- Pyrimidinone Derivatives as Antimalarial Agents
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The invention relates to novel pyrimidinone-based heterocyclic compounds which are parasite growth inhibitors, having the general formula (I) in which Y is a morpholine chosen from three bridged morpholines, L is a bond or a linker, n=0 or 1 and R2 is a methyl group when n=0 and a hydrogen atom when n=1. Process for the preparation thereof and therapeutic use thereof.
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Paragraph 1119; 1120; 1121
(2015/07/15)
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- Discovery of pyridyl-based inhibitors of Plasmodium falciparum N-myristoyltransferase
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N-Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3, providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19. This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3. Further structure-based inhibitor design led to the discovery of 30, the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity.
- Yu, Zhiyong,Brannigan, James A.,Rangachari, Kaveri,Heal, William P.,Wilkinson, Anthony J.,Holder, Anthony A.,Leatherbarrow, Robin J.,Tate, Edward W.
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supporting information
p. 1767 - 1772
(2015/10/20)
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- PYRIMIDINONE DERIVATIVES AS ANTIMALARIAL AGENTS
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The invention relates to novel pyrimidinone-based heterocyclic compounds which are parasite growth inhibitors, having the general formula (I) in which Y is a morpholine chosen from three bridged morpholines, L is a bond or a linker, n = 0 or 1 and R2 is a methyl group when n = 0 and a hydrogen atom when n = 1. Process for the preparation thereof and therapeutic use thereof.
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Page/Page column 136; 137
(2014/01/09)
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- Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure-activity relationship, and action mechanism studies
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Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC50 values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.
- Moret, Vincent,Laras, Younes,Cresteil, Thierry,Aubert, Genevieve,Ping, Dou Q.,Di, Chen,Barthelemy-Requin, Magali,Beclin, Christophe,Peyrot, Vincent,Allegro, Diane,Rolland, Amandine,De Angelis, Francesca,Gatti, Evelina,Pierre, Philippe,Pasquini, Luca,Petrucci, Eleonora,Testa, Ugo,Kraus, Jean-Louis
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experimental part
p. 558 - 567
(2009/09/05)
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- Pyrimidine derivatives useful as inhibitors of PKC-theta
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Disclosed are novel compounds of formula (I): wherein X, Y, R1, R2 and R3 are as defined herein, which are useful as inhibitors of PKC-theta and are thus useful for treating a variety of diseases and disorders that are mediated or sustained through the activity of PKC-theta, including immunological disorders and type II diabetes. This invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.
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Page/Page column 123
(2008/06/13)
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- Dopamine Receptor Agonist Activity of Some 5-(2-Aminoethyl)carbostyril Derivatives
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The potency of β-adrenoreceptor agonists, e.g.,isoproterenol, is strikingly increased by substitution of the meta catecholic hydroxyl group with the NH group of a carbostyril system.To explore the possibility that comparable potency enhacement might occur
- Kaiser, Carl,Dandrige, Penelope A.,Garvey, Eleanor,Flaim, Kathryn E.,Zeid, Robert L.,Hieble, J. Paul
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p. 1803 - 1810
(2007/10/02)
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- ELECTRONIC NATURE OF THE AZA SUBSTITUENT OF PYRIDYL AND QUINOLYL GROUPS FOR REACTIVITIES IN AN INSULATED SYSTEM
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A new set of ?0 values was determined for all positions of pyridyl and quinolyl groups, reliably excluding steric effect by perihydrogen, on the basis of the rates of the alkaline hydrolysis of substituted 2-methylbenzoates and pyridylmethyl and quinolylmethyl 2-methyl-benzoates in 70percent aq acetone.
- Sawada, Masami,Ichihara, Masaharu,Ando, Takashi,Yukawa, Yasuhide,Tsuno, Yuho
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p. 4917 - 4920
(2007/10/02)
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