Synthesis, docking, and biological studies of phenanthrene ¦Â-diketo acids as novel HIV-1 integrase inhibitors

详细信息    查看全文

• 作者：Horrick Sharma ; Tino W. Sanchez ; Nouri Neamati ; Mervi Detorio ; Raymond F. Schinazi ; Xiaolin Cheng ; John K. Buolamwini
• 关键词：HIV-1 ; HIV-1 integrase ; Phenanthrene ¦Â-diketo acids ; ST inhibitors ; Docking
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：15 November, 2013
• 年：2013
• 卷：23
• 期：22
• 页码：6146-6151
• 全文大小：912 K

文摘

In the present study we report the synthesis of halogen-substituted phenanthrene ¦Â-diketo acids as new HIV-1 integrase inhibitors. The target phenanthrenes were obtained using both standard thermal- and microwave-assisted synthesis. 4-(6-Chlorophenanthren-2-yl)-2,4-dioxobutanoic acid (18) was the most active compound of the series, inhibiting both 3¡ä-end processing (3¡ä-P) and strand transfer (ST) with IC₅₀ values of 5 and 1.3 ¦ÌM, respectively. Docking studies revealed two predominant binding modes that were distinct from the binding modes of raltegravir and elvitegravir, and suggest a novel binding region in the IN active site. Moreover, these compounds are predicted not to interact significantly with some of the key amino acids (Q148 and N155) implicated in viral resistance. Therefore, this series of compounds can further be investigated for a possible chemotype to circumvent resistance to clinical HIV-1 IN inhibitors.