title: Bis-alkylamine Indolo[3,2-b]quinolines as hemozoin ligands: implications for antimalarial cytostatic and cytocidal activities.
abstract: To get insight into the relevance of targeting hemozoin (Hz) crystals, two isomeric series, N5,N10-bis-alkylamine (2a-k) and N10,O11-bis-alkylamine (3a-k) indolo[3,2-b]quinolines, were evaluated for their in vitro activity against chloroquine (CQ)-resistant and sensitive strains of Plasmodium falciparum. In general, compounds of series 3 were more active than isomers 2, with IC50/LD50 ranging from 25/233 nM (3i) to 1.3 (3a)/10.7 (3b) μM. SAR analyses showed that lipophilicity and chlorine substitution at C3 increased both cytostatic and cytocidal activities. Both series bound to hematin monomer, inhibited β-hematin formation in vitro, delayed intraerythrocytic parasite development with apparent inhibition of Hz biocrystallization, and showed higher cytocidal activity against schizonts. In addition, cytostatic and cytocidal activities of series 3, but not those of isomers 2, correlated with calculated vacuole accumulation ratios, suggesting different capacities of 2 and 3 to bind to the Hz crystal face {001} exposed on the vacuole aqueous medium and different mechanisms of cytocidal potency.
authors.affiliation: Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa , Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paulo
authors.forename: Marta
authors.initials: M
authors.lastname: Figueiras
authors.forename: Marta
authors.initials: M
authors.lastname: Machado
authors.forename: Catarina
authors.initials: C
authors.lastname: Charneira
authors.forename: João
authors.initials: J
authors.lastname: Lavrado
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Santos
authors.forename: Dinora
authors.initials: D
authors.lastname: Lopes
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Fátima
authors.initials: F
authors.lastname: Nogueira
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D006420:Hemeproteins / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D006420:Hemeproteins; D008024:Ligands; D011804:Quinolines; C020753:hemozoin; D006427:Hemin; D002738:Chloroquine