8 research outputs found
Importance of C*–H Based Modes and Large Amplitude Motion Effects in Vibrational Circular Dichroism Spectra: The Case of the Chiral Adduct of Dimethyl Fumarate and Anthracene
The role played by the C*–H
based modes (C* being the chiral
carbon atom) and the large amplitude motions in the vibrational absorption
(VA) and vibrational circular dichroism (VCD) spectra is investigated.
The example of an adduct of dimethyl fumarate and anthracene, i.e.,
dimethyl-(+)-(11<i>R</i>,12<i>R</i>)-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboxylate,
and two deuterated isotopomers thereof specially synthesized for this
goal, are considered. By comparing the experimental and DFT calculated
spectra of the undeuterated and deuterated species, we demonstrate
that the C*–H bending, rocking, and stretching modes in the
VA and VCD spectra are clearly identified in well defined spectroscopic
features. Further, significant information about the conformer distribution
is gathered by analyzing the VA and VCD data of both the fingerprint
and the C–H stretching regions, with particular attention paid
to the band shape data. Effects related to the large amplitude motions
of the two methoxy moieties have been simulated by performing linear
transit (LT) calculations, which consists of varying systematically
the relative positions of the two methoxy moieties and calculating
VCD spectra for the partially optimized structures obtained in this
way. The LT method allows one to improve the quality of calculated
spectra, as compared to experimental results, especially in regard
to relative intensities and bandwidths
Improved Potency of Indole-Based NorA Efflux Pump Inhibitors: From Serendipity toward Rational Design and Development
The NorA efflux pump
is a potential drug target for reversal of
resistance to selected antibacterial agents, and recently we described
indole-based inhibitor candidates. Herein we report a second class
of inhibitors derived from them but with significant differences in
shape and size. In particular, compounds <b>13</b> and <b>14</b> are very potent inhibitors in that they demonstrated the
lowest IC<sub>50</sub> values (2 ÎĽM) ever observed among all
indole-based compounds we have evaluated
Long-Range Bonding/Nonbonding Interactions: A Donor–Acceptor Resonance Studied by Dynamic NMR
Long-range bonding interactions were
evaluated using variable-temperature
NMR spectroscopy and suitable 2′-CH<sub>2</sub>X-substituted
phenylpyridines (X = Me, NMe<sub>2</sub>, OMe, F). It was found that
the arylpyridyl rotational barriers were lower when electronegative
atoms were bound to the α carbon of the 2′ moiety. This
effect was ascribed to a stabilizing interaction in the transition
state due to the lone pair of the heterocyclic nitrogen with the α
carbon. Computational support for this hypothesis came from CCSDÂ(T)/6-31+GÂ(d)
calculations. Steric effects of the X moiety were ruled out by comparison
of the rotational barriers of analogous biphenyls
Indole Based Weapons to Fight Antibiotic Resistance: A Structure–Activity Relationship Study
Antibiotic resistance represents
a worldwide concern, especially
regarding the outbreak of methicillin-resistant <i>Staphylococcus
aureus</i>, a common cause for serious skin and soft tissues
infections. A major contributor to <i>Staphylococcus aureus</i> antibiotic resistance is the NorA efflux pump, which is able to
extrude selected antibacterial drugs and biocides from the membrane,
lowering their effective concentrations. Thus, the inhibition of NorA
represents a promising and challenging strategy that would allow recycling
of substrate antimicrobial agents. Among NorA inhibitors, the indole
scaffold proved particularly effective and suitable for further optimization.
In this study, some unexplored modifications on the indole scaffold
are proposed. In particular, for the first time, substitutions at
the C5 and N1 positions have been designed to give 48 compounds, which
were synthesized and tested against <i>norA</i>-overexpressing <i>S. aureus</i>. Among them, 4 compounds have NorA IC<sub>50</sub> values lower than 5.0 ÎĽM proving to be good efflux pump inhibitor
(EPI) candidates. In addition, preliminary data on their ADME (absorption,
distribution, metabolism, and excretion) profile is reported
Optimization of Small-Molecule Inhibitors of Influenza Virus Polymerase: From Thiophene-3-Carboxamide to Polyamido Scaffolds
Influenza
virus infections represent a serious concern to public
health, being characterized by high morbidity and significant mortality.
