Highly Potent Phosphinic HIV‑1 Protease Inhibitors: Synthesis, In Vitro Evaluation, and Docking Studies

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• HIV-1 protease is a critical target for antiretroviral therapy.
• Developing non-hydrolyzable and high-affinity inhibitors is crucial.
• Symmetrical phosphinic pseudopeptides offer a promising structural class.

Purpose of the Study:

• To synthesize and evaluate novel symmetrical phosphinic pseudopeptides (PACs) as HIV-1 protease inhibitors.
• To explore the structure-activity relationship (SAR) of these compounds.
• To provide a foundation for developing new antiretroviral agents.

Main Methods:

• Synthesis of symmetrical phosphinic pseudopeptides (PACs) using cost-effective procedures.
• In vitro evaluation of inhibitory activity against HIV-1 protease.
• Molecular docking studies to elucidate binding interactions.

Main Results:

• A series of novel PACs were synthesized and evaluated.
• The PAC-Phe-Val derivative (9c) showed potent inhibition (IC50 = 33 nM).
• The most potent isomer achieved an IC50 of 1 nM, with docking studies confirming strong binding interactions.

Conclusions:

• Symmetrical phosphinic pseudopeptides are effective HIV-1 protease inhibitors.
• The PAC-Phe-Val derivative (9c) is a highly promising lead compound.
• Further optimization for pharmacokinetic properties and resistance profiles is warranted for next-generation HIV treatments.