- Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase
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The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.
- Aylor, Samantha O.,Bhanot, Purnima,Bheemanaboina, Rammohan R. Yadav,Childers, Wayne E.,Colussi, Dennis J.,De Souza, Mariana Laureano,Eck, Tyler,Gonzalez, Mariana Lozano,Gordon, John,Kreiss, Tamara,Lee, Patricia,Mahmood, Shams Ul,Pybus, Brandon S.,Rotella, David P.,Roth, Alison,Siekierka, John J.
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supporting information
p. 1962 - 1967
(2021/12/01)
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- Atom-economical synthesis of N-heterocycles via cascade inter-/intramolecular C-N Bond-forming reactions catalyzed by Ti amides
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Direct and efficient catalytic reactions with excellent regioselectivity for the preparation of a series of substituted isoindoles, isoquinolines, and imidazoles are reported. Reaction of C6H4(2-CN)C≡C-R with an array of amines, catalyzed by 10 mol % of [σ:η1: η5-(OCH2)(Me2NCH2)C 2B9H9]Ti(NMe2) (1), gives a series of substituted isoindoles in very high yields. In a similar manner, interaction of C6H4(2-CH2CN)C≡C-Ph with various kinds of amines affords a wide range of substituted isoquinolines. On the other hand, treatment of propargylamines (R′C≡CCH2NHR′′) with nitriles in the presence of 10 mol % of 1 produces a class of substituted imidazoles in high yields. A possible reaction mechanism is proposed, involving sequential inter- and intramolecular C-N bond formation via hydroamination/ cyclization reaction of cyanoalkynes with amines or nitriles with propargylamines catalyzed by titanium amides.
- Shen, Hao,Xie, Zuowei
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supporting information; experimental part
p. 11473 - 11480
(2010/10/02)
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