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

Abstract

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 (3R,4S) absolute configuration exhibited high activity with a Ki 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 (Ki = 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).

Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS

“…Inhibitors 55 and 56 achieved single-digit nanomolar potency. 123 Both inhibitors were co-crystallized with protease containing the L63P, V82T, and I84V mutations. The β-hydroxy group of the pyrrolidinone ring in 55 forms tight hydrogen bonds with Asp25 and Asp25’.…”

“…The P1′ phenyl group forms hydrophobic contacts with Pro81 and an edge−face π−π interaction with Phe53′. 123 Inhibitor 56 binds similarly (Figure 34).…”

“…Other pyrrolidinone-containing inhibitors with a slightly different overall structure have been designed and evaluated. Inhibitors 55 and 56 achieved single-digit-nanomolar potency . Both inhibitors were cocrystallized with protease containing the L63P, V82T, and I84V mutations.…”

Amino Acid and Peptide‐Based Antiviral Agents

“…The common part for FDA approved and new PIs structure incorporates l ‐ tert ‐leucine residue. The X‐ray crystallography analysis revealed that novel PIs interact in a mode similar to the parent drug, but a less symmetrical manner [35] . Other atazanavir‐based inhibitors incorporating l ‐ tert ‐leucine residue were developed by Hallberg and co‐workers.…”

Study on Anti-Hiv Activity of Diarylaniline Derivatives Using Quantitative Structure-Activity Relationship (Qsar)

“…Those organic compounds are derivatives of benzilpirimidine [2], arylurasil [3], lactam [4], bevirimat [5] or betulinic acid [6]. Sun et al [7] reported that a series of diarylaniline (DAAN) compounds that is potent as anti-HIV against wild-type and HIV-1 RT-resistant viral strains have been discovered.…”