Design and Synthesis of P1–P3 Macrocyclic Tertiary-Alcohol-Comprising HIV‑1 Protease Inhibitors

To study P1–P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with <i>K</i>_i and EC₅₀ values down to 3.1 nM and 0.37 μM, respectively

Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors

In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3<i>R</i>,4<i>S</i>) absolute configuration exhibited high activity with a <i>K</i>_i of 2.1 nM and an EC₅₀ of 0.64 μM. Further optimization by decoration of the P1′ side chain furnished an even more potent HIV-1 protease inhibitor (<i>K</i>_i = 0.8 nM, EC₅₀ = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer)