title: Fragment-Based Discovery of 2-Aminoquinazolin-4(3H)-ones As Novel Class Nonpeptidomimetic Inhibitors of the Plasmepsins I, II, and IV.
abstract: 2-Aminoquinazolin-4(3H)-ones were identified as a novel class of malaria digestive vacuole plasmepsin inhibitors by using NMR-based fragment screening against Plm II. Initial fragment hit optimization led to a submicromolar inhibitor, which was cocrystallized with Plm II to produce an X-ray structure of the complex. The structure showed that 2-aminoquinazolin-4(3H)-ones bind to the open flap conformation of the enzyme and provided clues to target the flap pocket. Further improvement in potency was achieved via introduction of hydrophobic substituents occupying the flap pocket. Most of the 2-aminoquinazolin-4(3H)-one based inhibitors show a similar activity against digestive Plms I, II, and IV and >10-fold selectivity versus CatD, although varying the flap pocket substituent led to one Plm IV selective inhibitor. In cell-based assays, the compounds show growth inhibition of Plasmodium falciparum 3D7 with IC50 ∼ 1 μM. Together, these results suggest 2-aminoquinazolin-4(3H)-ones as perspective leads for future development of an antimalarial agent.
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Dace
authors.initials: D
authors.lastname: Rasina
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Martins
authors.initials: M
authors.lastname: Otikovs
authors.affiliation: Biomedical Research and Study Centre , Ratsupites 1, Riga LV-1067, Latvia.
authors.forename: Janis
authors.initials: J
authors.lastname: Leitans
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Rosario
authors.initials: R
authors.lastname: Recacha
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Oleksandr V
authors.initials: OV
authors.lastname: Borysov
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Iveta
authors.initials: I
authors.lastname: Kanepe-Lapsa
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Ilona
authors.initials: I
authors.lastname: Domraceva
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Teodors
authors.initials: T
authors.lastname: Pantelejevs
authors.affiliation: Biomedical Research and Study Centre , Ratsupites 1, Riga LV-1067, Latvia.
authors.forename: Kaspars
authors.initials: K
authors.lastname: Tars
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory , The Ridgeway, Mill Hill, London NW7 1AA, U.K.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Blackman
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Kristaps
authors.initials: K
authors.lastname: Jaudzems
authors.affiliation: Latvian Institute of Organic Synthesis , Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Aigars
authors.initials: A
authors.lastname: Jirgensons
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011799:Quinazolines; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin