Presence Of Piperidine Research Articles

Synthesis, Cytotoxicity, ADMET and Molecular Docking Studies of Some Quinoline-Pyrimidine Hybrid Compounds: 3-(2-Amino-6-arylpyrimidin-4- yl)-4-hydroxy-1-methylquinolin-2(1H)-ones.

This study aims are the synthesis of 3-(2-amino-6-arylpyrimidin-4-yl)-4-hydroxy-1- methylquinolin-2(1H)-ones and estimation their anticancer activities on HepG2 and KB cancer lines. Many derivatives of quinoline-2-on have been interested to synthesize and evaluate their biological properties by organic chemists due to their various biological effects, including antibacterial, antioxidant, anti-inflammatory, anticancer activities. Quinoline-pyrimidine hybrid compounds exhibited various biological activities, such as antituberculosis, antibacterial, anticancer, antifungal, etc. The connection of 4-hydroxyquinoline-2-one with 2-amino-pyrimidine could initiate the new activities. α,β-Unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one were prepared. Novel 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized by reaction of these corresponding α,β-unsaturated ketones with guanidine hydrochloride. Human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines were used for screening their cytotoxicity. 3-Acetyl-4-hydroxy-N-methylquinolin-2-one was prepared from N-methylaniline and diethyl malonate. Reaction of (un)substituted benzaldehydes with this 4-hydroxyquinoline-2-one produced corresponding substituted α,β-unsaturated ketones in the presence of piperidine as catalyst. 2- Amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines have been synthesized from these α,β-unsaturated ketones of 3-acetyl-4-hydroxy-N-methylquinolin-2-one by reaction of corresponding α,β-unsaturated ketones with guanidine hydrochloride. All obtained pyrimidines were screened for anticancer activity using MTT bio-assay method. Seven substituted (E)-4-hydroxy-3-(3-(aryl)acryloyl)-1-methylquinolin-2(1H)-ones were prepared and converted to corresponding substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin- 2'-on-3'-yl)pyrimidines with yields of 58-74%. All the synthesized pyrimidines were screened for their in vitro anticancer activity against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines. Compounds 6b and 6e had the best activity in the series, with IC50 values equal to 1.32 and 1.33 μM, respectively. ADMET properties showed that compounds 6b, 6e, and 6f possessed the drug-likeness behavior. Cross-docking results indicated that residues GLN778(A), DT8(C), DT9(D), DA12(F), and DG13(F) in the binding pocket as potential ligand binding hot-spot residues for compounds 6b, 6e, and 6f. New substituted 2-amino-6-aryl-4-(4'-hydroxy-N-methylquinolin-2'-on-3'-yl)pyrimidines were obtained and displayed significant inhibition against human hepatocellular carcinoma HepG2 and squamous cell carcinoma KB cancer lines.

A new finding in the old Knoevenagel condensation reaction

Reaction of benzaldehyde (5a) with defined quantities of ethyl cyanoacetate (6) in presence of piperidine was studied. In a neat condition, hexasubstituted cyclohexeneamine (7a) with three ester substituents was formed along with ethyl acrylate (9a); occasionally the triesters (7) were transformed to diesters (8). (7) and (8) had uniquely defined stereochemistry. Many substituted aromatic aldehydes and pyridine-3 and 4-aldehydes exhibited this reaction. Cyclohexenes were also formed in solutions. Mass spectral evidence showed the presence of small percentage of isomeric tri and diesters. Mechanistic and other aspects are discussed. Richly substituted cyclohexene amine esters are attractive substrates for medicinal chemistry.

Synthesis and Molecular Docking Studies of N,N-Dimethyl Arylpyranopyrimidinedione Derivatives

AbstractThe synthesis of N,N-dimethyl arylpyranopyrimidinedione derivatives from aromatic aldehydes, N-methyl-1-(methylthio)-2-nitroethamine (NMSM) and 1,3-dimethyl barbituric acid, in the presence of piperidine as a catalyst, is reported. The reaction mechanism involves a Knoevenagel condensation, followed by Michael addition and intramolecular O-cyclization reaction sequence. The synthesized compounds were docked with human kinesin Eg5 protein to calculate binding energy, inhibition constant and H-bond interaction. All the compounds show good binding affinity towards the protein, with significant docking score.

Interaction of 5-arylfurfurals with malononitrile dimer

The interaction of 5-arylfurfurals with dimer malononitrile was studied. A number of previously unknown 3-amino-2,4-dicyano-5-(5-arylfuran-2-yl) -penta-2,4-dienenitriles were obtained, which were investigated in the cyclocondensation reaction with dimedone. The reaction was performed by heating the reagents in ethanol in the presence of piperidine. The reaction was monitored by TLC (eluentbenzene–acetone, 4:1 by volume). It was found that the cyclocondensation reaction proceeds with the formation of pyran and pyridine cycles – fragments of 9-oxa-1-aza-anthracene. The structure of the obtained compounds was confirmed by 1 H NMR spectra. 1 H NMR spectra were recorded on a Bruker instrument with an operating frequency of 400 MHz, solvent – DMSO- d 6 . Chemical shifts are given relative to the solvent signal (DMSO, 2.50 ppm). General procedure of obtaining 3-amino-2,4-dicyano-5-(5-aryl-furan-2-yl)-penta-2,4-dienenitriles ( 1 ). A mixture of 0.003 mol of 5-arylfurfural, 0.003 mol of malonodinitrile dimer and 4 drops of piperidine in 20 ml of ethanol was heated on a boiling water bath until the precipitate dissolved. After cooling, formed precipitate was filtered off and recrystallized from ethanol–DMF (10:1). Synthesis of 2,4-diamino-7,7-dimethyl-5-oxo-10-(5-aryl-furan-2-yl)-6,7,8,10-tetrahydro-5 H -9-oxa-1-aza-anthracene-3-carbonitriles ( 2 ). A mixture of equimolar amounts of substances ( 1 ) and dimedone (0.0014 mol), 0.03 mol of piperidine in 15 ml of ethanol was boiled until complete dissolution of the precipitate. The reaction mixture was cooled, neutralized with concentrated hydrochloric acid. The formed precipitate was filtered off, washed with water and recrystallized from ethanol. Keywords: 5-arylfurfurals, malonodinitrile dimer, dimedone, cyclocondensation reactions, 9-oxa-1-aza-anthracene derivatives.

Synthesis and Spectral Characterisation of (E)-3-(3-(4 (Dimethylamino)Phenyl)Acrylo-yl)-4-Hydroxy-2H-Chromen-2-One and Their Antibacterial Activity and Acetylcholinesterase Inhibition

A new coumarin derivative, (E)-3-(3-(4-(dimethylamino) phenyl) acrylo-yl)-4-hydroxy-2H-chromen-2-one (3), was synthesized by the condensation of 3-acetyl-4-hydroxycoumarin (1) with 4-N,N-dimethylaminobenzaldehyde (2) in the presence of piperidine in ethanol. The structure of the synthesized compound was characterized using spectroscopic data (IR and 1H NMR) and elemental analysis. The antimicrobial properties and acetylcholinesterase inhibition activity (AChEI) of coumarin 3 were investigated, with the highest observed AChEI activity providing 48.25% inhibition. The electronic absorption and emission spectra revealed that 3 exists as two, main keto-enol tautomers. The ratios of these tautomers in both protic and aprotic solvents with different polarities and dielectric constants were calculated. The fluorescence of coumarin 3 was enhanced upon increasing the medium viscosity, which was due to the resultant molecular rigidity. This criterion was further investigated using DNA, whereby 3 showed enhanced fluorescence upon its uptake in DNA grooves and was therefore tested as a novel DNA fluorescent stain.

Highly Porous Poly(arylene cyano-vinylene) Beads Derived through the Knoevenagel Condensation of the Oil-in-Oil-in-Oil Double Emulsion Templates.

Conjugated porous polymers through the emulsion-templating polymerization process are typically prepared as monoliths, and the emulsions are cured via metal-catalyzed cross-coupling reactions. Herein, we report the design and synthesis of well-defined, millimeter-sized conjugated porous polymer beads by combining an oil-in-oil-in-oil (O/O/O) double emulsion as a de novo template and an amino-catalyzed Knoevenagel condensation reaction as a polymerization chemistry to cure such emulsions. The 1,4-phenylenediacetonitrile is reacted with aromatic multialdehydes in the presence of piperidine, and a series of metal-free poly(arylene cyano-vinylene) beads are prepared. All beads exhibit 3D-interconnected microcellular morphology and substantial semiconducting properties, such as strong light harvesting ability in the visible light region with electrochemical band gaps in the range of 2.05-2.33 eV. Finally, the promising photocatalytic activity of these conjugated beads is demonstrated for a model sulfoxidation reaction under visible light irradiation, and near quantitative conversions with excellent chemoselectivities (>99%) are obtained.

