An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors

被引：16

作者：

Wilson, Tyler A. ^{[1
]}

Koneru, Pratibha C. ^{[2
]}

Rebensburg, Stephanie V. ^{[2
]}

Lindenberger, Jared J. ^{[2
]}

Kobe, Matthew J. ^{[3
]}

Cockroft, Nicholas T. ^{[1
]}

Adu-Arnpratwum, Daniel ^{[1
]}

Larue, Ross C. ^{[3
]}

Kvaratskhelia, Mamuka ^{[2
]}

Fuchs, James R. ^{[1
]}

机构：

[1] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA

[2] Univ Colorado, Div Infect Dis, Sch Med, Aurora, CO 80045 USA

[3] Ohio State Univ, Coll Pharm, Div Pharmaceut & Pharmaceut Chem, Columbus, OH 43210 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 02期

基金：

美国国家卫生研究院;

关键词：

HIV-1; integrase; allosteric inhibitor; protein multimerization; OXIDATIVE DECARBOXYLATION; CARBOXYLIC-ACIDS; MECHANISM; MULTIMERIZATION;

D O I：

10.1021/acsmedchemlett.8b00633

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Allosteric HIV-1 integrase inhibitors (ALLINIs) are a new class of potential antiretroviral therapies with a unique mechanism of action and drug resistance profile. To further extend this class of inhibitors via a scaffold hopping approach, we have synthesized a series of analogues possessing an isoquinoline ring system. Lead compound 61 binds in the v-shaped pocket at the IN dimer interface and is highly selective for promoting higher-order multimerization of inactive IN over inhibiting IN-LEDGF/p75 binding. Importantly, 61 potently inhibited HIV-1(NL4-3) (A128T IN), which confers marked resistance to archetypal quinoline-based ALLINIs. Thermal degradation studies indicated that at elevated temperatures the acetic acid side chain of specific isoquinoline derivatives undergo decarboxylation reactions. This reactivity has implications for the synthesis of various ALLINI analogues.

引用

页码：215 / 220

页数：11

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