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

Abstract

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 EC₅₀ of 540 nM and an IC₅₀ of 33.89 μM, respectively, while maintaining low cytotoxicity (CC₅₀ > 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.

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Chemical structures of non-nucleoside HIV-1 reverse transcriptase inhibitors: (A) Structures of NNRTIs approved by the US FDA. (B) Chemical structures of representative pyridinone. The substituent at C-4 of the pyridinone nucleus is shown in red.

1. Synthesis of Cyclopentanepyridinone Derivatives

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ORTEP diagram of 21, with the labeling scheme and 50% probability ellipsoids.

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(A) Mode of binding of R221239 (green), 6 (purple), 9 (yellow), and 10 (blue) with NNIBP of WT HIV-1 RT. (B) Interactions of the cocrystallized ligand R221239 with the WT HIV-1 RT.

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(A) Mode of binding of HBY 097 (green), 6 (purple), 9 (yellow), and 10 (blue) with NNIBP of Tyr188Leu HIV-1 RT. (B) Interactions of the cocrystallized ligand HBY 097with Tyr188Leu HIV-1 RT.

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(A) The predicted binding modes of 6, 9 and 10 with WT RT HIV (PDB: 2BE2). (B) The predicted binding modes of 6, 9 and 10 with Tyr188Leu RT HIV (PDB: 1BQN).

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Stability of 6-RT, 9-RT, and 10-RT complexes during a 100 ns MD simulation. (A) RMSD values. (B) RMSF values of the amino acids. (C) R _g (radius of gyration) as a function of time. (D) Number of intermolecular H-bonds.