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

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• 作者：Erin Milner ; Sean Gardner ; Jay Moon ; Kristina Grauer ; Jennifer Auschwitz ; Ian Bathurst ; Diana Caridha ; Lucia Gerena ; Montip Gettayacamin ; Jacob Johnson ; Michael Kozar ; Patricia Lee ; Susan Leed ; Qigui Li ; William McCalmont ; Victor Melendez ; Norma Roncal ; Richard Sciotti ; Bryan Smith ; Jason Sousa ; Anchalee Tungtaeng ; Peter Wipf ; Geoffrey Dow
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：September 22, 2011
• 年：2011
• 卷：54
• 期：18
• 页码：6277-6285
• 全文大小：1177K
• 年卷期：v.54,no.18(September 22, 2011)
• ISSN：1520-4804

文摘

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.