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Structure–Activity Relationships of 4-Position Diamine Quinoline Methanols as Intermittent Preventative Treatment (IPT) against Plasmodium falciparum

2011; American Chemical Society; Volume: 54; Issue: 18 Linguagem: Inglês

10.1021/jm200647u

1520-4804

Erin Milner, Sean Gardner, Jay Moon, Kristina Grauer, Jennifer M. Auschwitz, Ian Bathurst, Diana Caridha, Lucia Gerena, Montip Gettayacamin, Jacob D. Johnson, Michael P. Kozar, Patricia Lee, Susan E. Leed, Qigui Li, William McCalmont, Victor Meléndez, Norma Roncal, Richard J. Sciotti, Bryan Smith, Jason Sousa, Anchalee Tungtaeng, Peter Wipf, Geoffrey S. Dow,

Drug Transport and Resistance Mechanisms

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.