Quinolin-4(1H)-imines are potent antiplasmodial drugs targeting the liver stage of malaria.

We present a novel series of quinolin-4(1H)-imines as dual-stage antiplasmodials, several-fold more active than primaquine in vitro against Plasmodium berghei liver stage. Among those, compounds 5g and 5k presented low nanomolar IC50 values. The compounds are metabolically stable and modulate several drug targets. These results emphasize the value of quinolin-4(1H)-imines as a new chemotype and their suitable properties for further drug development.

[1]  Yuexin Li,et al.  Quinolone-3-Diarylethers: A New Class of Antimalarial Drug , 2013, Science Translational Medicine.

[2]  J. Gut,et al.  N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads. , 2013, Journal of medicinal chemistry.

[3]  D. Kyle,et al.  4(1H)-Quinolones with Liver Stage Activity against Plasmodium berghei , 2012, Antimicrobial Agents and Chemotherapy.

[4]  Miguel Prudêncio,et al.  Liver-stage malaria parasites vulnerable to diverse chemical scaffolds , 2012, Proceedings of the National Academy of Sciences.

[5]  D. Kyle,et al.  Lead optimization of 3-carboxyl-4(1H)-quinolones to deliver orally bioavailable antimalarials. , 2012, Journal of medicinal chemistry.

[6]  J. Hemingway,et al.  Generation of quinolone antimalarials targeting the Plasmodium falciparum mitochondrial respiratory chain for the treatment and prophylaxis of malaria , 2012, Proceedings of the National Academy of Sciences.

[7]  J. Clardy,et al.  Characterization of Plasmodium Liver Stage Inhibition by Halofuginone , 2012, ChemMedChem.

[8]  Cécilie Martin,et al.  Drug Screen Targeted at Plasmodium Liver Stages Identifies a Potent Multistage Antimalarial Drug , 2012, The Journal of infectious diseases.

[9]  Peter D Gibbons,et al.  Identification, Design and Biological Evaluation of Bisaryl Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2) , 2012, Journal of medicinal chemistry.

[10]  M. Mota,et al.  Targeting the liver stage of malaria parasites: a yet unmet goal. , 2012, Journal of Medicinal Chemistry.

[11]  Yingyao Zhou,et al.  Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery , 2011, Science.

[12]  Yongyuth Yuthavong,et al.  A Research Agenda for Malaria Eradication: Drugs , 2011, PLoS medicine.

[13]  D. Kyle,et al.  Endochin optimization: structure-activity and structure-property relationship studies of 3-substituted 2-methyl-4(1H)-quinolones with antimalarial activity. , 2010, Journal of medicinal chemistry.

[14]  James R. Brown,et al.  Thousands of chemical starting points for antimalarial lead identification , 2010, Nature.

[15]  Anang A. Shelat,et al.  Chemical genetics of Plasmodium falciparum , 2010, Nature.

[16]  R. Moreira,et al.  Inhibitors of the mitochondrial electron transport chain and de novo pyrimidine biosynthesis as antimalarials: The present status. , 2010, Current medicinal chemistry.

[17]  J. Baird,et al.  Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination. , 2010, Trends in parasitology.

[18]  J. Gut,et al.  Imidazoquines as antimalarial and antipneumocystis agents. , 2009, Journal of medicinal chemistry.

[19]  L. Rénia,et al.  A pre-emptive strike against malaria's stealthy hepatic forms , 2009, Nature Reviews Drug Discovery.

[20]  J. Gut,et al.  Design, synthesis and structure-activity relationships of (1H-pyridin-4-ylidene)amines as potential antimalarials. , 2009, Bioorganic & medicinal chemistry letters.

[21]  R. Moreira,et al.  Bis{(E)-3-[(diethylmethylammonio)methyl]-N-[3-(N,N-dimethylsulfamoyl)-1-methylpyridin-4-ylidene]-4-methoxyanilinium} tetraiodide pentahydrate , 2009, Acta crystallographica. Section E, Structure reports online.

[22]  Joel S. Freundlich,et al.  The fatty acid biosynthesis enzyme FabI plays a key role in the development of liver-stage malarial parasites. , 2008, Cell host & microbe.

[23]  James M. Woolven,et al.  Synthesis and structure-activity relationships of 4-pyridones as potential antimalarials. , 2008, Journal of medicinal chemistry.

[24]  David Hinrichs,et al.  Antimalarial quinolones: synthesis, potency, and mechanistic studies. , 2008, Experimental parasitology.

[25]  Xinxia Peng,et al.  A combined transcriptome and proteome survey of malaria parasite liver stages , 2008, Proceedings of the National Academy of Sciences.

[26]  Joanne M. Morrisey,et al.  Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum , 2007, Nature.

[27]  Ana Rodriguez,et al.  The silent path to thousands of merozoites: the Plasmodium liver stage , 2006, Nature Reviews Microbiology.

[28]  A. Magill,et al.  Primaquine: report from CDC expert meeting on malaria chemoprophylaxis I. , 2006, The American journal of tropical medicine and hygiene.

[29]  T. Egan.  Interactions of quinoline antimalarials with hematin in solution. , 2006, Journal of inorganic biochemistry.

[30]  C. Nickel,et al.  Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. , 2006, Bioorganic & medicinal chemistry letters.

[31]  Albert P. Li,et al.  Preclinical in vitro screening assays for drug-like properties. , 2005, Drug discovery today. Technologies.

[32]  R. Moreira,et al.  Amidomethylation of Amodiaquine: Antimalarial N-Mannich Base Derivatives. , 2005 .

[33]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[34]  Christopher J. Tonkin,et al.  Tropical infectious diseases: Metabolic maps and functions of the Plasmodium falciparum apicoplast , 2004, Nature Reviews Microbiology.

[35]  G. K. Jain,et al.  A simple and rapid evaluation of methemoglobin toxicity of 8-aminoquinolines and related compounds. , 2000, Ecotoxicology and environmental safety.

[36]  T. Egan,et al.  Thermodynamic factors controlling the interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX. , 1997, Journal of inorganic biochemistry.

[37]  Corwin Hansch,et al.  A survey of Hammett substituent constants and resonance and field parameters , 1991 .

[38]  A. Leo,et al.  ′AROMATIC′ SUBSTITUENT CONSTANTS FOR STRUCTURE-ACTIVITY CORRELATIONS , 1974 .

[39]  G. Biagini,et al.  The development of quinolone esters as novel antimalarial agents targeting the Plasmodium falciparum bc1 protein complex , 2012 .