A one-pot synthesis of piperidinium spirooxindoline-pyridineolates and indole-substituted pyridones in aqueous or ethanol medium.

Piperidinium spirooxindoline-pyridineolate has been prepared via one-pot multicomponent reaction of isatin, malononitrile, cyanoacetohydrazide, and piperidine in water or ethanol medium at room temperature. In addition, the synthesis of two indole-substituted 2-pyridones from indole-3-carbaldehyde, malononitrile, and cyanoacetohydrazide in the presence of piperidine is described.

Synthesis of Azido and Triazolyl Purine Ribonucleosides.

Here, we describe detailed synthetic protocols for preparation of 6-amino/thio-2-triazolylpurine ribonucleosides. First, 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2,6-diazido-9H-purine, to be used as a key starting material, is synthesized in an SN Ar reaction with NaN3 starting from commercially available 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine. Next, 2,6-bis-triazolylpurine ribonucleoside is obtained in a CuAAC reaction between diazidopurine derivative and phenyl acetylene, and used in SN Ar reactions with N- and S-nucleophiles. In these reactions, the triazolyl ring at the purine C6 position acts as a good leaving group. Cleavage of acetyl protecting groups from the ribosyl moiety is achieved in presence of piperidine. In the SN Ar reaction with amino acid derivatives, the acetyl groups remain intact. Moreover, 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-2,6-diazido-9H-purine is selectively reduced at the C6 position using a CuSO4 ·5H2 O/sodium ascorbate system. This provides a straightforward approach for synthesis of 9-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-6-amino-2-azido-9H-purine. © 2021 Wiley Periodicals LLC Basic Protocol 1: Synthesis of 6-amino-2-triazolylpurine ribonucleosides Basic Protocol 2: Synthesis of 6-thio-2-triazolylpurine ribonucleosides Basic Protocol 3: Synthesis of 6-amino-2-azidopurine ribonucleoside.

Simple Synthesis of 2-Amino-N'-(9H-Fluoren-9-Ylidene)-Hexahydroquinoline-3-Carbohydrazide Derivatives

This work represents a simple and efficient synthesis of novel 2-amino-N'-(9H-fluoren-9-ylidene)-hexahydroquinoline-3-carbohydrazide derivatives via the multi-component reaction of diverse anilines, dimedone, 9-fluorenone, cyanoacetohydrazide, and aromatic aldehydes in the presence of piperidine as a catalyst. The proposed approach has some advantages as good yields, green medium, short reaction times, simple work-up, and purification process with no chromatographic technique compared with other methods. Supplemental data for this article is available online at at the publisher’s website.

Three-Component Condensation of Pyridinium Ylides, β-Ketonitriles, and Aldehydes with Divergent Regioselectivity: Synthesis of 4,5-Dihydrofuran-3- and 2H-Pyran-5-carbonitriles.

A library of trans-4,5-dihydrofuran-3-carbonitriles was synthesized in a diastereoselective manner in good yields by the three-component reaction of β-ketonitriles, carbonyl- and semistabilized pyridinium ylide precursors, and aldehydes in the presence of piperidine. This one-pot transformation generates two C-C and one C-O bond and proceeds through a cascade Knoevenagel condensation, a Michael addition, and intramolecular SN2 cyclization. Formation of cyclopropanecarbonitrile derivatives, which in some cases were obtained as major products, was found to be a competing reaction. The use of arylglyoxals changes regioselectivity and leads to 2-hydroxy-2H-pyran-5-carbonitriles.

Synthesis and Antimicrobial Activity of Some New Coumarin Incorporated Pyridine-3-carbonitrile Derivatives

Drug resistance causes serious difficulties in the routine therapy for curing common microbial infections. Thus it is very essential to develop new antimicrobial agents which can offer alternative treatments. The development of potent and effective antimicrobial agents is of utmost importance to overcome the emerging multidrug resistance strains of bacteria and fungi. The technique involves Knoevenagel reaction between substituted salicylaldehyde and ethyl acetoacetate in presence of piperidine as catalyst to give 3-acetyl coumarin. The intermediate coumarinyl chalcones was synthesized by condensing with various substituted benzaldehyde in presence of ethanolic KOH. The final synthesized pyridine-3-carbonitrile derivative was prepared upon refluxing with coumarinyl chalcones with malononitrile in presence of ammonium acetate. All the newly synthesized compounds were assigned on the basis of IR, 1H NMR and mass spectral data. The finalsynthesized compounds were screened for their antibacterial activity tube dilution method. Most of the compounds showed promising MIC by tube dilution method as compared to standard Cephalosporin.

