Protic Ionic Liquid Promoted One Pot Synthesis of 2‐amino‐4‐(phenyl)‐7‐methyl‐5‐oxo‐4H,5H‐pyrano[4,3‐b]pyran‐3‐carbonitrile Derivatives in Water and Their Antimycobacterial Activity

One pot three component reaction of 4‐hydroxy‐6‐methylpyran‐2‐one, 3‐methoxy benzaldehyde, and malononitrile in water using protic ionic liquid as a catalyst at room temperature afforded pyrano[4,3‐b]pyran derivatives. Protic ionic liquid has been proved to be an efficient and mild catalyst for the synthesis of pyrano[4,3‐b]pyran scaffolds due to their highly polar nature. The notable aspects of protic ionic liquid are easy availability, improved reaction rates, high product yields, simple workup procedure, recyclability, and reusability. Molecules docking studies have been performed on enzyme enoyl‐ACP‐reductase from Mycobacterium tuberculosis. The molecular docking simulation indicated plausible π‐alkyl and alkyl‐alkyl interactions between the amino acids and scaffolds. The synthesized derivatives have been evaluated for their in vitro antituberculotic activity against M. tuberculosis H₃₇RV strain using Microplate Alamar Blue Assay method. Together, biological activity data and docking data showed that the tested scaffolds exhibited excellent antituberculotic activity.     

An Expedient Approach for the Synthesis of Bioactive Pyrazole,Isoxazole and Benzodiazepine‐Substituted Quinolin‐2(1H)‐one Derivatives

A sequence of functionalized pyrazole, isoxazole and benzodiazepine‐substituted quinolone derivatives were synthesized in good yield starting from readily available starting precursors. These approaches lead to the synthesis of hitherto unknown compounds with a varied substitution pattern by both conventional and microwave‐assisted method. A good number of analogues were evaluated for their in vitro cytotoxicity against human cervical and colon cancer cell lines by MTT protocol. Almost all the selected compounds showed remarkable cytotoxic activities. Among them, compound 4g and 4i emerged as the most promising scaffolds. These scaffolds will be used for further molecular level studies.     

Synthesis of high‐molecular‐weight aliphatic–aromatic copolyesters from poly(ethylene‐co‐1,6‐hexene terephthalate) and poly(L‐lactic acid) by chain extension

A series of aliphatic–aromatic multiblock copolyesters consisting of poly(ethylene‐co‐1,6‐hexene terephthalate) (PEHT) and poly(L ‐lactic acid) (PLLA) were synthesized successfully by chain‐extension reaction of dihydroxyl terminated PEHT‐OH prepolymer and dihydroxyl terminated PLLA‐OH prepolymer using toluene‐2,4‐diisoyanate as a chain extender. PEHT‐OH prepolymers were prepared by two step reactions using dimethyl terephthalate, ethylene glycol, and 1,6‐hexanediol as raw materials. PLLA‐OH prepolymers were prepared by direct polycondensation of L ‐lactic acid in the presence of 1,4‐butanediol. The chemical structures, the molecular weights and the thermal properties of PEHT‐OH, PLLA‐OH prepolymers, and PEHT‐PLLA copolymers were characterized by FTIR, ¹H NMR, GPC, TG, and DSC. This synthetic method has been proved to be very efficient for the synthesis of high‐molecular‐weight copolyesters (say, higher than M_w = 3 × 10⁵ g/mol). Only one glass transition temperature was found in the DSC curves of PEHT‐PLLA copolymers, indicating that the PLLA and PEHT segments had good miscibility. TG curves showed that all the copolyesters had good thermal stabilities. The resulting novel aromatic–aliphatic copolyesters are expected to find a potential application in the area of biodegradable polymer materials. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5898–5907, 2009     

3D and Porous RGDC‐Functionalized Polyester‐Based Scaffolds as a Niche to Induce Osteogenic Differentiation of Human Bone Marrow Stem Cells

Polyester‐based scaffolds covalently functionalized with arginine‐glycine‐aspartic acid‐cysteine (RGDC) peptide sequences support the proliferation and osteogenic differentiation of stem cells. The aim is to create an optimized 3D niche to sustain human bone marrow stem cell (hBMSC) viability and osteogenic commitment, without reliance on differentiation media. Scaffolds consisting of poly(lactide‐co‐trimethylene carbonate), poly(LA‐co‐TMC), and functionalized poly(lactide) copolymers with pendant thiol groups are prepared by salt‐leaching technique. The availability of functional groups on scaffold surfaces allows for an easy and straightforward method to covalently attach RGDC peptide motifs without affecting the polymerization degree. The strategy enables the chemical binding of bioactive motifs on the surfaces of 3D scaffolds and avoids conventional methods that require harsh conditions. Gene and protein levels and mineral deposition indicate the osteogenic commitment of hBMSC cultured on the RGDC functionalized surfaces. The osteogenic commitment of hBMSC is enhanced on functionalized surfaces compared with nonfunctionalized surfaces and without supplementing media with osteogenic factors. Poly(LA‐co‐TMC) scaffolds have potential as scaffolds for osteoblast culture and bone grafts. Furthermore, these results contribute to the development of biomimetic materials and allow a deeper comprehension of the importance of RGD peptides on stem cell transition toward osteoblastic lineage.     

A Green Approach for the One‐Pot,Three‐Component Synthesis of 2‐Arylpyrroloacridin‐1(2H)‐Ones using Lactic Acid as a Bio‐based Catalyst under Solvent‐Free Conditions

A facile and benign synthetic strategy is proposed for the synthesis of 2‐arylpyrroloacridin‐1(2H )‐ones via a lactic acid‐catalyzed three‐component reaction of dimedone, various anilines, and isatins under solvent‐free conditions. Avoidance of hazardous organic solvents, the use of a one‐pot multicomponent procedure for the synthesis of 2‐arylpyrroloacridin‐1(2H )‐ones, operational simplicity, no need for column chromatography, lactic acid utilization as a bio‐based organic compound, reusability, homogeneity, and commercial availability of the catalyst, and superior synthetic performance are some important aspects of this methodology to access a series of pyrroloacridine motifs with potentially biological scaffolds.     

Convenient Structural Diversity‐Guided Synthesis of Functionalized Sulfur‐Containing Heterocycles via α‐Substituted Cyanoacetamides

A convenient molecular diversity‐oriented synthesis of various functional sulfur‐containing heterocyclic scaffolds mainly including isothiazole, 2H‐1,3‐thiazine, and thiazolidine via different methods from α‐substituted cyanoacetamides is described. The target molecules have been identified on the basis of analytical spectral data, which may serve as useful structural subunits in the fields of drug discovery.     

Fabrication of poly(lactide‐co‐glycolide) scaffold embedded spatially with hydroxyapatite particles on pore walls for bone tissue engineering

Poly(lactide‐co‐glycolide) (PLGA) scaffolds embedded spatially with hydroxyapatite (HA) particles on the pore walls (PLGA/HA‐S) were fabricated by using HA‐coated paraffin spheres as porogens, which were prepared by Pickering emulsion. For comparisons, PLGA scaffolds loaded with same amount of HA particles (2%) in the matrix (PLGA/HA‐M) and pure PLGA scaffolds were prepared by using pure paraffin spheres as porogens. Although the three types of scaffolds had same pore size (450–600 µm) and similar porosity (90%–93%), the PLGA/HA‐S showed the highest compression modulus. The embedment of the HA particles on the pore walls endow the PLGA/HA‐S scaffold with a stronger ability of protein adsorption and mineralization as well as a larger mechanical strength against compression. In vitro culture of rat bone marrow stem cells revealed that cell morphology and proliferation ability were similar on all the scaffolds. However, the alkaline phosphatase activity was significantly improved for the cells cultured on the PLGA/HA‐S scaffolds. Therefore, the method for fabricating scaffolds with spatially embedded nanoparticles provides a new way to obtain the bioactive scaffolds for tissue engineering. Copyright © 2011 John Wiley & Sons, Ltd.     

Highly Efficient Non‐Palladium‐Catalyzed Controlled Synthesis and X‐ray Analysis of Functionalized 1,2‐Diaryl‐, 1,2,3‐Triaryl‐, and 1,2,3,4‐Tetraarylbenzenes

A general, two‐step, highly efficient synthesis of 1,2‐diaryl‐, 1,2,3‐triaryl‐, and 1,2,3,4‐tetraarylbenzenes from simple stitching of α‐oxo‐ketene‐S,S‐acetals and active methylene compounds via a lactone intermediate is described. This procedure offers easy access to highly functionalized arylated benzenes that contain sterically demanding groups in good to excellent yields. The novelty of the procedure lies in the construction of aromatic compounds with the desired conformational flexibility along the molecular axis in a transition‐metal‐free environment through easily accessible precursors. Crystal analysis of these arylated benzene scaffolds showed that the peripheral aryl rings are arranged in a propeller‐like fashion with respect to the central benzene ring. Examination of the crystal packing in the structure of a 1,2,3,4‐tetraarylbenzene revealed an N???π interaction between molecules related by a two‐fold screw axis running in the direction of the a axis. Interestingly, the repeating array of N???π interactions around the axis of this 1,2,3,4‐tetraarylbenzene forces the molecules into a helical pattern.     

