title: Structural optimization of quinolon-4(1H)-imines as dual-stage antimalarials: toward increased potency and metabolic stability.
abstract: Discovery of novel effective and safe antimalarials has been traditionally focused on targeting erythrocytic parasite stages that cause clinical symptoms. However, elimination of malaria parasites from the human population will be facilitated by intervention at different life-cycle stages of the parasite, including the obligatory developmental phase in the liver, which precedes the erythrocytic stage. We have previously reported that N-Mannich-based quinolon-4(1H)-imines are potent antiplasmodial agents but present several stability liabilities. We now report our efforts to optimize quinolon-4(1H)-imines as dual-stage antiplasmodial agents endowed with chemical and metabolic stability. We report compounds active against both the erythrocytic and exoerythrocytic forms of malaria parasites, such as the quinolon-4(1H)-imine 5p (IC50 values of 54 and 710 nM against the erythrocytic and exoerythrocytic forms), which constitute excellent starting points for further lead optimization as dual-stage antimalarials.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon , Av. Prof. Gama Pinto, 1649-019 Lisbon, Portugal.
authors.forename: Ana S
authors.initials: AS
authors.lastname: Ressurreição
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonçalves
authors.forename: Ana R
authors.initials: AR
authors.lastname: Sitoe
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Ana
authors.initials: A
authors.lastname: Góis
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Gonçalves
authors.forename: Maria R
authors.initials: MR
authors.lastname: Bronze
authors.forename: Thomas
authors.initials: T
authors.lastname: Hanscheid
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Paul
authors.initials: P
authors.lastname: O'Neill
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Francisca
authors.initials: F
authors.lastname: Lopes
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003460:Crystallization; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D057809:HEK293 Cells; D006420:Hemeproteins / Q000737:chemistry; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008018:Life Cycle Stages / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; D007097:Imines; D015363:Quinolones; C020753:hemozoin; D014450:Electron Transport Complex III