Solution-phase Combinatorial Synthesis Research Articles

Liquid-Phase Combinatorial Library Synthesis: Recent Advances and Future Perspectives

Liquid-phase combinatorial library synthesis is commonly developed into the viable alternatives or adjunct across the broad spectrum of polymer-supported organic chemistry. It includes the use of soluble polymer supports in the combinatorial synthesis of peptides and small-molecular library compounds which act as catalyst and reagent supports. It also includes high throughput biological screening with generation and evaluation of chemical leads for drug discovery development. In this review, liquid-phase combinatorial library synthesis is shown as the most efficient method of choice for the synthesis of most of the combinatorial library compounds with specific approaches from different groups that state potentials of solution-phase combinatorial synthesis.

A Remarkably High-Speed Solution-Phase Combinatorial Synthesis of 2-Substituted-Amino-4-Aryl Thiazoles in Polar Solvents in the Absence of a Catalyst under Ambient Conditions and Study of Their Antimicrobial Activities

Remarkably high-speed synthesis of 2-substituted amino-4-aryl thiazoles in polar solvents with a minimum threshold polarity index of 4.8 was found to proceed to completion in just 30–40 sec. affording excellent yields of thiazoles under ambient temperature conditions without the use of any additional catalyst. The purification-free procedure afforded libraries based around a known pharmacophore, namely, substituted arylthiazoles and generated samples of high purity. In terms of combinatorial synthesis in a single solution phase, our protocol is significantly better than those hitherto reported and is amenable for HTS. The in vitro biological tests of some thiazoles showed good activity towards gram-positive bacteria, gram-negative bacteria and fungi comparable with the standard drugs, nitrofurantoin and griseofulvin, for their antibacterial and antifungal activities, respectively.

ChemInform Abstract: Amino‐Functionalized Carbon Nanotubes as Nucleophilic Scavengers in Solution Phase Combinatorial Synthesis.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

산업생산 제조조건에서의 나트륨 디아세테이트 합성

and it has several characteristics: 1) Trophicity. It is an additive in animal feed to increase the trophicity of animal feed effectively. And the animal feed which contains the SDA can improve the growth of pigs and milk performance. 2) Special taste. The sour taste of SDA can cover all the bad odor of other synthesis additives in the feed. 3) High-performance. The efficiency of SDA is much higher than traditional preservative agents. For example, the dosage of SDA is only half or one third of sodium propionate and the price of SDA is much lower. 4) Security. SDA has no toxic effect to human and animals.Right now, the production technologies of SDA are acetic acid-sodium acetate solution-phase combinatorial synthesis method, acetic acid-sodium acetate vapor synthesis method, aceticanhydride-sodium acetate solution-phase combina-torial synthesis method, ace tic acid-acetica nhydride-sodium acetate solution-phase combinatorial synthesis method, and acetic acid-sodium carbonate synthesis method.

Amino-functionalized carbon nanotubes as nucleophilic scavengers in solution phase combinatorial synthesis

A versatile method for fast scavenging a variety of electrophiles using carbon nanotubes functionalized by amino groups (CNT–NH2) is reported. Following the scavenging event, CNT–NH2 can be easily separated from the reaction mixture by filtration, leaving the desired products in excellent yields and purities.

Combinatorial approach: identification of potential antifungals from triazole minilibraries

Employing basic principles of solution phase combinatorial chemistry, a solution phase combinatorial synthesis and screening of mini libraries of 1,2,4-triazole derivatives has been carried out. 6 × 6 indexed mini libraries were synthesized comprising of 36 compounds. The libraries were analyzed by liquid chromatography–mass spectrometry–mass spectrometry (LC–MS–MS) analysis. All the synthesized mini libraries were screened for antifungal activity and by deconvolution methodology leads for every fungi used for study were identified. The leads were synthesized individually and screened for activity. The antifungal activity of individually synthesized leads was improved as anticipated, in comparison with that of any of the mini libraries.

