Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

被引：7
作者：
Iyidogan, Pinar [1 ]
Sullivan, Todd J. [1 ]
Chordia, Mahendra D. [2 ]
Frey, Kathleen M. [1 ]
Anderson, Karen S. [1 ]
机构：
[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA
[2] Chemin Pharma, New Haven, CT 06511 USA
来源：
ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 12期
关键词：
HIV; reverse transcriptase; nucleoside H-phosphonate; NNRTI; synthesis; POTENTIAL MULTIFUNCTIONAL INHIBITORS; BIFUNCTIONAL INHIBITION; DEOXYCYTIDINE KINASE; MOLECULAR-MECHANISM; HETERODIMERS; NUCLEOSIDE; ABACAVIR; PRODRUG; SITE;
D O I：
10.1021/ml4002979
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
In a continuing study of potent bifunctional anti-HIV agents, we rationally designed a novel chimeric inhibitor utilizing thymidine (THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a polymethylene linker (ALK). The nucleoside, 5'-hydrogen-phosphonate (H-phosphonate), and S'-triphosphate forms of this chimeric inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (11) and the H-phosphonate (10) derivatives inhibited RT polymerization with an IC50 value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (9) and H-phosphonate (10) derivatives reduced HIV replication in a cell-based assay with low nanomolar antiviral potencies.
引用
收藏
页码：1183 / 1188
页数：6
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