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

In the search for effective HIV-1 protease inhibitors, the design of symmetrical phosphinic pseudopeptides derived from a dual addition of hypophosphorous acid to acrylates (PACs) has emerged as a promising strategy due to their nonhydrolyzable nature and high affinity for this protease. In this study, we report the synthesis, in vitro evaluation, and docking studies of a series of new symmetrical phosphinic inhibitors, synthesized via simple and cost-effective procedures. This approach overcomes the complexities of previous methods and utilizes commercially or readily available reagents. The synthesized PACs, featuring various P2 and P2' substituents, have been evaluated for their inhibitory activity against the HIV-1 protease. Among them, the PAC-Phe-Val derivative (9c) demonstrated potent inhibition, with an IC₅₀ value of 33 nM, comparable to the FDA-approved Darunavir. Resolution of the isomers of 9c revealed the most potent candidate, with an IC₅₀ value of 1 nM. Molecular docking studies revealed strong hydrogen bonding interactions between PAC-Phe-Val and key active site residues, suggesting a stable and effective binding profile. The compound's structure-activity relationship (SAR) was explored, identifying crucial features for its inhibitory potency. This work highlights the potential of symmetrical phosphinic pseudopeptides as HIV-1 protease inhibitors and provides a foundation for further development of these compounds as novel antiretroviral therapies. Future research will focus on optimizing the pharmacokinetic properties and evaluating resistance profiles, aiming to advance the next generation of HIV treatments.