Fragment-Based Discovery of 8-Hydroxyquinoline Inhibitors of the HIV-1 Integrase鈥揕ens Epithelium-Derived Growth Factor/p75 (IN鈥揕EDGF/p75) Interaction

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• 作者：Erik Serrao ; Bikash Debnath ; Hiroyuki Otake ; Yuting Kuang ; Frauke Christ ; Zeger Debyser ; Nouri Neamati
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2311-2322
• 全文大小：615K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

On the basis of an initial molecular modeling study suggesting the favorable binding of the 鈥減rivileged鈥?fragment 8-hydroxyquinoline with HIV-1 integrase (IN) at the IN鈥搇ens epithelium-derived growth factor/p75 (LEDGF/p75) interface , we developed a set of modified 8-hydroxyquinoline fragments demonstrating micromolar IC₅₀ values for inhibition of the IN鈥揕EDGF/p75 interaction, but significant cytotoxicity was associated with these initial compounds. Diverse modifications at the C5 and C7 carbons of the 8-hydroxyquinoline core improved potency, but reduction of diversity to only modifications at the C5 position ultimately yielded potent inhibitors with low cytotoxicity. Two of these particular compounds, 5-((p-tolylamino)methyl)quinolin-8-ol and 5-(((3,4-dimethylphenyl)amino)methyl)quinolin-8-ol, inhibited viral replication in MT-4 cells with low micromolar EC₅₀. This is the first study providing evidence for 8-hydroxyquinolines as novel inhibitors of the IN鈥揕EDGF/p75 interaction. Our lead compounds are druglike, have low molecular weights, and are amenable to various substitutions suitable for enhancing their potency and selectivity.