Design, Synthesis, and Biological Evaluation of 1,2-Dihydroisoquinolines as HIV-1 Integrase Inhibitors
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- 作者：Vibha Tandon ; Urvashi ; Pooja Yadav ; Souvik Sur ; Sheenu Abbat ; Vinod Tiwari ; Raymond Hewer ; Maria A. Papathanasopoulos ; Rameez Raja ; Akhil C. Banerjea ; Akhilesh K. Verma ; Shrikant Kukreti ; Prasad V. Bharatam
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2015
- 出版时间：October 8, 2015
- 年：2015
- 卷：6
- 期：10
- 页码：1065-1070
- 全文大小：402K
- ISSN：1948-5875
文摘
6-Endo-dig-cyclization is an efficient method for the synthesis of 1,2-dihydroisoquinolines. We have synthesized few 1,2-dihydroisoquinolines having different functionality at the C-1, C-3, C-7, and N-2 positions for evaluation against HIV-1 integrase (HIV1-IN) inhibitory activity. A direct nitro-Mannich condensation of o-alkynylaldimines and dual activation of o-alkynyl aldehydes by inexpensive cobalt chloride yielded desired compounds. Out of 24 compounds, 4m and 6c came out as potent integrase inhibitors in in vitro strand transfer (ST) assay, with IC50 value of 0.7 and 0.8 渭M, respectively. Molecular docking of these compounds in integrase revealed strong interaction between metal and ligands, which stabilizes the enzyme鈥搃nhibitor complex. The ten most active compounds were subjected to antiviral assay. Out of those, 6c reduced the level of p24 viral antigen by 91%, which is comparable to RAL in antiviral assay. Interestingly, these compounds showed similar ST inhibitory activity in G140S mutant, suggesting they can act against resistant strains.