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

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• Non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV often have poor pharmacological properties and face drug resistance.
• There is a continuous need for novel reverse transcriptase (RT) inhibitors to combat HIV infection.

Purpose of the Study:

• To synthesize and evaluate novel amine-type cyclopentanepyridinone derivatives as potential NNRTIs.
• To investigate the anti-HIV activity and binding mechanisms of these new compounds.

Main Methods:

• Synthesis of 20 novel amine-type cyclopentanepyridinone derivatives.
• Evaluation of anti-HIV activity (EC50) and cytotoxicity (CC50).
• Molecular docking and molecular dynamics (MD) simulations to assess binding interactions with HIV-1 RT.

Main Results:

• Compounds with alkyl and alkenyl chains at the C-4 position displayed anti-HIV activity at nanomolar to micromolar concentrations.
• Compound 9 demonstrated potent inhibition of HIV and wild-type (WT) HIV-1 RT (EC50 = 540 nM, IC50 = 33.89 μM) with low cytotoxicity (CC50 > 100 μM).
• Molecular modeling indicated favorable interactions with key residues in the NNRTI binding pocket (NNIBP) and stable hydrogen bond formation.

Conclusions:

• Amine-type cyclopentanepyridinone derivatives represent a promising class of novel NNRTIs.
• Compound 9 is a potent candidate for further development as an anti-HIV agent.
• The synthesized compounds effectively bind to the NNRTI binding pocket of HIV-1 RT.