Fast Efficient and General PASE Approach to Medicinally Relevant 4H,5H‐Pyrano‐[4,3‐b]pyran‐5‐one and 4,6‐Dihydro‐5H‐pyrano‐[3,2‐c]pyridine‐5‐one Scaffolds

The general ‘on‐solvent’ PASE approach was found to be medicinally relevant for 4H,5H‐pyrano[4,3‐b]pyran‐5‐one and 4,6‐dihydro‐5H‐pyrano[3,2‐c]pyridine‐5‐one scaffolds. Ammonium acetate‐catalyzed multicomponent reaction of aldehydes and two different C–H acids in the presence of small amounts of EtOH results in fast (3 – 15 min) and efficient formation of scaffolds, promising for many diverse oriented medical applications.     

Preparation and mechanical properties of poly(chitosan‐g‐DL‐lactic acid) fibrous mesh scaffolds

DL ‐lactic acid was grafted onto chitosan to produce poly(chitosan‐g‐DL ‐lactic acid)(PCLA) without using a catalyst. These PCLAs were then spun into filaments and further fabricated into fibrous mesh scaffolds using an improved wet‐spinning technique. The diameter of filaments in different scaffolds could vary from a few micrometers to several tens of micrometers. The scaffolds exhibited various pore sizes ranging from about 20 µm to more than 200 µm and different porosities up to 80%. The several main processing conditions were optimized for obtaining the desired scaffolds with well‐controlled structures. The tensile and compressive mechanical properties of the mesh scaffolds in both dry and hydrated states were mainly examined. Significantly improved tensile strength and modulus, enhanced compressive modulus, and stress as well as the dimensional stability for these mesh scaffolds in their hydrated state were observed. Copyright © 2007 John Wiley & Sons, Ltd.     

Reagent‐Based DOS: Developing a Diastereoselective Methodology to Access Spirocyclic‐ and Fused Heterocyclic Ring Systems

Herein, we report a diversity‐oriented‐synthesis (DOS) approach for the synthesis of biologically relevant molecular scaffolds. Our methodology enables the facile synthesis of fused N‐heterocycles, spirooxoindolones, tetrahydroquinolines, and fused N‐heterocycles. The two‐step sequence starts with a chiral‐bicyclic‐lactam‐directed enolate‐addition/substitution step. This step is followed by a ring‐closure onto the built‐in scaffold electrophile, thereby leading to stereoselective carbocycle‐ and spirocycle‐formation. We used in silico tools to calibrate our compounds with respect to chemical diversity and selected drug‐like properties. We evaluated the biological significance of our scaffolds by screening them in two cancer cell‐lines. In summary, our DOS methodology affords new, diverse scaffolds, thereby resulting in compounds that may have significance in medicinal chemistry.     

One Pot Synthesis of Medicinally Important cis‐2‐Methyl‐4‐amino substituted‐1,2,3,4‐tetrahydroquinolines

A simple synthesis of medicinally important cis‐2‐methyl‐4‐azapan‐2‐one‐1,2,3,4‐tetrahydroquinolines/cis‐9‐(2‐methyl‐1,2,3,4‐tetrahydroquinolin‐4‐yl)‐9H‐carbazole was reported. Multicomponent one pot synthesis with anilines and N‐vinylcaprolactam/N‐vinyl carbazole via imino Diels‐Alder reaction by using antimony trichloride as catalyst and acetonitrile as solvent was employed. NMR technique (2D) was used to study the regio‐ and stereo‐chemistry of newly synthesized compounds. The cis diastereo‐selectivity of the products was predicted by COSY and NOESY studies.     

Copper‐Catalyzed Domino Synthesis of 2‐Imino‐1H‐imidazol‐5(2H)‐ones and Quinoxalines Involving CC Bond Cleavage with a 1,3‐Dicarbonyl Unit as a Leaving Group

Although 2‐imino‐1H‐imidazol‐5(2H)‐ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as “privileged scaffolds” in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper‐catalyzed domino reactions for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones and quinoxalines involving C?C bond‐cleavage with a 1,3‐dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones includes aza‐Michael addition, intramolecular cyclization, C?C bond‐cleavage, 1,2‐rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza‐Michael addition, intramolecular cyclization, elimination reaction, and C?C bond‐cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.     

