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 IC₅₀ 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