Synthesis of P1′-Functionalized Macrocyclic Transition-State Mimicking HIV‑1 Protease Inhibitors Encompassing a Tertiary Alcohol

Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the <i>para</i> position of the benzyl group in the P1′ side with (hetero)­aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1–P3 macrocyclization, 14- and 15-membered macrocyclic PIs were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound <b>10f</b>, with a 2-thiazolyl group in the P1′ position, was the most potent PI of this new series (<i>K</i>_i 2.2 nM, EC₅₀ 0.2 μM). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed

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)