34 research outputs found
2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis:Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization
<i>Mycobacterium tuberculosis</i> (<i>MTb</i>) possesses
two nonproton pumping type II NADH dehydrogenase (NDH-2)
enzymes which are predicted to be jointly essential for respiratory
metabolism. Furthermore, the structure of a closely related bacterial
NDH-2 has been reported recently, allowing for the structure-based
design of small-molecule inhibitors. Herein, we disclose <i>MTb</i> whole-cell structure–activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the <i>ndh</i> encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in <i>MTb</i> was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by <i>ndhA</i> in <i>MTb</i>. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial <i>MTb</i> SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors
Defining the clinical and cognitive phenotype of child savants with autism spectrum disorder
Objective: Whilst savant syndrome is most commonly observed in individuals with Autism Spectrum Disorder (ASD), it has historically been associated with intellectual impairment, and little is known about the clinical and cognitive characteristics of intellectually able individuals with ASD and savant skills. Methods: Participants with ASD and validated savant skills were compared with age and intelligence matched non-savants with ASD using a range of diagnostic and standardised tests. Results: Although the analysis of the clinical data revealed few differences between the groups, striking differences emerged during cognitive testing. Children with savant skills exhibited highly superior working memory and their scores on tests of analytic skills were also superior to those of non-savants. Conclusion: We propose that obsessionality, focused attention, superior working memory and analytic skills facilitate veridical mapping and pattern perception abilities characteristic in savant syndrome
3D-QSAR Modeling and Synthesis of New Fusidic Acid Derivatives as Antiplasmodial Agents
Wide spread Plasmodium
falciparum (P. falciparum) resistance has compromised
existing antimalarial therapies to varying degrees. Novel agents,
able to circumvent antimalarial drug resistance, are therefore needed.
Fusidic acid is a unique antibiotic with a unique mode of action,
which has shown weak <i>in vitro</i> antiplasmodial activity.
Toward identifying new fusidic acid derivatives with superior antiplasmodial
activity, a 3D-QSAR model was developed based on the antiplasmodial
activity of previously synthesized fusidic acid derivatives. The validated
Hypo 2 model was used as the 3D-structural search query to screen
a fusidic acid-based combinatorial library. On the basis of the predicted
activity and pharmacophore fit value, eight virtual hit compounds
were selected and synthesized, including C-21 amide and C-3 ether
derivatives. All synthesized hit compounds showed superior antiplasmodial
activity compared to fusidic acid. Two C-21 amide derivatives displayed
significant activity against the drug-sensitive NF54 strain with IC<sub>50</sub> values of 0.3 μM and 0.7 μM, respectively. These
two derivatives also displayed activity against the multidrug-resistant
K1 strain, with an IC<sub>50</sub> value of 0.2 μM and were
found to be relatively noncytotoxic
Design, Synthesis, and Antiplasmodial Activity of Hybrid Compounds Based on (2<i>R</i>,3<i>S</i>)‑<i>N</i>‑Benzoyl-3-phenylisoserine
A series of hybrid compounds based
on (2<i>R</i>,3<i>S</i>)-<i>N</i>-benzoyl-3-phenylisoserine,
artemisinin,
and quinoline moieties was synthesized and tested for in vitro antiplasmodial
activity against erythrocytic stages of K1 and W2 strains of <i>Plasmodium falciparum.</i> Two hybrid compounds incorporating
(2<i>R</i>,3<i>S</i>)-<i>N</i>-benzoyl-3-phenylisoserine
and artemisinin scaffolds were 3- to 4-fold more active than dihydroartemisinin,
with nanomolar IC<sub>50</sub> values against <i>Plasmodium falciparum</i> K1 strain
In silico Comparison of Antimycobacterial Natural Products with Known Antituberculosis Drugs
The
chemical space based on physicochemical properties and structural
features of a diverse group of natural products with reported in vitro
activity against different Mycobacterium tuberculosis strains is investigated using in silico tools. This is compared
to the chemical space occupied by drugs currently recommended for
the treatment of various forms of tuberculosis as well as compounds
in preclinical and clinical development. Docking studies exploring
possible binding affinities and modes of two main clusters of natural
products on two different mycobacterial targets are also reported.