In situ green synthesis of Cu‐Ni bimetallic nanoparticles supported on reduced graphene oxide as an effective and recyclable catalyst for the synthesis of N‐benzyl‐N‐aryl‐5‐amino‐1H‐tetrazoles

In the present work, for the first time we have designed a novel approach for the synthesis of N‐benzyl‐N‐aryl‐5‐amino‐1H‐tetrazoles using reduced graphene oxide (rGO) decorated with Cu‐Ni bimetallic nanoparticles (NPs). In situ synthesis of Cu/Ni/rGO nanocomposite was performed by a cost efficient, surfactant‐free and environmentally benign method using Crataegus azarolus var. aronia L. leaf extract as a stabilizing and reducing agent. Phytochemicals present in the extract can be used to reduce Cu²⁺ and Ni²⁺ ions and GO to Cu NPs, Ni NPs and rGO, respectively. Analyses by means of FT‐IR, UV–Vis, EDS, TEM, FESEM, XRD and elemental mapping confirmed the Cu/Ni/rGO formation and also FT‐IR, NMR, and mass spectroscopy as well as elemental analysis were used to characterize the tetrazoles. The Cu/Ni/rGO nanocomposite showed the superior catalytic activity for the synthesis of N‐benzyl‐N‐aryl‐5‐amino‐1H‐tetrazoles within a short reaction time and high yields. Furthermore, this protocol eliminates the need to handle HN₃.     

Imprinted silica nanoparticles coated with N‐propylsilylmorpholine‐4‐carboxamide for the determination of m‐cresol in synthetic and real samples

m‐Cresol‐imprinted silica nanoparticles coated with N‐propylsilylmorpholine‐4‐carboxamide have been developed that contain specific pockets for the selective uptake of m‐cresol. Silica nanoparticles were synthesized by a sol–gel process followed by functionalization of their surface with N‐propylsilylmorpholine‐4‐carboxamide. The formation of m‐cresol‐imprinted silica nanoparticles was confirmed by UV‐Vis spectrophotometry, infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy and transmission electron microscopy. Electron microscopic studies revealed the formation of monodispersed imprinted silica nanoparticles with spherical shape and an average size of 83 nm. The developed nanoparticles were filled in a syringe and used for the extraction of m‐cresol from aqueous samples followed by quantification using high‐performance liquid chromatography with diode array detection. Various adsorption experiments showed that developed m‐cresol‐imprinted silica nanoparticles exhibited a high adsorption capacity and selectivity and offered a fast kinetics for rebinding m‐cresol. The chromatographic quantification was achieved using mobile phase consisting of acetonitrile/water (70:30 v/v) at an isocratic flow rate of 1.0 mL/min using a reversed‐phase C₁₈ column and detection at λ_max = 275 nm. The limits of detection and quantification were 1.86 and 22.32 ng/mL, respectively, for the developed method. The percent recoveries ranged from 96.66–103.33% in the spiked samples. This combination of this nanotechnique with molecular imprinting was proved as a reliable, sensitive and selective method for determining the target from synthetic and real samples.     

One‐Pot Cascade Transformation of Glucal into Structurally Diverse Drug‐Like Scaffolds

A diversity‐oriented synthesis strategy to produce three types of structurally drug‐like N‐heterocyclic‐fused rings has been developed from abundant biomass‐derived d ‐glucal, aniline and water in a stereoselective manner. The overall transformation which entails a cascade of Ferrier reaction and 4π conrotatory imino‐Nazarov cyclization was performed in one‐pot allowing convenient preparation of scaffolds of high molecular complexity from relatively simple starting materials. While indoline‐fused products were readily accessible using ortho‐unsubstituted secondary anilines as substrates, reactions with ortho‐hydroxyl‐anilines furnished fused 1,4‐benzoxazines instead. In both cases, InBr₃ acted as the Lewis acid catalyst. By altering InBr₃ to Ln(OTf)₃, the indoline‐fused products could be further converted into tetrahydroquinoline‐fused cyclopentenones via ensuing retro‐ene rearrangement.     

