6 research outputs found
Structure-Based Design of Potent HIV‑1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X‑ray Structural Studies
We
report the design, synthesis, X-ray structural studies, and biological
evaluation of a novel series of HIV-1 protease inhibitors. We designed
a variety of functionalized biphenyl derivatives to make enhanced
van der Waals interactions in the S1 subsite of HIV-1 protease. These
biphenyl derivatives were conveniently synthesized using a Suzuki–Miyaura
cross-coupling reaction as the key step. We examined the potential
of these functionalized biphenyl-derived P1 ligands in combination
with 3-(<i>S</i>)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl
urethane as the P2 ligands. Inhibitor <b>21e</b>, with a 2-methoxy-1,1′-biphenyl
derivative as P1 ligand and bis-THF as the P2 ligand, displayed the
most potent enzyme inhibitory and antiviral activity. This inhibitor
also exhibited potent activity against a panel of multidrug-resistant
HIV-1 variants. A high resolution X-ray crystal structure of related
Boc-derivative <b>17a</b>-bound HIV-1 protease provided important
molecular insight into the ligand-binding site interactions of the
biphenyl core in the S1 subsite of HIV-1 protease
Simultaneous Online Monitoring of Multiple Reactions Using a Miniature Mass Spectrometer
Advances in chemical
sampling using miniature mass spectrometer
technology are used to monitor slow reactions at a frequency of ca.
180 h<sup>–1</sup> (on the Mini 12) with no sample carryover
and with inline derivatization in the case of poorly ionizing compounds.
Moreover, we demonstrate high reproducibility with a relative error
of less than 10% for major components. Monitoring is enabled using
a continuous-flow nanoelectrospray (CF-nESI) probe contained in a
custom-built 3D-printed rotary holder. The holder position is automatically
set using a stepper motor controlled by a microcontroller. Reaction
progress of up to six reactions, including hydrazone formation and
Katritzky transamination, can be monitored simultaneously without
carryover for several hours
Highly Potent HIV‑1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein–Ligand X‑ray Studies
The
design, synthesis, and biological evaluation of a series of
HIV-1 protease inhibitors incorporating stereochemically defined fused
tricyclic P2 ligands are described. Various substituent effects were
investigated to maximize the ligand-binding site interactions in the
protease active site. Inhibitors <b>16a</b> and <b>16f</b> showed excellent enzyme inhibitory and antiviral activity, although
the incorporation of sulfone functionality resulted in a decrease
in potency. Both inhibitors <b>16a</b> and <b>16f</b> maintained
activity against a panel of multidrug resistant HIV-1 variants. A
high-resolution X-ray crystal structure of <b>16a</b>-bound
HIV-1 protease revealed important molecular insights into the ligand-binding
site interactions, which may account for the inhibitor’s potent
antiviral activity and excellent resistance profiles
Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis
The design, synthesis,
and biological evaluation of a new class
of HIV-1 protease inhibitors containing stereochemically defined fused
tricyclic polyethers as the P2 ligands and a variety of sulfonamide
derivatives as the P2′ ligands are described. A number of ring
sizes and various substituent effects were investigated to enhance
the ligand–backbone interactions in the protease active site.
Inhibitors <b>5c</b> and <b>5d</b> containing this unprecedented
fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole
as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand
exhibited exceptional enzyme inhibitory potency and maintained excellent
antiviral activity against a panel of highly multidrug-resistant HIV-1
variants. The umbrella-like P2 ligand for these inhibitors has been
synthesized efficiently in an optically active form using a Pauson–Khand
cyclization reaction as the key step. The racemic alcohols were resolved
efficiently using a lipase catalyzed enzymatic resolution. Two high
resolution X-ray structures of inhibitor-bound HIV-1 protease revealed
extensive interactions with the backbone atoms of HIV-1 protease and
provided molecular insight into the binding properties of these new
inhibitors
Design and Synthesis of Highly Potent HIV‑1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure–Activity Studies, Biological and X‑ray Structural Analysis
The design, synthesis,
and biological evaluation of a new class
of HIV-1 protease inhibitors containing stereochemically defined fused
tricyclic polyethers as the P2 ligands and a variety of sulfonamide
derivatives as the P2′ ligands are described. A number of ring
sizes and various substituent effects were investigated to enhance
the ligand–backbone interactions in the protease active site.
Inhibitors <b>5c</b> and <b>5d</b> containing this unprecedented
fused 6–5–5 ring system as the P2 ligand, an aminobenzothiazole
as the P2′ ligand, and a difluorophenylmethyl as the P1 ligand
exhibited exceptional enzyme inhibitory potency and maintained excellent
antiviral activity against a panel of highly multidrug-resistant HIV-1
variants. The umbrella-like P2 ligand for these inhibitors has been
synthesized efficiently in an optically active form using a Pauson–Khand
cyclization reaction as the key step. The racemic alcohols were resolved
efficiently using a lipase catalyzed enzymatic resolution. Two high
resolution X-ray structures of inhibitor-bound HIV-1 protease revealed
extensive interactions with the backbone atoms of HIV-1 protease and
provided molecular insight into the binding properties of these new
inhibitors
Design and Development of Highly Potent HIV‑1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants
Design, synthesis,
and evaluation of a new class of exceptionally
potent HIV-1 protease inhibitors are reported. Inhibitor <b>5</b> displayed superior antiviral activity and drug-resistance profiles.
In fact, this inhibitor showed several orders of magnitude improved
antiviral activity over the FDA approved drug darunavir. This inhibitor
incorporates an unprecedented 6–5–5 ring-fused crown-like
tetrahydroÂpyranofuran as the P2 ligand and an aminobenzoÂthiazole
as the P2′ ligand with the (<i>R</i>)-hydroxyethylÂsulfonamide
isostere. The crown-like P2 ligand for this inhibitor has been synthesized
efficiently in an optically active form using a chiral Diels–Alder
catalyst providing a key intermediate in high enantiomeric purity.
Two high resolution X-ray structures of inhibitor-bound HIV-1 protease
revealed extensive interactions with the backbone atoms of HIV-1 protease
and provided molecular insight into the binding properties of these
new inhibitors