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

• Synthesize a series of substituted nitropyridine derivatives as NNRTIs.
• The proposed binding mode was investigated by molecular docking.
• A preliminary structure–activity relationship was discussed.

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 μM and a selective index (SI) of 1251, which were much better than those of NVP (EC50 = 0.23 μM) and DLV (EC50 = 0.51 μM). 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 μM, 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.

A series of substituted nitropyridine derivatives were identified as potent HIV NNRTIs via a structure-based core refining approach.Figure optionsDownload as PowerPoint slide