Chalcogen‐Bonding Catalysis: From Neutral to Cationic Benzodiselenazole Scaffolds

Benzodiselenazoles (BDS) are emerging as privileged structures for chalcogen‐bonding catalysis in the focal point of conformationally immobilized σ holes on strong selenium donors in a neutral scaffold. Whereas much attention has been devoted to work out the advantages of selenium compared to the less polarizable sulfur donors, high expectations concerning bidentate, rigid, and neutral scaffolds have been generated with little experimental support. Here we report design, synthesis and evaluation of the necessary catalysts to confirm that i) bidentate BDS are more effective than their monodentate analogs, ii) conformationally immobilized scaffolds are more effective than more flexible ones, iii) cationic BDS scaffolds are more effective than neutral ones, and iv) in dicationic‐bidentate BDS, contributions from chalcogen‐bonding dominate possible contributions from ion‐pairing catalysis. These conclusions result from rate enhancements found for a Ritter‐type anion‐binding reaction and an X‐ray crystal structure of dicationic BDS with a triflate anion bound with highest precision in the focal point of the σ holes.     

Anionic polymerization of 4‐phenyl‐1‐buten‐3‐yne derivatives bearing electron‐withdrawing groups

The anionic polymerization of derivatives of 4‐phenyl‐1‐buten‐3‐yne was carried out to investigate the effect of substituents on the polymerization behavior. The polymerization of 4‐(4‐fluorophenyl)‐1‐buten‐3‐yne and 4‐(2‐fluorophenyl)‐1‐buten‐3‐yne in tetrahydrofuran at −78 °C with n‐BuLi/sparteine as an initiator gave polymers consisting of 1,2‐ and 1,4‐polymerized units in quantitative yields with ratios of 80/20 and 88/12, respectively. The molecular weights of the polymers were controlled by the ratio of the monomers to n‐BuLi, and the distribution was relatively narrow (weight‐average molecular weight/number‐average molecular weight < 1.2), supporting the living nature of the polymerization. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 1016–1023, 2001     

SET‐LRP synthesis of PMHDO‐g‐PNIPAM well‐defined amphiphilic graft copolymer

A well‐defined amphiphilic graft copolymer, consisting of hydrophobic polyallene‐based backbone and hydrophilic poly(N‐isopropylacrylamide) (PNIPAM) side chains, was prepared by the combination of living coordination polymerization, single electron transfer‐living radical polymerization (SET‐LRP), and the grafting‐from strategy. First, the double‐bond‐containing backbone was prepared by [(η³‐allyl)NiOCOCF₃]₂‐initiated living coordination polymerization of 6‐methyl‐1,2‐heptadiene‐4‐ol (MHDO). Next, the pendant hydroxyls in every repeating unit of poly(6‐methyl‐1,2‐heptadiene‐4‐ol) (PMHDO) homopolymer were treated with 2‐chloropropionyl chloride to give PMHDO‐Cl macroinitiator. Finally, PNIPAM side chains were grown from PMHDO backbone via SET‐LRP of N‐isopropylacrylamide initiated by PMHDO‐Cl macroinitiator in N,N‐dimethylformamide/2‐propanol using copper(I) chloride/tris(2‐(dimethylamino)ethyl)amine as catalytic system to afford PMHDO‐g‐PNIPAM graft copolymers with a narrow molecular weight distribution (M_w/M_n = 1.19). The critical micelle concentration (cmc) in water was determined by fluorescence probe technique and the effects of pH and salinity on the cmc of PMHDO‐g‐PNIPAM were also investigated. The micellar morphology was found to be spheres using transmission electron microscopy. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Stimuli‐responsive brush‐shaped conjugated polymers with pendant well‐defined poly(vinyl ether)s

For the synthesis of brush‐shaped conjugated polymers consisting of a poly(phenylene butadiynylene) backbone and well‐defined poly(vinyl ether) (polyVE) side chains, we designed polyVE‐based macromonomers bearing a diethynyl benzene group at the terminus and applied them to the grafting through synthesis. The macromonomer (DE‐PIBVE) was synthesized by living cationic polymerization of isobutyl VE (IBVE) using a functionalized initiator (TMS‐DEVE‐TFA) having a TMS protected diethynyl benzene moiety, followed by deprotection of the TMS groups. As a result, we succeeded in the synthesis of the target brush‐shaped conjugated polymers [poly(DE‐PIBVE)] by oxidative coupling reaction of the diethynyl benzene groups. We found that the solution of poly(DE‐PIBVE) with a specific side chain length exhibited solvatochromism and thermochromism depending on the polarity of the media employed. This phenomenon was attributed to self‐assembly in polar media due to the intermolecular π–π interaction between neighboring conjugated polymer backbones, where the self‐assembly behavior would be closely related to the pendant polyVE structure. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3318–3325