A Concise and Diversity-Oriented Approach to the Synthesis of SAG Derivatives

An efficient and rapid solution-phase combinatorial synthesis of the SAG library was developed. The salient features for this library synthesis is the application of carbothioamide-derived palladacycle-catalyzed Suzuki coupling reactions for the parallel synthesis of a series of pyridine-based biaryl aldehydes under aerobic conditions and a direct N-alkylation of carbamates using NaH as base in DMF in the presence of catalytic amount of water. The resultant library has been submitted to biological screening to evaluate their potential role in the regulation of Hedgehog pathway.

An Efficient Selective Reduction of Aromatic Azides to Amines Employing BF3·OEt2/NaI: Synthesis of Pyrrolobenzodiazepines

A selective and facile method for the reduction of aromatic azides to amines by employing borontrifluoride diethyl etherate and sodium iodide. This methodology has been applied towards the preparation of biologically important imine-containing pyrrolobenzodiazepines and their dilactams through intramolecular reductive-cyclization process. In this protocol the reagent systems are amenable for the generation of solution-phase combinatorial synthesis.

Solution Phase Combinatorial Synthesis and Screening of Mini Libraries of Arylchalcones for Antibacterial Activity

The solution-phase combinatorial synthesis of aryl chalcones was studied by synthesizing a 6x4 array mini library. The mini libraries of chalcones were synthesized by condensation of 4-substituted acetophenones and various aryl/heteroaryl carbaldehydes. All the synthesized mini libraries were screened for antibacterial activity using serial dilution method. The mini-libraries 3{1a,2a–d}, 3{1b,2a–d}, 3{1a–f,2a} and 3{1a–f,2c}were found to be most active of the synthesized mini libraries. The common elements present in the identified pool of interest were used to individually synthesize four compounds which were individually subjected to antibacterial activity evaluation. The compound 3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one exhibited significant activity that was better than that of the other three compounds synthesized. The anti-bacterial activity of the identified hit was also found to be better than all mini-libraries, indicating utility of combinatorial synthesis and the assumption there in for lead identification.

Expedient Lewis Acid Catalyzed Synthesis of a 3-Substituted 5-Arylidene-1-methyl-2-thiohydantoin Library

An efficient and rapid solution phase combinatorial synthesis of a 3-substituted 5-arylidene-1-methyl-2-thiohydantoin library was developed. The salient feature for this library production procedure is the addition of the Lewis acid catalyst, indium(III) trifluoromethanesulfonate, which serves to facilitate the direct condensation of aldehydes with 3-substituted 1-methyl-2-thiohydantoins. Use of this Lewis acid catalyst has resulted in faster reaction times, higher conversions and better purity profiles for these condensation reactions as compared to traditional uncatalyzed reactions. The resulting 315 member library of 3-substituted 5-arylidene-1-methyl-2-thiohydantoin is described.

Combinatorial Solution-Phase Synthesis of (2S,4S)-4-Acylamino-5-oxopyrrolidine-2-carboxamides

Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides.

Amino-Functionalized Ionic Liquid as A Nucleophilic Scavenger in Solution Phase Combinatorial Synthesis

A new functionalized ionic liquid, 1-aminoethyl-3-methylimidazolium hexafluorophosphate was synthesized from 1-methylimidazole and 2-bromoethylamine hydrobromide. This ionic liquid was found to be an efficient scavenger for removing excess electrophiles, such as benzoyl chloride, p-toluenesulfochloride, phenyl isothiocyanate, and p-chlorophenyl isocyanate, in a solution-phase parallel synthesis. The resulting ionic liquid derivatives can be separated directly from the reaction mixture. Desired products were obtained with high purity. Only 1.5-2.0 equiv of this scavenger was needed with a sequestration time of less than 35 min. In addition, the used ionic liquid can be regenerated and recycled several times without significant loss of activity.