Synthesis, structural elucidation, and antioxidant activity of new phenolic derivatives containing piperidine moiety: Experimental and theoretical investigations

The incorporation of the piperidine ring into drugs may play an interesting role to fulfill significant tasks and act as an active ingredient in various treatments. Herein, three novel derivatives of 3‐acetyl‐2‐hydroxybenzoic acid (3‐5) containing a piperidine ring were synthesized through the rearrangement of triacetic acid lactone in the presence of piperidine. Their molecular structures were characterized by 1H and 13C NMR and single crystal X‐ray diffraction techniques. The experimental data were compared with the predicted ones obtained in the polarizable continuum model at the B3LYP/6‐311++G(d,p) level of theory. Relatively good correlations were obtained between the experimental data (spectral and Z‐matrix coordinates) and the predicted ones, with correlation coefficients higher than 97%. The intercontacts between the closest units of 3‐5 were identified through the analysis of the Hirshfeld surface and electrostatic potentials (ESP) maps. Hirshfeld surface and ESPs analyses reveal that the closest interactions between the units of the compounds are between hydrogen atoms (59%‐67%). The antioxidant activity of 3‐5 was evaluated using DPPH free radical scavenging and ABTS assays. They exhibit moderate antioxidant activity, which probably is attributable to the presence of a phenolic moiety in their basic skeleton. Molecular docking calculations suggest that 3‐5 may mainly bind to the active binding site of peroxiredoxin 5 through strong and weak intermolecular hydrogen bonds.

Synthesis, Characterization and Biological Evaluation of Indole-Pyrazole Amalgamated α-Cyano Substituted Chalcones

Indole and pyrazole constitute a major class of biologically active scaffolds. The amalgamation of two or more pharmacophores would generate novel molecular templates that are likely to unveil remarkable biological properties. An efficient and high yielding synthesis of indole-pyrazole integrated α-cyano substituted chalcones and their in vitro antibreast cancer and antioxidant evaluation. The synthesis of a series of indole-pyrazole amalgamated α-cyano substituted chalcones (6a-o) was achieved by reacting substituted 3-cyanoacetyl indole 2 with substituted pyrazole aldehyde 5 in the presence of piperidine. All the newly synthesized compounds have been characterized by IR, 1H NMR and HRMS spectroscopy. Anti-breast cancer evaluation of the synthesized compounds in vitro against MCF-7 cell line revealed high anti-breast cancer activities. Amongst the compounds screened 6f, 6g, 6h, 6c, 6d, 6e, 6i and 6k unveiled excellent activity against breast carcinoma (GI50 <0.1µM) as good as adriamycin (GI50 <0.1µM). The compounds were also screened against the normal Vero monkey cell line and the results demonstrated more selectivity against MCF-7. In other hand, compounds, 6b, 6c, 6d, 6h and 6i have shown moderate DPPH and NO radical scavenging activity. Most of the synthesized compounds exhibited significant antitumor activities. These results further support its safety margin by studying the activity on normal Vero monkey cell line. These results acclaim the possible use of these compounds for the design and development of potent anti-breast cancer agents.

Copper(I)-catalyzed tandem synthesis of 2-acylquinolines from 2-ethynylanilines and glyoxals.

An efficient one-step synthesis of 2-acylquinolines using a copper-catalyzed tandem reaction of 2-ethynylanilines with glyoxals in the presence of piperidine has been developed. This new protocol successfully avoids multi-step operation and the use of highly toxic cyanides required in traditional methods, and provides a practical tool for synthetic and pharmaceutical chemists. Various 2-acylquinolines are obtained with perfect regioselectivity in moderate to good yields (up to 86%). The potential synthetic utility of this method is exemplified by a large-scale experiment and synthetic transformation of the products.

Stereoselective synthesis of (Z)-1,3-bis(α,β-unsaturated carbonyl)-isoindolines from aldehydes and phenacyl azides under metal free conditions

We report herein our observation of an unprecedented stereoselective synthesis of 2H-isoindolin-1,3-ylidenes from 2-formylphenyl acrylates and phenacylazide in the presence of piperidine.

Pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles: A three-component synthesis and AChE inhibitory studies

The one-pot three-component reaction of 3-methyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one, aromatic aldehydes, and malononitrile in the presence of piperidine in ethanol has been carried out. The reaction proceeded through domino Knoevenagel condensation – Michael addition – O-cyclization sequence of reactions in a single transformation affording structurally intriguing novel pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles in excellent yields in short reaction time. The high-throughput AChE inhibition studies of these pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles disclosed one compound with maximum potency with an IC50 value of 2.6 µM/L. The structure–activity relationship revealed that the pyrano[2,3-f]pyrazolo[3,4-b]quinoline-3-carbonitriles bearing alkyl or alkoxy substituted phenyl ring at C-4 exhibited more potency than the compounds with halogen-substituted phenyl ring.

Synthesis and Theoretical Studies of [2-amino-3-(ethoxycarbonyl)-1,4-dihydro-1-phenyl-4-pyridinyl] Ferrocene Derivatives

In this study, syntheses of [2-amino-3-(ethoxycarbonyl)-1,4-dihydro-1-phenyl-4-pyridinyl]ferrocene derivatives from reaction of ferrocenecarboxaldehyde, ethyl cyanoacetate, aniline, and acetylenic esters in the presence of piperidine were reported in good yields. The reaction proceeded smoothly and cleanly under mild reaction conditions and no side reactions were observed. The structures of the products were confirmed by IR, 1H NMR, 13C NMR, mass spectroscopy, and elemental analysis. Then, structure, electronic and spectroscopic properties of the synthesized molecules were computed at the CAM-B3LYP/jorge-DZP (H,C,N,O) and Def2-TZVPPD (Fe) level of theory. First hyperpolarizability value were calculated to describe the nonlinear optical (NLO) properties of these molecules. The HOMO-LUMO study to find the band gap of the prepared molecules was extended to calculate global hardness, chemical potential and global electrophilicity for the investigation of the chemical behavior of the compounds. The energies of iron d-orbitals and formal electron configurations of iron atom were calculated by natural bond orbital (NBO) analysis.

Synthesis and Biological Activity of 2-Aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamides

The reaction of unsubstituted acetoacetamide with aromatic aldehydes in ethanol in the presence of piperidine gave 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxamides and 4-aryl-5-acetyl-2-hydroxy-2-methyl-6-oxopiperidine-3-carboxamides. Structures of the obtained compounds were proved using IR, 1H and 13C NMR spectroscopy methods. The synthesized compounds were tested for antimicrobial and analgesic activities.

Reaction of 2-Imino-2,5-dihydrofuran-3-carboxamides with Benzaldehyde

The reaction of 2-imino-2,5-dihydrofuran-3-carboxamides with benzaldehyde in pentan-1-ol in the presence of piperidine gave new dihydrofuran derivatives with a fused pyrimidine ring and two phenyl rings, 2-phenyl-5-(2-phenylethylidene)-5,6-dihydrofuro[2,3-d]pyrimidin-4(3H)-ones. The product structure was confirmed by spectroscopic methods (1H and 13C NMR) and independent synthesis from previously reported 2-imino-5,5-dimethyl-4-(2-phenylethenyl)-2,5-dihydrofuran-3-carboxamide and benzaldehyde under similar conditions.

Sample Flow Rate Scan in Electrospray Ionization Mass Spectrometry Reveals Alterations in Protein Charge State Distribution.

Sample flow rate is one of the parameters that influence the sensitivity of electrospray ionization (ESI) mass spectrometry. By varying the sample flow rate, initial droplets of different sizes can be generated. Protein molecules in small droplets may form gas-phase ions earlier than the ones in large droplets. Here, we have systematically studied the influence of sample flow rate on the ESI charge state distributions (CSDs) of model proteins. A dedicated programmable sample flow rate scanner was used to infuse protein samples at different flow rates into a mass spectrometer. The synergistic influence of sample flow rate and various electrolytes (ammonium acetate, ammonium bicarbonate, ammonium formate, and piperidine) was studied. Significant alterations to the CSDs with increasing flow rate were observed. For example, in the presence of ammonium acetate, at low flow rates, lower charge states of proteins showed high intensities, while at high flow rates, ions related to higher charge states of proteins dominated the spectra. On the other hand, in the presence of piperidine, a significant reduction in the ion currents of all charge states was observed during the flow rate scan. Our observations suggest that at low flow rates the protein molecules follow a charged residue model of ionization mechanism, and at high flow rates-due to structural changes in protein molecules in large ESI droplets-the charged residue and chain ejection models can possibly coexist. We propose the use of sample flow rate scan as a way to reveal the influence of flow rate on the CSDs of the studied proteins.