6 research outputs found
Combinatorial Synthesis of Oxazol-Thiazole Bis-Heterocyclic Compounds
A combinatorial library of novel
oxazol-thiazole bis-heterocycles
was synthesized in good to excellent overall yields with high purity
using a solution and solid-phase parallel synthesis approach. Oxazole
amino acids, prepared from serine methyl ester and amino acids via
coupling and cyclodehydration, were treated with Fmoc-NCS and α-haloketones
for the parallel synthesis of diverse bis-heterocycles. Fmoc-isothiocyanate
is used as a traceless reagent for thiazole formation. Oxazole diversity
can be achieved by using variety of amino acids, whereas thiazole
diversity is produced with various haloketones
Synthesis of Trifunctional Thiazolyl Amino Acids And Their Use for the Solid-Phase Synthesis of Small Molecule Compounds and Cyclic Peptidomimetics
Chiral
thiazolyl amino acid building blocks for the solid-phase
synthesis of small molecules, peptides, and cyclic peptides have been
designed and synthesized starting from Fmoc protected asparagine and
glutamine. In efforts to demonstrate the usefulness and validity of
such building blocks, a small library of 16 new thiazole containing
small molecules has been prepared and characterized. Additionally,
we report the use of the newly prepared trifunctional thiazolyl glutamine
for the on-resin, head-to-tail synthesis of cyclic peptides
Easy Conversion of Dimethyl α-(Bromomethyl)fumarate into Functionalized Allyl Ethers Mediated by DABCO
<div><p></p><p>New functionalized allyl ethers were obtained in good yields following the mild selective reaction of different alcohols with allyl bromide in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) and a catalytic amount of triethylamine (TEA) at room temperature.</p></div
Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors
In the development of analgesics
with mixed-opioid agonist activity, peripherally selective activity
is expected to decrease side effects, minimizing respiratory depression
and reinforcing properties generating significantly safer analgesic
therapeutics. We synthesized diazaheterocyclics from reduced tripeptides.
In vitro screening with radioligand competition binding assays demonstrated
variable affinity for μ (MOR), δ (DOR), and κ (KOR)
opioid receptors across the series, with the diimidazodiazepine <b>14</b> (2065-14) displaying good affinity for DOR and KOR. Central
(icv), intraperitoneal (ip), or oral (po) administration of <b>14</b> produced dose-dependent, opioid-receptor mediated antinociception
in the mouse, as determined from a 55 °C warm-water tail-withdrawal
assay. Only trace amounts of compound <b>14</b> was found in
brain up to 90 min later, suggesting poor BBB penetration and possible
peripherally restricted activity. Central administration of <b>14</b> did not produce locomotor effects, acute antinociceptive
tolerance, or conditioned-place preference or aversion. The data suggest
these diazaheterocyclic mixed activity opioid receptor agonists may
hold potential as new analgesics with fewer liabilities of use
Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens
Mixture based synthetic combinatorial
libraries offer a tremendous
enhancement for the rate of drug discovery, allowing the activity
of millions of compounds to be assessed through the testing of exponentially
fewer samples. In this study, we used a scaffold-ranking library to
screen 37 different libraries for antibacterial activity against the
ESKAPE pathogens. Each library contained between 10000 and 750000
structural analogues for a total of >6 million compounds. From
this,
we identified a bis-cyclic guanidine library that displayed strong
antibacterial activity. A positional scanning library for these compounds
was developed and used to identify the most effective functional groups
at each variant position. Individual compounds were synthesized that
were broadly active against all ESKAPE organisms at concentrations
<2 μM. In addition, these compounds were bactericidal, had
antibiofilm effects, showed limited potential for the development
of resistance, and displayed almost no toxicity when tested against
human lung cells and erythrocytes. Using a murine model of peritonitis,
we also demonstrate that these agents are highly efficacious in vivo
Scaffold Ranking and Positional Scanning Utilized in the Discovery of nAChR-Selective Compounds Suitable for Optimization Studies
Nicotine
binds to nicotinic acetylcholine receptors (nAChR), which can exist
as many different subtypes. The α4β2 nAChR is the most
prevalent subtype in the brain and possesses the most evidence linking
it to nicotine seeking behavior. Herein we report the use of mixture
based combinatorial libraries for the rapid discovery of a series
of α4β2 nAChR selective compounds. Further chemistry optimization
provided compound <b>301</b>, which was characterized as a selective
α4β2 nAChR antagonist. This compound displayed no agonist
activity but blocked nicotine-induced depolarization of HEK cells
with an IC<sub>50</sub> of approximately 430 nM. <b>301</b> demonstrated
nearly 500-fold selectivity for binding and 40-fold functional selectivity
for α4β2 over α3β4 nAChR. In total over 5
million compounds were assessed through the use of just 170 samples
in order to identify a series of structural analogues suitable for
future optimization toward the goal of developing clinically relevant
smoking cessation medications