title: The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.
abstract: A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement.
authors.affiliation: Department of Chemistry and Biochemistry, Northern Illinois University, 300 Normal Road, Dekalb, IL 60115, USA.
authors.forename: Travis R
authors.initials: TR
authors.lastname: Helgren
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 2460 Linden Lane, Silver Spring, MD 20910, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sciotti
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 2460 Linden Lane, Silver Spring, MD 20910, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lee
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Department of Chemistry and Biochemistry, Northern Illinois University, 300 Normal Road, Dekalb, IL 60115, USA.
authors.forename: Osayawemwen
authors.initials: O
authors.lastname: Igbinoba
authors.affiliation: Department of Chemistry and Biochemistry, Northern Illinois University, 300 Normal Road, Dekalb, IL 60115, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Akoto
authors.affiliation: Department of Chemistry and Biochemistry, Northern Illinois University, 300 Normal Road, Dekalb, IL 60115, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hagen
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000145:classification / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000962:Antimalarials; D011794:Quercetin
keywords: Antimalarial; CoMFA; Malaria; Mannich; Quercetin