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Journal articles on the topic 'Piperazinic scaffolds'

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Author: Grafiati

Published: 10 March 2023

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1

Hafeez, Freeha, Ameer Fawad Zahoor, Azhar Rasul, Asim Mansha, Razia Noreen, Zohaib Raza, Kulsoom Ghulam Ali, Ali Irfan, and Gamal A. El-Hiti. "Ultrasound-Assisted Synthesis and In Silico Modeling of Methanesulfonyl-Piperazine-Based Dithiocarbamates as Potential Anticancer, Thrombolytic, and Hemolytic Structural Motifs." Molecules 27, no. 15 (July 26, 2022): 4776. http://dx.doi.org/10.3390/molecules27154776.

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Piperazine-based dithiocarbamates serve as important scaffolds for numerous pharmacologically active drugs. The current study investigates the design and synthesis of a series of dithiocarbamates with a piperazine unit as well as their biological activities. Under ultrasound conditions, the corresponding piperazine-1-carbodithioates 5a–5j were synthesized from monosubstituted piperazine 2 and N-phenylacetamides 4a–4j in the presence of sodium acetate and carbon disulfide in methanol. The structures of the newly synthesized piperazines were confirmed, and their anti-lung carcinoma effects were evaluated. A cytotoxic assay was performed to assess the hemolytic and thrombolytic potential of the synthesized piperazines 5a–5j. The types of substituents on the aryl ring were found to affect the anticancer activity of piperazines 5a–5j. Piperazines containing 2-chlorophenyl (5b; cell viability = 25.11 ± 2.49) and 2,4-dimethylphenyl (5i; cell viability = 25.31 ± 3.62) moieties demonstrated the most potent antiproliferative activity. On the other hand, piperazines containing 3,4-dichlorophenyl (5d; 0.1%) and 3,4-dimethylphenyl (5j; 0.1%) rings demonstrated the least cytotoxicity. The piperazine with the 2,5-dimethoxyphenyl moiety (5h; 60.2%) showed the best thrombolytic effect. To determine the mode of binding, in silico modeling of the most potent piperazine (i.e., 5b) was performed, and the results were in accordance with those of antiproliferation. It exhibits a similar binding affinity to PQ10 and an efficient conformational alignment with the lipophilic site of PDE10A conserved for PQ10A.

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2

Wierschem, Frank, and Karola Rück-Braun. "Introduction of Substituents on the 2-Oxo-piperazine Skeleton by [3+2] Cycloaddition and Subsequent Transformation." Zeitschrift für Naturforschung B 61, no. 4 (April 1, 2006): 431–36. http://dx.doi.org/10.1515/znb-2006-0410.

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The 3,4-substituted 2-oxo-piperazines 5 - 9 are obtained by [3+2] cycloaddition from nitrone 1 and a variety of alkenes. Subsequent functionalization of the bicyclic adducts involves reductive N-O bond cleavage. A route towards libraries of immobilized 1,3-aminoalcohols with a 3,4-substituted 2-oxo-piperazine scaffold is briefly discussed for adducts derived from N-substituted maleic imides

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3

Ye, Zhishi, Kristen E. Gettys, and Mingji Dai. "Opportunities and challenges for direct C–H functionalization of piperazines." Beilstein Journal of Organic Chemistry 12 (April 13, 2016): 702–15. http://dx.doi.org/10.3762/bjoc.12.70.

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Piperazine ranks within the top three most utilized N-heterocyclic moieties in FDA-approved small-molecule pharmaceuticals. Herein we summarize the current synthetic methods available to perform C–H functionalization on piperazines in order to lend structural diversity to this privileged drug scaffold. Multiple approaches such as those involving α-lithiation trapping, transition-metal-catalyzed α-C–H functionalizations, and photoredox catalysis are discussed. We also highlight the difficulties experienced when successful methods for α-C–H functionalization of acyclic amines and saturated mono-nitrogen heterocyclic compounds (such as piperidines and pyrrolidines) were applied to piperazine substrates.

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4

Zoidis, Grigoris, María Isabel Loza, and Marco Catto. "Design, Synthesis and 5-HT1A Binding Affinity of N-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)tricyclo[3.3.1.13,7]decan-1-amine and N-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-3,5-dimethyl-tricylo[3.3.1.13,7]decan-1-amine." Molbank 2022, no. 1 (March 10, 2022): M1353. http://dx.doi.org/10.3390/m1353.

