Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit
Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.
1,5-DIPHENYL-PYRROLIDIN-2-ONE COMPOUNDS AS CB-1 LIGANDS
CB-1 receptor inverse agonist compounds of Formula and pharmaceutical compositions for the treatment of obesity or cognitive impairment associated with schizophrenia.
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(2009/12/05)
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