Efficient Optimization Strategy for Marginal Hits Active Against abl Tyrosine Kinases

Primary high-throughput screening of commercially available small molecules collections often results in hit compounds with unfavorable ADME/Tox properties and low IP potential. These issues are addressed empirically at follow-up lead development and optimization stages. In this work, we describe a rational approach to the optimization of hit compounds discovered during screening of a kinase focused library against abl tyrosine kinase. The optimization strategy involved application of modern chemoinformatics techniques, such as automatic bioisosteric transformation of the initial hits, efficient solution-phase combinatorial synthesis, and advanced methods of knowledge-based libraries design.

Solution-phase combinatorial synthesis of nonpeptide bradykinin antagonists

We describe the solution-phase combinatorial synthesis and pharmacological effect of fifty N, N ′-substituted- N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide derivatives as nonpeptide B2 antagonists. The synthesized compounds were tested for their antibradykinin activity by utilizing guinea-pig ileum smooth muscle. Most of the compounds showed antagonistic effects on bradykinin induced contraction. N-acetyl- N ′-(4-methylbenzyl)- N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide ( A3B1C1) showed the 46% inhibition at 100 nM.

Solution-phase combinatorial synthesis of nonpeptide bradykinin antagonists

We describe the solution-phase combinatorial synthesis and pharmacological effect of fifty N,N′-substituted-N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide derivatives as nonpeptide B2 antagonists. The synthesized compounds were tested for their antibradykinin activity by utilizing guinea-pig ileum smooth muscle. Most of the compounds showed antagonistic effects on bradykinin induced contraction. N-acetyl-N′-(4-methylbenzyl)-N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide (A3B1C1) showed the 46% inhibition at 100 nM.

Ultrasound-Promoted Scavenging: A Rapid Parallel Purification for Solution Phase Combinatorial Synthesis

Ultrasound irradiation enhances the mass transfer and reaction rate in scavenging, avoiding the trouble of time-consuming purification procedure in solution-phase parallel synthesis. An application of this technique is demonstrated in the scavenging of excess isothiocyanates from reaction mixtures.

Pyridazines. Part 37: Facile solution phase combinatorial synthesis of highly substituted pyridazin-3-ones.

Arrays of polysubstituted pyridazinones were prepared through three- or four-component transformations starting from the readily accessible ene-adducts 2.

Synthesis of a Novel Pyrrole Oxazole Analogue of the Insecticide Pirate

The pyrrole oxazole 4 is a novel analogue of the broad-spectrum insecticide and miticide pirate 2. The expedient synthesis of pyrrole oxazole 4 in six steps from pyrrole is reported using a synthetic route that could have potential for the solution-phase combinatorial synthesis of analogues. Preliminary biological evaluation of the protected pyrrole oxazole 4 (LD50 1.13 μg mL–1) and the deprotected pyrrole oxazole 5 (LD50 1.06 μg mL–1) for potential cytotoxicity was carried out.

A Facile Solution Phase Combinatorial Synthesis of Tetrasubstituted Pyridines Using the Bohlmann—Rahtz Heteroannulation Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Scavenger Resins in Solution-Phase CombiChem

This chapter provides an overview of the several advances in the solid-phase assisted solution-phase combinatorial synthesis, specifically the use of scavenger resins in assisting the isolation of pure product without the need for chromatography. The most popular methodology for solution-phase combinatorial chemistry is the use of scavenger resins that are also known as polymer-supported quenching/scavenging reagents. Additional methodologies applied for the same purpose of rapid purification include chemical tagging of reagents, solid-phase extraction, and fluorous-phase extraction. Solution-phase combinatorial synthesis provides a homogeneous reaction medium and overcomes the drawbacks of a solid-phase strategy. An easy and reliable purification method is required in solution-phase combinatorial (parallel) synthesis to facilitate automation. The throughput in solution-phase automated synthesis is directly related to the facility of performing, for example, a purification process (work-up), compound separation. During the past several years, polymer-assisted solution-phase synthesis has become the prevalent method for the parallel synthesis of chemical libraries. A key step in the parallel solution-phase combinatorial synthesis of compound collections involves the purification of each member of the library. The possibility of avoiding aqueous work-up, crystallization, and chromatographic procedures makes the whole process more suitable for automation, and enhances its efficiency from economic and ecological viewpoints.