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Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against plasmodium falciparum

Milner, E and Gardner, S and Moon, J and Grauer, K and Auschwitz, J and Bathurst, I and Caridha, D and Gerena, L and Gettayacamin, M and Johnson, J and Kozar, M and Lee, P and Leed, S and Li, Q and McCalmont, W and Melendez, V and Roncal, N and Sciotti, R and Smith, B and Sousa, J and Tungtaeng, A and Wipf, P and Dow, G (2011) Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against plasmodium falciparum. Journal of Medicinal Chemistry, 54 (18). 6277 - 6285. ISSN 0022-2623

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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 IC90) 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. © 2011 American Chemical Society.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Milner, E
Gardner, S
Moon, J
Grauer, K
Auschwitz, J
Bathurst, I
Caridha, D
Gerena, L
Gettayacamin, M
Johnson, J
Kozar, M
Lee, P
Leed, S
Li, Q
McCalmont, W
Melendez, V
Roncal, N
Sciotti, R
Smith, B
Sousa, J
Tungtaeng, A
Wipf, Ppwipf@pitt.eduPWIPF
Dow, G
Date: 22 September 2011
Date Type: Publication
Journal or Publication Title: Journal of Medicinal Chemistry
Volume: 54
Number: 18
Page Range: 6277 - 6285
DOI or Unique Handle: 10.1021/jm200647u
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-2623
MeSH Headings: Animals; Antimalarials--chemical synthesis; Antimalarials--pharmacology; Cell Line; Cell Membrane Permeability; Dimerization; Dogs; Drug Resistance; Ethanolamines--chemical synthesis; Ethanolamines--pharmacology; Ethylenediamines--chemical synthesis; Ethylenediamines--pharmacology; Malaria--prevention & control; Mefloquine--analogs & derivatives; Mefloquine--chemical synthesis; Mefloquine--pharmacology; Methanol--analogs & derivatives; Methanol--chemical synthesis; Methanol--pharmacology; Mice; Plasmodium berghei; Plasmodium falciparum--drug effects; Quinolines--chemical synthesis; Quinolines--pharmacology; Stereoisomerism; Structure-Activity Relationship
PubMed ID: 21854078
Date Deposited: 28 May 2013 15:26
Last Modified: 22 Jun 2021 12:55


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