Our docking results suggest that scytoscalarol, an antibacterial and
antifungal guanidine-bearing sesterterpene, can inhibit arabinosyltransferase Mtb EmbC, and the β-carboline alkaloids 8-hydroxymanzamine
A and manzamine A can bind to the oxidoreductase of Mtb INHA. On this basis, these products showing high
binding affinities to the two targets in silico could be rationally
selected for in vitro testing against these targets and/or semisynthetic
modification
Synthesis and Evaluation of a Carbosilane Congener of Ferroquine and Its Corresponding Half-Sandwich Ruthenium and Rhodium Complexes for Antiplasmodial and β‑Hematin Inhibition Activity
A silicon-containing
congener of ferroquine (<b>1</b>) was
synthesized by incorporating an organosilicon motif in the lateral
side chain of ferroquine. Compound <b>1</b> was then further
reacted with dinuclear half-sandwich transition-metal precursors [RuÂ(Ar)Â(μ-Cl)ÂCl]<sub>2</sub> (Ar = η<sup>6</sup>-<i>p</i>-<sup>i</sup>PrC<sub>6</sub>H<sub>4</sub>Me, η<sup>6</sup>-C<sub>6</sub>H<sub>6</sub>, η<sup>6</sup>-C<sub>6</sub>H<sub>5</sub>OCH<sub>2</sub>CH<sub>2</sub>OH), [RhÂ(COD)Â(μ-Cl)]<sub>2</sub>, and
[RhCp*Â(μ-Cl)ÂCl]<sub>2</sub>, to yield a series of heterometallic
organometallic complexes (<b>2</b>–<b>6</b>). Compound <b>1</b> coordinates selectively in a monodentate manner to the transition
metals via the quinoline nitrogen of the aminoquinoline scaffold.
All of the compounds were characterized using various analytical and
spectroscopic techniques, and the molecular structure of compound <b>1</b> was elucidated by single-crystal X-ray diffraction analysis.
Furthermore, the <i>in vitro</i> antiplasmodial activity
of compounds <b>1</b>–<b>6</b> was established
against the chloroquine-sensitive (NF54) and chloroquine-resistant
(Dd2) strains of the malaria parasite Plasmodium falciparum
Synthesis, Antiplasmodial Activity, and β‑Hematin Inhibition of Hydroxypyridone–Chloroquine Hybrids
A series
of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were
synthesized on the basis of a synergistic in vitro combination of
a precursor <i>N</i>-alkyl-3-hydroxypyridin-4-one with chloroquine
(CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive
(3D7) strains of <i>Plasmodium falciparum</i>. In vitro
antiplasmodial activity of the precursors was negated by blocking
the chelator moiety via complexation with galliumÂ(III) or benzyl protection.
None of the precursors inhibited β-hematin formation. Most hybrids
were more potent inhibitors of β-hematin formation than CQ,
and a correlation between antiplasmodial activity and inhibition of
β-hematin formation was observed. Potent hybrids against K1,
3D7, and W2, respectively, were <b>8c</b> (0.13, 0.004, and
0.1 μM); <b>8d</b> (0.08, 0.01, and 0.02 μM); and <b>7g</b> (0.07, 0.03, and 0.08 μM)
Synthesis and Evaluation of a Carbosilane Congener of Ferroquine and Its Corresponding Half-Sandwich Ruthenium and Rhodium Complexes for Antiplasmodial and β‑Hematin Inhibition Activity
A silicon-containing
congener of ferroquine (<b>1</b>) was
synthesized by incorporating an organosilicon motif in the lateral
side chain of ferroquine. Compound <b>1</b> was then further
reacted with dinuclear half-sandwich transition-metal precursors [RuÂ(Ar)Â(μ-Cl)ÂCl]<sub>2</sub> (Ar = η<sup>6</sup>-<i>p</i>-<sup>i</sup>PrC<sub>6</sub>H<sub>4</sub>Me, η<sup>6</sup>-C<sub>6</sub>H<sub>6</sub>, η<sup>6</sup>-C<sub>6</sub>H<sub>5</sub>OCH<sub>2</sub>CH<sub>2</sub>OH), [RhÂ(COD)Â(μ-Cl)]<sub>2</sub>, and
[RhCp*Â(μ-Cl)ÂCl]<sub>2</sub>, to yield a series of heterometallic
organometallic complexes (<b>2</b>–<b>6</b>). Compound <b>1</b> coordinates selectively in a monodentate manner to the transition
metals via the quinoline nitrogen of the aminoquinoline scaffold.
