<b>Studies of New Classes of Potent HIV-1 Protease Inhibitors Incorporating Substituted Oxaspirocyclic Carbamates or Thiazoles as the P2 Ligands</b>

<p dir="ltr">Since the first officially reported cases of AIDS during the start of the epidemic in 1981, no cure exists for either AIDS or its causative infection, HIV-1. Among current treatment regiments, protease inhibitors remain an irreplaceable element of the most effective options for HIV-1 infected patients. This treatment, referred to as combination antiretroviral therapy (cART), is incredibly effective at reducing patient viral loads to virtually undetectable levels. However, current treatments are contending with the emergence of multi-drug-resistant strains of HIV-1. Yet even darunavir, which has been wildly implemented since its FDA approval in 2006 due to its remarkable activity against drug-resistant strains of HIV-1, has been stymied by this issue. Herein, we report the design, synthesis, stereochemical and x-ray crystallographic analysis, and biological evaluation of novel HIV-1 protease inhibitors featuring an oxaspirocyclic P2 ligand. These inhibitors were designed to promote hydrogen bonding with the HIV-1 backbone via methoxy dialed, aryl oxaspirocycles while also exploring the effects of ligand stereochemistry on the binding affinity and antiviral profile. Amongst the inhibitors synthesized, we observed a range of activity as low as sub-nanomolar binding affinities and nanomolar antiviral activity, while revealing a unique mode of binding. The insightful ligand-protein binding site interactions were captured by means of x-ray crystal structure of the inhibitor complexed with wild-type HIV-1.</p><p dir="ltr">In addition, protease inhibitors utilizing trifluoromethyl aryl thiazoles as P2 ligands were also explored as novel protease inhibitors. These planar, heterocyclic ligands were inspired by the structure of known kinase inhibitors, namely, Dasatinib. The lack of stereochemistry allows for a more facile synthesis while incorporating the trifluoromethyl substitution was believed to aid in cell permeability by improving the lipophilicity of the inhibitors. This research contributes to the ongoing quest for innovative HIV-1 therapies underscoring the significance of stereochemical investigations and modifications in the development of potent and selective protease inhibitors.</p>