To date, compounds targeting the viral ion-channel M2 or the viral
neuraminidase are the drugs available for treatment of influenza,
but the emergence of drug-resistant viral mutants renders the search
for novel targets and their possible inhibitors a major priority.
Recently, we demonstrated that the viral RNA-dependent RNA polymerase
(RdRP) complex can be an optimal target of protein–protein
disruption by small molecules, with thiophene-3-carboxamide derivatives
emerging as promising candidates for the development of new anti-influenza
drugs with broad-spectrum activity. Here, we report a further dissection
of the thiophene-3-carboxamide structure. By using a GRID molecular
interaction field (MIF)-based scaffold-hopping approach, more potent
and nontoxic polyamido derivatives were identified, highlighting a
new space in the chemical variability of RdRP inhibitors. Finally,
a possible pharmacophoric model highlighting the key features required
for RdRP inhibition is proposed
From Experiments to a Fast Easy-to-Use Computational Methodology to Predict Human Aldehyde Oxidase Selectivity and Metabolic Reactions
Aldehyde oxidase (AOX) is a molibdo-flavoenzyme
that has raised
great interest in recent years, since its contribution in xenobiotic
metabolism has not always been identified before clinical trials,
with consequent negative effects on the fate of new potential drugs.
The fundamental role of AOX in metabolizing xenobiotics is also due
to the attempt of medicinal chemists to stabilize candidates toward
cytochrome P450 activity, which increases the risk for new compounds
to be susceptible to AOX nucleophile attack. Therefore, novel strategies
to predict the potential liability of new entities toward the AOX
enzyme are urgently needed to increase effectiveness, reduce costs,
and prioritize experimental studies. In the present work, we present
the most up-to-date computational method to predict liability toward
human AOX (<i>h</i>AOX), for applications in drug design
and pharmacokinetic optimization. The method was developed using a
large data set of homogeneous experimental data, which is also disclosed
as Supporting Information
From Experiments to a Fast Easy-to-Use Computational Methodology to Predict Human Aldehyde Oxidase Selectivity and Metabolic Reactions
Aldehyde oxidase (AOX) is a molibdo-flavoenzyme
that has raised
great interest in recent years, since its contribution in xenobiotic
metabolism has not always been identified before clinical trials,
with consequent negative effects on the fate of new potential drugs.
The fundamental role of AOX in metabolizing xenobiotics is also due
to the attempt of medicinal chemists to stabilize candidates toward
cytochrome P450 activity, which increases the risk for new compounds
to be susceptible to AOX nucleophile attack. Therefore, novel strategies
to predict the potential liability of new entities toward the AOX
enzyme are urgently needed to increase effectiveness, reduce costs,
and prioritize experimental studies. In the present work, we present
the most up-to-date computational method to predict liability toward
human AOX (<i>h</i>AOX), for applications in drug design
and pharmacokinetic optimization. The method was developed using a
large data set of homogeneous experimental data, which is also disclosed
as Supporting Information
Discovery of a Chemical Probe Bisamide (CCT251236): An Orally Bioavailable Efficacious Pirin Ligand from a Heat Shock Transcription Factor 1 (HSF1) Phenotypic Screen
Phenotypic screens, which focus on
measuring and quantifying discrete
cellular changes rather than affinity for individual recombinant proteins,
have recently attracted renewed interest as an efficient strategy
for drug discovery. In this article, we describe the discovery of
a new chemical probe, bisamide (CCT251236), identified using an unbiased
phenotypic screen to detect inhibitors of the HSF1 stress pathway.
The chemical probe is orally bioavailable and displays efficacy in
a human ovarian carcinoma xenograft model. By developing cell-based
SAR and using chemical proteomics, we identified pirin as a high affinity
molecular target, which was confirmed by SPR and crystallography