Synthesis, biological evaluation and 3D-QSAR studies of 3-keto salicylic acid chalcones and related amides as novel HIV-1 integrase inhibitors

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• 作者：Horrick Sharma^a ; Shivaputra Patil^a ; Tino W. Sanchez^b ; Nouri Neamati^b ; Raymond F. Schinazi^c ; John K. Buolamwini^a ; ^{jbuolamwini@uthsc.edu}
• 关键词：HIV-1 ; HIV integrase ; Integrase inhibitors ; 3-Keto salicylic acids ; Antiviral activity ; Strand transfer inhibitors ; Chalcones ; Synthesis ; 3D-QSAR ; CoMFA ; CoMSIA
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2011
• 出版时间：15 March 2011
• 年：2011
• 卷：19
• 期：6
• 页码：2030-2045
• 全文大小：851 K

文摘

HIV-1 integrase is one of the three most important enzymes required for viral replication and is therefore an attractive target for anti retroviral therapy. We herein report the design and synthesis of 3-keto salicylic acid chalcone derivatives as novel HIV-1 integrase inhibitors. The most active compound, 5-bromo-2-hydroxy-3-[3-(2,3,6-trichlorophenyl)acryloyl]benzoic acid (25) was selectively active against integrase strand transfer, with an IC₅₀ of 3.7 μM. While most of the compounds exhibited strand transfer selectivity, a few were nonselective, such as 5-bromo-3-[3-(4-bromophenyl)acryloyl]-2-hydroxybenzoic acid (15), which was active against both 3′-processing and strand transfer with IC₅₀ values of 11 ± 4 and 5 ± 2 μM, respectively. The compounds also inhibited HIV replication with potencies comparable with their integrase inhibitory potencies. Thus, 5-bromo-2-hydroxy-3-[3-(2,3,6-trichlorophenyl)acryloyl]benzoic acid (25) and 5-bromo-3-[3-(4-bromophenyl)acryloyl]-2-hydroxybenzoic acid (15) inhibited HIV-1 replication with EC₅₀ values of 7.3 and 8.7 μM, respectively. A PHASE pharmacophore hypothesis was developed and validated by 3D-QSAR, which gave a predictive r² of 0.57 for an external test set of ten compounds. Phamacophore derived molecular alignments were used for CoMFA and CoMSIA 3D-QSAR modeling. CoMSIA afforded the best model with q² and r² values of 0.54 and 0.94, respectively. This model predicted all the ten compounds of the test set within 0.56 log units of the actual pIC₅₀ values; and can be used to guide the rational design of more potent novel 3-keto salicylic acid integrase inhibitors