Synthesis, biological evaluation and 3D-QSAR studies of 3-keto salicylic acid chalcones and related amides as novel HIV-1 integrase inhibitors.
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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DOI：
10.1016/j.bmc.2011.01.047
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发表时间：
2011-03-15
影响因子：
3.5
通讯作者：
Buolamwini, John K.
中科院分区：
文献类型：
--
作者：
Sharma, Horrick;Patil, Shivaputra;Sanchez, Tino W.;Neamati, Nouri;Schinazi, Raymond F.;Buolamwini, John K.
关键词：
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 IC50of 3.7μM. 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 IC50values of 11±4 and 5±2μM, 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 EC50values of 7.3 and 8.7μM, respectively. A PHASE pharmacophore hypothesis was developed and validated by 3D-QSAR, which gave a predictive r2of 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 q2and r2values 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 pIC50values; and can be used to guide the rational design of more potent novel 3-keto salicylic acid integrase inhibitors
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影响因子：
5.4
作者：
SAKAI, H;KAWAMURA, M;ADACHI, A
通讯作者：
ADACHI, A
影响因子：
3.5
作者：
Dixon, Steven L.;Smondyrev, Alexander M.;Friesner, Richard A.
通讯作者：
Friesner, Richard A.
影响因子：
7.3
作者：
Kuo, CL;Assefa, H;Neamati, N
通讯作者：
Neamati, N
影响因子：
7.3
作者：
Dubois, Manie;Bailly, Fabrice;Cotelle, Philippe
通讯作者：
Cotelle, Philippe
DOI：
10.1002/qsar.19930120205
发表时间：
1993-06-01
期刊：
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS
影响因子：
--
作者：
CLARK, M;CRAMER, RD
通讯作者：
CRAMER, RD