Aim: To design and synthesize a series of novel 7-hydroxy-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-4- carboxylate derivatives and evaluate their anti-HIV-1 activities. Methods: Holding the same triad of metal-chelating heteroatoms for the catalytic site of IN and introducing a new hydroxyl group into the adjacent position of the amide to form another three-heteroatoms group for metal chelation, a series of novel 7-hydroxy-1,3-dioxo-2,3-dihydro-1Hpyrrolo[ 3,4-c]pyridine-4-carboxylate derivatives were designed and synthesized through multi-step chemical reactions. All the synthesized compounds were evaluated for their inhibitory activities against HIV-1 replication. Results: Thirtyfive new compounds (5–13) have been designed, synthesized and bioassayed. Their structural features were determined by 1H-NMR spectra, and low- and high-resolution mass spectra. Most of the synthesized compounds showed moderate to potent activities against HIV-1. Among the analogs, compounds 7d, 7f, 7i-7j, 8d and 9c exhibited potent anti-HIV-1 activities (EC50<10 μM). In particular, 7d exhibited significant anti-HIV-1 activities with EC50 values of 1.65 μM. Conclusion: This study provides a new template for further development of potent anti-HIV-1 drugs, and the preliminary SAR among the newly synthesized analogs provided useful indications for guiding further rational design of potent anti-HIV-1 agents.
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