Laurent Rénia,Véronique Dartois,Thomas H. Keller,David A. Fidock,Elizabeth A. Winzeler,Elizabeth A. Winzeler,Thierry T. Diagana +33 more
TLDR
The preclinical profile for an optimized spiroindolone drug candidate, NITD609, shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.Abstract:
Recent reports of increased tolerance to artemisinin derivatives—the most recently adopted class of antimalarials—have prompted a need for new treatments. The spirotetrahydro-β-carbolines, or spiroindolones, are potent drugs that kill the blood stages of Plasmodium falciparum and Plasmodium vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect that is ablated in parasites bearing nonsynonymous mutations in the gene encoding the P-type cation-transporter ATPase4 (PfATP4). The optimized spiroindolone NITD609 shows pharmacokinetic properties compatible with once-daily oral dosing and has single-dose efficacy in a rodent malaria model.read more
Citations
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Isatins As Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks
Journal ArticleDOI
Organocatalytic Asymmetric Assembly Reactions: Synthesis of Spirooxindoles via Organocascade Strategies
TL;DR: This review focuses on the enantioselective synthesis of spirooxindoles via organocascade strategies and is organized on the basis of three primary starting materials and then further subdivided according to the types of organocatalyst.
Journal ArticleDOI
Recent Advances in Asymmetric Organocatalytic Construction of 3,3′-Spirocyclic Oxindoles
Liang Hong,Rui Wang,Rui Wang +2 more
TL;DR: Recent advances in asymmetric organocatalysis are summarized and classified according to the spiro ring fused at the 3-position of the oxindole core.
Journal ArticleDOI
Strategies for the enantioselective synthesis of spirooxindoles.
TL;DR: This review features efficient strategies for the enantioselective synthesis of spirocyclic oxindoles, focusing on reports in 2010 and 2011, and is organized based on two primary disconnection strategies, and then further subdivided into the type and ring size of the spirocycle that is generated.
Journal ArticleDOI
Spirooxindoles: Promising scaffolds for anticancer agents.
Bin Yu,De-Quan Yu,Hong-Min Liu +2 more
TL;DR: This review highlights recent progress of biologically active spirooxindoles for their anticancer potentials, mainly focusing on the discussions of SARs and modes of action.
References
More filters
Journal ArticleDOI
EMBOSS: The European Molecular Biology Open Software Suite
TL;DR: The European Molecular Biology Open Software Suite is a mature package of software tools developed for the molecular biology community that includes a comprehensive set of applications for molecular sequence analysis and other tasks and integrates popular third-party software packages under a consistent interface.
Journal ArticleDOI
Genome sequence of the human malaria parasite Plasmodium falciparum
Malcolm J. Gardner,Neil Hall,Eula Fung,Owen White,Matthew Berriman,Richard W. Hyman,Jane M. Carlton,Arnab Pain,Karen E. Nelson,Sharen Bowman,Ian T. Paulsen,Keith D. James,Jonathan A. Eisen,Kim Rutherford,Steven L. Salzberg,Alister Craig,Sue Kyes,Man Suen Chan,Vishvanath Nene,Shamira J. Shallom,Bernard B. Suh,Jeremy Peterson,Samuel V. Angiuoli,Mihaela Pertea,Jonathan E. Allen,Jeremy D. Selengut,Daniel H. Haft,Michael W. Mather,Akhil B. Vaidya,David M. A. Martin,Alan H. Fairlamb,Martin Fraunholz,David S. Roos,Stuart A. Ralph,Geoffrey I. McFadden,Leda M. Cummings,G. Mani Subramanian,Christopher J. Mungall,J. Craig Venter,Daniel J. Carucci,Stephen L. Hoffman,Chris I. Newbold,Ronald W. Davis,Claire M. Fraser,Bart Barrell +44 more
TL;DR: The genome sequence of P. falciparum clone 3D7 is reported, which is the most (A + T)-rich genome sequenced to date and is being exploited in the search for new drugs and vaccines to fight malaria.
Journal ArticleDOI
Artemisinin Resistance in Plasmodium falciparum Malaria
Arjen M. Dondorp,François Nosten,Poravuth Yi,Debashish Das,Aung Phae Phyo,Joel Tarning,Khin Maung Lwin,Frédéric Ariey,Warunee Hanpithakpong,Sue J. Lee,Pascal Ringwald,Kamolrat Silamut,Mallika Imwong,Kesinee Chotivanich,Pharath Lim,Trent Herdman,Sen Sam An,Shunmay Yeung,Pratap Singhasivanon,Nicholas P. J. Day,Niklas Lindegardh,Duong Socheat,Nicholas J. White +22 more
TL;DR: The overall median clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours in Wang Pha (P<0.001) in each of the two locations as discussed by the authors.
Journal ArticleDOI
Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 Å resolution
TL;DR: Comparison with a low-resolution electron density map of the enzyme in the absence of calcium and with biochemical data suggests that large domain movements take place during active transport.
Journal ArticleDOI
Evidence of Artemisinin-Resistant Malaria in Western Cambodia
TL;DR: Artemisinins are potent and rapidly acting antimalarial drugs, and their widespread use for treating patients with Plasmodium falciparum malaria raises the question of emerging drug resistance.
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