Synthesis and biological evaluation of pyridazine derivatives as novel HIV-1 NNRTIs.

Dongyue Li, Peng Zhan, Huiqing Liu, Christophe Pannecouque, Jan Balzarini, Erik De Clercq, Xinyong Liu

文献索引：Bioorg. Med. Chem. 21(7) , 2128-34, (2013)

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摘要

In continuation of our efforts toward identification and optimization of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), we have employed a structure-based bioisosterism strategy, with which a new series of diarylpyridazine (DAPD) derivatives were synthesized and evaluated for their anti-HIV-1 (human immunodeficiency virus type 1) activity. Most of the title compounds displayed excellent anti-HIV-1 activity at submicromolar concentrations ranging from 34 nM to 5.08 μM. The most promising compound 8g inhibited HIV-1 IIIB in MT-4 cells at a low EC50 value (0.034 μM), which was lower than the reference drug nevirapine and delavirdine. The structure activity relationships (SARs) were discussed and rationalized by docking simulations.Copyright © 2013 Elsevier Ltd. All rights reserved.