- Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin
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Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.
- Hidaka, Koushi,Kimura, Tooru,Ruben, Adam J.,Uemura, Tsuyoshi,Kamiya, Mami,Kiso, Aiko,Okamoto, Tetsuya,Tsuchiya, Yumi,Hayashi, Yoshio,Freire, Ernesto,Kiso, Yoshiaki
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scheme or table
p. 10049 - 10060
(2009/04/07)
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- PYRROLE DERIVATIVES AS THERAPEUTIC COMPOUNDS
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Novel pyrrole derivatives are disclosed as Aβ42-lowering agents for the treatment and prevention of neurodegenerative disorders characterized by the formation or accumulation of amyloid plaques comprising the Aβ42 peptide.
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Page/Page column 42
(2010/11/26)
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- C-KIT MODULATORS AND METHODS OF USE
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The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Even more specifically, the invention
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Page/Page column 81-82
(2008/06/13)
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- Gamma-Glutamyl-4-azoanilides
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The present invention provides gamma-glutamyl-4-azoanilides, processes for their preparation and their use as substrates for gamma-glutamyl transferase determination, of the formula STR1 wherein X is alkyl, --(CH2)m --COOH or --O--(CH2)n --COOH wherein m is 0-4 and n is 1-4; R is optionally substituted p-nitrophenyl; an optionally substituted thiophene residue; an optionally substituted thiazole residue; an optionally substituted benzothiazole residue; an optionally substituted benzoisothiazole residue; an N-alkylthiazole residue; or an optionally substituted 1,3,5-thiodiazole residue; as well as the alkali metal, alkaline earth metal and ammonium salts thereof.
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