title: Synthesis and antimalarial activity of E-2-quinolinylbenzocycloalcanones.
abstract: A series of E-2-quinolinylbenzocycloalcanones 5-21 were prepared and evaluated for their activity to inhibit beta-hematin formation and the hydrolysis of hemoglobin in vitro. Positive compounds for both assays were also tested for their efficacy in rodent Plasmodium berghei. Compounds 6, 16, 19, and 20, were the most promising. Inhibition of beta-hematin formation was minimal when a hydrogen or methoxy groups were present on the position 8 of the quinoline and position 4' of the indanone ring as it appeared for compounds 5, 7-15, 17, 18, and 21, and greatest with compounds (52%) and (90%) with a substitution of methoxy on position 6 and 7 or methyl on position 8 of the quinoline nucleus and methoxy or methyl groups on position 4' of the indanone. The most active compound to emerge from this study is 2-chloro-8-methyl-3-[(4'-methoxy-1'-indanoyl)-2'-methyliden]-quinoline 20 effective as antimalarial that target beta-hematin formation and the inhibition of the hydrolysis of hemoglobin in vitro together with a good survival in a murine malaria model, which should help delay the rapid onset of resistance to drugs acting at only a single site. Results with these assays suggest that quinolinylbenzocycloalcanones exert their antimalarial activity via multiple mechanisms.
authors.affiliation: Laboratorio de Síntesis Orgánica, Facultad de Farmacia, Universidad Central de Venezuela, Apartado 47206, Los Chaguaramos, Caracas 1041-A, Venezuela. charrisj@camelot.rect.ucv.ve
authors.forename: Jaime E
authors.initials: JE
authors.lastname: Charris
authors.forename: José N
authors.initials: JN
authors.lastname: Domínguez
authors.forename: Neira
authors.initials: N
authors.lastname: Gamboa
authors.forename: Juan R
authors.initials: JR
authors.lastname: Rodrigues
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Angel
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D006420:Hemeproteins / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006868:Hydrolysis / Q000187:drug effects; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000737:chemistry / Q000187:drug effects*; D011806:Quinolinium Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015996:Survival Rate
chemical_list: D000962:Antimalarials; D006420:Hemeproteins; D006576:Heterocyclic Compounds, 4 or More Rings; D011806:Quinolinium Compounds