4 research outputs found
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><sub>i</sub> 2.2 nM, EC<sub>50</sub> 0.2
μM). Co-crystallized complexes of both linear and macrocyclic
PIs with the HIV-1 protease enzyme were prepared and analyzed
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><sub>i</sub> and EC<sub>50</sub> 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><sub>i</sub> of 2.1 nM and
an EC<sub>50</sub> 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><sub>i</sub> = 0.8 nM, EC<sub>50</sub> = 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)
Nucleotide Prodrugs of 2′-Deoxy-2′-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase
The limited efficacy, in particular
against the genotype 1 virus,
as well as the variety of side effects associated with the current
therapy for hepatitis C virus (HCV) infection necessitates more efficacious
drugs. We found that phosphoramidate prodrugs of 2′-deoxy-2′-spirooxetane
ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase
inhibitors, displaying EC<sub>50</sub> values ranging from 0.2 to
>98 μM, measured in the Huh7-replicon cell line, with no
apparent
cytotoxicity (CC<sub>50</sub> > 98.4 μM). Confirming recent
findings, the 2′-spirooxetane moiety was identified as a novel
structural motif in the field of anti-HCV nucleosides. A convenient
synthesis was developed that enabled the synthesis of a broad set
of nucleotide prodrugs with varying substitution patterns. Extensive
formation of the triphosphate metabolite was observed in both rat
and human hepatocyte cultures. In addition, after oral dosing of several
phosphoramidate derivatives of compound <b>21</b> to rats, substantial
hepatic levels of the active triphosphate metabolite were found