title: Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against Plasmodium falciparum.
abstract: A library of diamine quinoline methanols were designed based on the mefloquine scaffold. The systematic variation of the 4-position amino alcohol side chain led to analogues that maintained potency while reducing accumulation in the central nervous system (CNS). Although the mechanism of action remains elusive, these data indicate that the 4-position side chain is critical for activity and that potency (as measured by IC(90)) does not correlate with accumulation in the CNS. A new lead compound, (S)-1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol (WR621308), was identified with single dose efficacy and substantially lower permeability across MDCK cell monolayers than mefloquine. This compound could be appropriate for intermittent preventative treatment (IPTx) indications or other malaria treatments currently approved for mefloquine.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA. erin.milner@amedd.army.mil
authors.forename: Erin
authors.initials: E
authors.lastname: Milner
authors.forename: Sean
authors.initials: S
authors.lastname: Gardner
authors.forename: Jay
authors.initials: J
authors.lastname: Moon
authors.forename: Kristina
authors.initials: K
authors.lastname: Grauer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Auschwitz
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.forename: Montip
authors.initials: M
authors.lastname: Gettayacamin
authors.forename: Jacob
authors.initials: J
authors.lastname: Johnson
authors.forename: Michael
authors.initials: M
authors.lastname: Kozar
authors.forename: Patricia
authors.initials: P
authors.lastname: Lee
authors.forename: Susan
authors.initials: S
authors.lastname: Leed
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: William
authors.initials: W
authors.lastname: McCalmont
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.forename: Norma
authors.initials: N
authors.lastname: Roncal
authors.forename: Richard
authors.initials: R
authors.lastname: Sciotti
authors.forename: Bryan
authors.initials: B
authors.lastname: Smith
authors.forename: Jason
authors.initials: J
authors.lastname: Sousa
authors.forename: Anchalee
authors.initials: A
authors.lastname: Tungtaeng
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Dow
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002463:Cell Membrane Permeability; D019281:Dimerization; D004285:Dogs; D004351:Drug Resistance; D004983:Ethanolamines / Q000138:chemical synthesis* / Q000494:pharmacology; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000494:pharmacology; D008288:Malaria / Q000517:prevention & control*; D015767:Mefloquine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D000432:Methanol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C562234:1-(2,8-bis(trifluoromethyl)quinolin-4-yl)-2-(2-(cyclopropylamino)ethylamino)ethanol; D000962:Antimalarials; D004983:Ethanolamines; D005029:Ethylenediamines; D011804:Quinolines; D015767:Mefloquine; D000432:Methanol