Design, Synthesis, and Biological Activity of Amine-Type Cyclopentanepyridinone Derivatives as HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitors.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting human immunodeficiency virus (HIV) frequently exhibit suboptimal pharmacological properties and are often compromised by drug-resistant mutations. This underscores the ongoing need for the development of developing novel reverse transcriptase (RT) inhibitors. In this study, we report the synthesis of 20 novel amine-type cyclopentanepyridinone derivatives as NNRTIs. The chlorinated C-4 core was functionalized with various amines of differing chain lengths, yielding final products in 43-88% yields. Derivatives bearing alkyl and alkenyl chains at the C-4 position demonstrated anti-HIV activity at nanomolar to micromolar concentrations. Among them, compound 9 exhibited the most potent inhibitory activity against HIV and wild-type (WT) HIV-1 RT, with an EC(50) of 540 nM and an IC(50) of 33.89 μM, respectively, while maintaining low cytotoxicity (CC(50) > 100 μM). Molecular docking analysis revealed interactions with key residues in the NNRTI binding pocket (NNIBP), including Lys101, Tyr181, Tyr188, and the conserved residues Phe227, Trp229, and Leu234, both in WT HIV-1 RT and Tyr188Leu HIV-1 RT. Moreover, molecular dynamics (MD) simulations with WT HIV-1 RT showed that compounds 6, 9, and 10 formed up to two hydrogen bonds with RT, supporting their ability to bind effectively within the NNIBP.