Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme鈥揑nhibitor X-ray Structural Studies

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• 作者：Arun K. Ghosh ; Xufen Yu ; Heather L. Osswald ; Johnson Agniswamy ; Yuan-Fang Wang ; Masayuki Amano ; Irene T. Weber ; Hiroaki Mitsuya
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：58
• 期：13
• 页码：5334-5343
• 全文大小：518K
• ISSN：1520-4804

文摘

We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki鈥揗iyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1鈥?biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease.