A simple and efficient microwave assisted synthesis of imidazobenzoxazines, imidazobenzoxazin-5-ones, and imidazobenzoxazin-5-thiones with broad chemistry scope is described. The molecules were prepared both under conven...A simple and efficient microwave assisted synthesis of imidazobenzoxazines, imidazobenzoxazin-5-ones, and imidazobenzoxazin-5-thiones with broad chemistry scope is described. The molecules were prepared both under conventional as well as microwave heating conditions, to provide in high yields with clean and scalable reactions a small library of imidazole-based privileged structures for drug discovery.
The substitution-cyclization reaction of heterocyclic ketene aminals with polyhalo isophthalonitrile in the presence of t-BuOK to form 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-imines, followed by hydrolysis wi...The substitution-cyclization reaction of heterocyclic ketene aminals with polyhalo isophthalonitrile in the presence of t-BuOK to form 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-imines, followed by hydrolysis with 1 N HCl, provides a concise and efficient route for the synthesis of highly functional polyhalo 1,3-diazaheterocycle fused [1,2-b]isoquinolin-1(2H)-ones.
Access to privileged heterocyclic scaffolds involving 4-aryl-6-(1H-indol-3-yl)-2,2-bipyridine-5-carbonitriles and 6-(2-furyl)-2-(1H-indol-3-yl)-4-arylpyridine-3-carbonitriles frameworks has been achieved via a single-ste...Access to privileged heterocyclic scaffolds involving 4-aryl-6-(1H-indol-3-yl)-2,2-bipyridine-5-carbonitriles and 6-(2-furyl)-2-(1H-indol-3-yl)-4-arylpyridine-3-carbonitriles frameworks has been achieved via a single-step multicomponent reaction of structurally diverse aldehydes, 2-acetylpyridine (or) 2-acetylfuran and 3-cyanoacetyl indole in ammonium acetate under neat condition. Also a series of 6,6'-di(1H-indol-3-yl)-4,4'-diaryl-2,2'-bipyridine-5,5'-dicarbonitrile and 7,7,7',7'-tetramethyl-4,4'-bis(aryl)-4,6,7,8,4',6',7',8'-octahydro-1H,1H-[2,2']biquinolinyl-5,5'-dione derivatives are synthesized using cinnamil, 3-cyanoacetyl indole (or) dimedone and ammonium acetate.
A one-pot, three-component reaction between pyridine, phenacyl bromide, and thiocyanate is described. The reaction afforded the corresponding special type of fully substituted imidazo[1,2-a]pyridine derivatives in good y...A one-pot, three-component reaction between pyridine, phenacyl bromide, and thiocyanate is described. The reaction afforded the corresponding special type of fully substituted imidazo[1,2-a]pyridine derivatives in good yields without using any catalyst or activation.
A novel series of HIV-1 integrase inhibitors were identified from a 100 member (4R(1) x 5R(2) x 5R(3)) library of pyrrolidinedione amides. A solid-phase route was developed which facilitates the simultaneous variation at...A novel series of HIV-1 integrase inhibitors were identified from a 100 member (4R(1) x 5R(2) x 5R(3)) library of pyrrolidinedione amides. A solid-phase route was developed which facilitates the simultaneous variation at R(1), R(2), and R(3) of the pyrrolidinedione scaffold. The resulting library samples were assayed for HIV-1 integrase activity and analyzed to determine the R(1), R(2), and R(3) reagent contributions towards the activity.
Controlled delivery of therapeutic protein drugs using biodegradable polymer carriers is a desired characteristic that enables effective, application-specific therapy and treatment. Previous studies have focused on prote...Controlled delivery of therapeutic protein drugs using biodegradable polymer carriers is a desired characteristic that enables effective, application-specific therapy and treatment. Previous studies have focused on protein delivery from polymers using conventional "one-sample-at-a-time" techniques, which are time-consuming and costly. In addition, many therapeutic proteins are in limited supply and are expensive, so it is desirable to reduce sample size for design and development of delivery devices. We have developed a rapid, high throughput technique based on a highly sensitive fluorescence-based assay to detect and quantify protein released from polyanhydrides while utilizing relatively small amounts of protein (approximately 40 microg). These studies focused on the release of a model protein, Texas Red conjugated bovine serum albumin, from polyanhydride copolymers based on sebacic acid (SA) and 1,6-bis(p-carboxyphenoxy)hexane (CPH). The protein release profiles were assessed simultaneously to investigate the effect of polymer device geometry (nanospheres vs films), polymer chemistry, and pH of the release medium. The results indicated that the nanosphere geometry, SA-rich chemistries, and neutral pH release medium led to a more rapid release of the protein compared to the film geometry, CPH-rich chemistries, and acidic pH release medium, respectively. This high throughput fluorescence-based method can be readily extended to study release kinetics for other proteins and polymer systems.
A promising method for the synthesis of cyclic peptides through the direct aminolysis of peptide thioesters is presented. The cyclization step was carried out in a mixture of acetonitrile and 1.5 M aqueous imidazole solu...A promising method for the synthesis of cyclic peptides through the direct aminolysis of peptide thioesters is presented. The cyclization step was carried out in a mixture of acetonitrile and 1.5 M aqueous imidazole solution with no observable oligomers. Studies on the N- and C-terminal residues show that the choice of C-terminal residue has a more significant effect on the success rate of cyclization than the choice at the N-terminal residue.
SO(3)H-functionalized ionic liquid was successfully applied as a water tolerant-acidic catalyst for the one-pot domino approach quinoline synthesis in aqueous medium. Various types of quinolines from 2-aminoaryl ketones...SO(3)H-functionalized ionic liquid was successfully applied as a water tolerant-acidic catalyst for the one-pot domino approach quinoline synthesis in aqueous medium. Various types of quinolines from 2-aminoaryl ketones and beta-ketoesters/ketones were prepared in 85-98% yields using the catalytic system of SO(3)H-functionalized ionic liquid/H(2)O. The ionic liquids was synthesized in a combinatorial fashion. The quinoline products could be conveniently separated from the reaction mixture by filtration, indicating that the whole process was performed in water and exemplifying a green chemistry. More importantly, the catalyst could be easily recycled for five times without loss of much activity. The catalytic system, reported here, possesses advantages of both homogeneous and heterogeneous catalysts.
Combinatorial libraries can be characterized in detail by high resolving power mass spectrometry. We here demonstrate this for synthetic decapeptide libraries using a state-of-the-art 15 T Fourier transform ion cyclotron...Combinatorial libraries can be characterized in detail by high resolving power mass spectrometry. We here demonstrate this for synthetic decapeptide libraries using a state-of-the-art 15 T Fourier transform ion cyclotron resonance mass spectrometer. Using comparison between predicted and measured spectra, a number of metrics can be derived that shed light on the library composition and degeneracy of elemental compositions. These techniques can be used to rapidly quality control combinatorial synthesis products or follow combinatorial libraries in more detail, for instance during binding studies or chemical reactions. The methods are in principle equally applicable to the analysis of other types of combinatorial libraries.
A one-pot, pseudo four-component method for the efficient and simple synthesis of spiro[diindeno[1,2-b:2',1'-e]pyridine-11,3'-indoline]-2',10,12-trione derivatives in refluxing acetonitrile is reported. The features of t...A one-pot, pseudo four-component method for the efficient and simple synthesis of spiro[diindeno[1,2-b:2',1'-e]pyridine-11,3'-indoline]-2',10,12-trione derivatives in refluxing acetonitrile is reported. The features of this procedure are mild reaction conditions, high yields of products, and operational simplicity.
A series of new naphtho[1,2-e][1,3]oxazine derivatives such as trans-1,3-diaryl-1H-naphtho[1,2-e][1,3]oxazine-2(3H)-carbonyl chloride, 1-aryl-2-benzyl-1,2- dihydronaphtho[1,2-e][1,3]oxazine-3-one, and trans-1,3-diaryl-1H...A series of new naphtho[1,2-e][1,3]oxazine derivatives such as trans-1,3-diaryl-1H-naphtho[1,2-e][1,3]oxazine-2(3H)-carbonyl chloride, 1-aryl-2-benzyl-1,2- dihydronaphtho[1,2-e][1,3]oxazine-3-one, and trans-1,3-diaryl-1H-naphtho[1,2-e] [1,3]oxazine-2(3H)-carbaldehyde were selectively synthesized via a chemoselective reaction of 1,3-diaryl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines and triphosgene or triethyl orthoformate, respectively, induced by different low-valent titanium systems. This method has the advantages of short reaction time (15 min), convenient manipulation, and high chemoselectivity.
A practical protocol for the preparation of parallel solution-phase libraries of the quaternary carbon-containing oxazatricycles and spiropyrans is reported. Target compounds were obtained in moderate to excellent yields...A practical protocol for the preparation of parallel solution-phase libraries of the quaternary carbon-containing oxazatricycles and spiropyrans is reported. Target compounds were obtained in moderate to excellent yields by an Et(3)N-mediated multicomponent reaction from various N-methylisoquinolium or flavylium salts and 4-hydroxycoumarins or dimedone in acetone. Purification of the final products by recrystallization in ethyl acetate/methylene chloride or by column chromatography allowed easy isolation of nine compounds of each array. Preliminary studies indicated that some of the prepared compounds exhibit redox switching, photochromic, and thermochromic properties.
A sequential three-component reaction of 3,5-diarylidenepiperidin-4-one, malononitrile, and amine (such as aromatic amine, cyclopropanamine, and NH(4)OAc) in acetic acid under microwave irradiation has been developed. In...A sequential three-component reaction of 3,5-diarylidenepiperidin-4-one, malononitrile, and amine (such as aromatic amine, cyclopropanamine, and NH(4)OAc) in acetic acid under microwave irradiation has been developed. In this one-pot reaction, a series of new N-substituted 2-amino-1,6-naphthyridine derivatives were synthesized with excellent yields. This method has the advantages of operational simplicity and increased safety for small-scale fast synthesis of N-aryl 2-amino-1,6-naphthyridines for biomedical screening.
Pharmaceutically interesting, angular bis-benzimidazoles with three appendages have been synthesized successfully through a diversity-oriented approach with soluble support under microwave irradiation. Polymer immobilize...Pharmaceutically interesting, angular bis-benzimidazoles with three appendages have been synthesized successfully through a diversity-oriented approach with soluble support under microwave irradiation. Polymer immobilized o-phenylenediamine was selectively N-acylated with 2-chloro-3-nitrobenzoic acid in a primary aromatic amino moiety. The obtained amide was cyclized to benzimidazole in an acidic condition, and subsequently nucleophilic aromatic substitution with different amines was performed. Successive reduction, cyclization with various aldehydes and activated isothiocyanates yielded angular biheterocyclic benzimidazoles in good quantities. Reaction progress on polymer support was precisely monitored using the conventional proton NMR spectroscopy. Preliminary screening results showed some of these interesting compounds exhibited moderately to good inhibition against vascular endothelial growth factor receptor 3 (VEGFR-3), which is related to invasion and migration of cancer cells.
Diketopiperazines (DKPs) are a well-known class of heterocycles that have emerged as promising biologically active scaffolds. Solid-phase organic synthesis has become an important tool in the combinatorial exploration of...Diketopiperazines (DKPs) are a well-known class of heterocycles that have emerged as promising biologically active scaffolds. Solid-phase organic synthesis has become an important tool in the combinatorial exploration of these privileged structures, expediting the synthesis and, often, the discovery of active compounds. We recently identified several DKPs that are capable of inhibiting the luminescence response of the bacterial symbiont Vibrio fischeri, and we sought to further test the scope of this biological activity. Herein, we report the synthesis of DKP macroarrays using a SPOT-synthesis approach based on an Ugi/DeBoc/Cyclize strategy. Neither a spacer nor a linker was required for macroarray construction on cellulose support, and the cyclative cleavage produced high purity DKPs in good yields. Using this protocol, we prepared a library of 400 DKPs on cellulose support and evaluated its members as luminescence inhibitors in V. fischeri. We found six DKPs capable of inhibiting luminescence by at least 80% at 500 muM. Collectively, this work serves to further highlight the utility of the small molecule macroarray platform for the synthesis and evaluation of focused libraries.
A mild, efficient, one-pot protocol for the synthesis of indazole-3(2H)-ones via cyclization of nitro-aryl substrates through low-valent titanium reagent has been described. The method used Triethylamine (TEA) to control...A mild, efficient, one-pot protocol for the synthesis of indazole-3(2H)-ones via cyclization of nitro-aryl substrates through low-valent titanium reagent has been described. The method used Triethylamine (TEA) to control pH. Particularly, 2-aminobenzonitriles were synthesized by one step easily. The mechanistic course of the reaction suggests the involvement of an anion leading to an intramolecular cyclization via N-N bond formation.