15 research outputs found
An Oxidopyrylium Cyclization/Ring-Opening Route to Polysubstituted α‑Hydroxytropolones
α-Hydroxytropolones are a class of molecules with therapeutic potential against several human diseases. However, structure–activity relationship studies on these molecules have been limited due to a scarcity of efficient synthetic methods to access them. It is demonstrated herein that α-hydroxytropolones can be generated through a BCl<sub>3</sub>-mediated ring-opening/aromatization/demethylation process on 8-oxabicyclo[3.2.1]octenes. Used in conjunction with an improved method based on established oxidopyrylium dipolar cycloadditions, several polysubstituted α-hydroxytropolones can be accessed in three steps from readily available α-hydroxy-γ-pyrones
Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV‑1 Reverse Transcriptase
We
report the results of a binding free energy-based virtual screening
campaign of a library of 77 α-hydroxytropolone derivatives against
the challenging RNase H active site of the reverse transcriptase (RT)
enzyme of human immunodeficiency virus-1. Multiple protonation states,
rotamer states, and binding modalities of each compound were individually
evaluated. The work involved more than 300 individual absolute alchemical
binding free energy parallel molecular dynamics calculations and over
1 million CPU hours on national computing clusters and a local campus
computational grid. The thermodynamic and structural measures obtained
in this work rationalize a series of characteristics of this system
useful for guiding future synthetic and biochemical efforts. The free
energy model identified key ligand-dependent entropic and conformational
reorganization processes difficult to capture using standard docking
and scoring approaches. Binding free energy-based optimization of
the lead compounds emerging from the virtual screen has yielded four
compounds with very favorable binding properties, which will be the
subject of further experimental investigations. This work is one of
the few reported applications of advanced-binding free energy models
to large-scale virtual screening and optimization projects. It further
demonstrates that, with suitable algorithms and automation, advanced-binding
free energy models can have a useful role in early-stage drug-discovery
programs
Catalytic Enantioselective Intermolecular [5 + 2] Dipolar Cycloadditions of a 3‑Hydroxy-4-pyrone-Derived Oxidopyrylium Ylide
The
first catalytic enantioselective [5 + 2] dipolar cycloaddition
of a 3-hydroxy-4-pyrone-derived oxidopyrylium ylide is described.
These studies leveraged the recently recognized ability of oxidopyrylium
dimers to serve as the source of ylide, which was found to be key
to increasing yields and achieving enantiomeric excesses up to 99%.
General reaction conditions were identified for an array of α,β-unsaturated
aldehyde dipolarophiles. Reaction products possess four stereocenters,
and subsequent reduction introduced a fifth contiguous stereocenter
with total stereocontrol
Antiviral effect of compounds on bunyavirus replication.
Vero cells were infected with either RVFV ZH501 (A) or LACV (B) then treated with decreasing concentrations of antiviral compound. Viral growth was measured by FFA. Data represents three independent experiments completed with biological replicates. Error bars represent standard deviation.</p
Development and validation of RVFV antiviral screen.
A. Identification of optimal mAb for the detection of RVFV by mAb staining of a serial dilution of RVFV strain MP-12 in an FFA. B. Impact of cell number on the sensitivity of antiviral compound screen. C. Evaluation of the sensitivity of the antiviral compound screen based upon the evaluation of ribavirin and β-D-N4-Hydroxycytidine N4-Hydroxycytidine (NHC/EIDD-1931), a known antiviral for RVFV. Data is presented as focus forming units. These data are the cumulation of three independent experiments with technical duplicates.</p
EC<sub>50</sub> against LACV and ZIKV replication.
EC50 against LACV and ZIKV replication.</p
Representative structures of RFVF inhibitors.
(A) Inactive and active troponoid natural products, illustrating preference for oxygen triad, along with common nuclease inhibition mode for αHTs. (B) Synthetic αHTs with activity under 10 μM against RVFV, demonstrating broad substitution tolerance. (C) Representative examples of alternative scaffolds with activity against RFVF.</p