All of the compounds were characterized using various analytical and
spectroscopic techniques, and the molecular structure of compound <b>1</b> was elucidated by single-crystal X-ray diffraction analysis.
Furthermore, the <i>in vitro</i> antiplasmodial activity
of compounds <b>1</b>–<b>6</b> was established
against the chloroquine-sensitive (NF54) and chloroquine-resistant
(Dd2) strains of the malaria parasite Plasmodium falciparum
Identification of New Human Malaria Parasite Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors by Pharmacophore and Structure-Based Virtual Screening
Plasmodium falciparum dihydroorotate
dehydrogenase (<i>Pf</i>DHODH), a key enzyme in the de novo
pyrimidine biosynthesis pathway, which the Plasmodium
falciparum relies on exclusively for survival, has
emerged as a promising target for antimalarial drugs. In an effort
to discover new and potent <i>Pf</i>DHODH inhibitors, 3D-QSAR
pharmacophore models were developed based on the structures of known <i>Pf</i>DHODH inhibitors and the validated Hypo1 model was used
as a 3D search query for virtual screening of the National Cancer
Institute database. The virtual hit compounds were further filtered
based on molecular docking and Molecular Mechanics/Generalized Born
Surface Area binding energy calculations. The combination of the pharmacophore
and structure-based virtual screening resulted in the identification
of nine new compounds that showed >25% inhibition of <i>Pf</i>DHODH at a concentration of 10 μM, three of which exhibited
IC<sub>50</sub> values in the range of 0.38–20 μM. The
most active compound, NSC336047, displayed species-selectivity for <i>Pf</i>DHODH over human DHODH and inhibited parasite growth with
an IC<sub>50</sub> of 26 μM. In addition to this, 13 compounds
inhibited parasite growth with IC<sub>50</sub> values of ≤50
μM, 4 of which showed IC<sub>50</sub> values in the range of
5–12 μM. These compounds could be further explored in
the identification and development of more potent <i>Pf</i>DHODH and parasite growth inhibitors
The Dynamic Nonprime Binding of Sampatrilat to the C‑Domain of Angiotensin-Converting Enzyme
Sampatrilat is a vasopeptidase inhibitor
that inhibits both angiotensin
I-converting enzyme (ACE) and neutral endopeptidase. ACE is a zinc
dipeptidyl carboxypeptidase that contains two extracellular domains
(nACE and cACE). In this study the molecular basis for the selectivity
of sampatrilat for nACE and cACE was investigated. Enzyme inhibition
assays were performed to evaluate the in vitro ACE domain selectivity
of sampatrilat. The inhibition of the C-domain (<i>K</i><sub>i</sub> = 13.8 nM) by sampatrilat was 12.4-fold more potent
than that for the N-domain (171.9 nM), indicating differences in affinities
for the respective ACE domain binding sites. Interestingly, replacement
of the P<sub>2</sub> group of sampatrilat with an aspartate abrogated
its C-selectivity and lowered the potency of the inhibitor to activities
in the micromolar range. The molecular basis for this selective profile
was evaluated using molecular modeling methods. We found that the
C-domain selectivity of sampatrilat is due to occupation of the lysine
side chain in the S<sub>1</sub> and S<sub>2</sub> subsites and interactions
with Glu748 and Glu1008, respectively. This study provides new insights
into ligand interactions with the nonprime binding site that can be
exploited for the design of domain-selective ACE inhibitors