Discovery of nitropyridine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors via a structure-based core refining approach

作者：Wang, Jun; Zhan, Peng^*; Li, Zhenyu; Liu, Huiqing; De Clercq, Erik; Pannecouque, Christophe; Liu, Xinyong

来源：European Journal of Medicinal Chemistry, 2014, 76: 531-538.

DOI：10.1016/j.ejmech.2014.02.047

• HIV-1
• Reverse transcriptase
• NNRTIs
• Drug design
• Organic synthesis
• Pyridine
• Bioactivity

As a continuation of our efforts to discover and develop back-up analogs of DAPYs, novel substituted nitropyridine derivatives were designed via a structure-based core refining approach, synthesized and evaluated for their in vitro HIV-1 activity in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against wild-type HIV-1 IIIB. Most notably, the compound 7b was identified as the most promising candidate in inhibiting HIV-1 replication with an EC50 value of 0.056 mu M and a selective index (SI) of 1251, which were much better than those of NVP (EC50 = 0.23 mu M) and DLV (EC50 = 0.51 mu M). Some other compounds, 7k, 7c, 7j and 7e, were also endowed with a favorable anti-HIV-1 potency (EC50 = 0.034, 0.11, 0.11 and 0.16 mu M, respectively). Some antivirally active compounds also showed moderate inhibitory activity against RT. Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogs provide valuable avenues for future molecular optimization.

• 出版日期2014-4-9
• 单位山东大学; 河北医科大学