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Based on previously highlighted structural features, the development of highly selective 5-HT1A receptor inhibitors is closely linked to the incorporation of a 4-alkyl-1-arylpiperazine scaffold on them. In this paper, we present the synthesis of two new compounds bearing the 2-MeO-Ph-piperazine moiety linked via a three carbon atom linker to the amine group of 1-adamantanamine and memantine, respectively. Both were tested for their binding affinity against 5-HT1A receptor. N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)tricyclo[3.3.1.13,7]decan-1-amine fumarate (8) and N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-3,5-dimethyl-tricylo[3.3.1.13,7]decan-1-amine fumarate (10) proved to be highly selective ligands towards 5-HT1A receptor with a binding constant of 1.2 nM and 21.3 nM, respectively, while 5-carboxamidotriptamine (5-CT) (2) was used as an internal standard for this assay with a measured Ki = 0.5 nM.

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5

Aboutabl, Mona Elsayed, Ahmed Ragab Hamed, Mohamed Farouk Hamissa, and Emad Khairy Ahmed. "Anti-Inflammatory and Analgesic Activities of 7-Chloro-4-(Piperazin-1-yl) Quinoline Derivative Mediated by Suppression of InflammatoryMediators Expression in Both RAW 264.7 and Mouse Models." Pharmaceutical Sciences 27, no. 3 (December 30, 2020): 326–38. http://dx.doi.org/10.34172/ps.2020.101.

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Background: 4-Aminoquinoline derivatives possess various potential biological properties.The introduction of additional piperazine heterocyclic pharmacophoric moiety tends to haveprofound impact in increasing the activity. The present work was undertaken to investigate thein-vitro and in-vivo anti-inflammatory activity as well as the peripheral and central analgesicactivities of compound 1-(4-(7-chloroquinoline-4-yl)piperazin-1-yl)-2-(4-phenylpiperazin-1-yl)ethanone (5) in experimental models. Methods: The percentage inhibition of the lipopolysaccharide induced NO release of 7-chloro-4-(piperazin-1-yl)quinoline derivatives 1-9 was determined in RAW 264.7 murine macrophagemodel. Western blot analysis was performed to evaluate the effect of compound 5 on proteinexpression of inducible nitric oxide synthase (iNOS). Gene expression of inflammatory markerswas evaluated using real-time polymerase chain reaction. The peripheral and central analgesicactivities of compound 5 were evaluated in mice using writhing and hot-plate tests, respectively.Anti-inflammatory activity was assessed using carrageenan-induced paw edema assay in miceand serum NO and COX-2 levels were measured. Results: Compound 5 demonstrated the highest NO inhibitory activity that was accompaniedby inhibition of iNOS protein expression and decreased gene expression levels of inflammatorymarkers. It revealed a potential peripheral analgesic effect through inhibition of abdominalwrithing in mice treated with doses of 15 and 30 mg/kg and its effect was comparable to diclofenacsodium. Compound 5 possessed an analgesic activity starting from 15 min post administrationand reached its peak at 45 min which was significantly higher than that of tramadol hydrochloridesuggesting its potential as central analgesic agent. It also showed percentage of inhibition ofedema of 34, 50 and 64% at 1, 2, and 3 h respectively, post carrageenan challenge together with asignificant decrease in serum NO and COX-2 levels. Conclusion: The remarkable anti-inflammatory and analgesic activities of compound 5 couldbe attributed to the advantageous introduction of the heterocyclic 7-chloro-4-(piperazin1-yl)quinoline scaffold incorporated with N-phenylpiperzine functional groups linked together withthe ethanone pharmacophoric chain.

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6

Rani, Anu, Sumit Kumar, Jenny Legac, Adebayo A. Adeniyi, Paul Awolade, Parvesh Singh, Philip J. Rosenthal, and Vipan Kumar. "Design, synthesis, heme binding and density functional theory studies of isoindoline-dione-4-aminoquinolines as potential antiplasmodials." Future Medicinal Chemistry 12, no. 3 (February 2020): 193–205. http://dx.doi.org/10.4155/fmc-2019-0260.

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Aim: WHO Malaria report 2017 estimated 216 million cases of malaria and 445,000 deaths worldwide, with 91% of deaths affecting the African region. Results/methodology: Microwave promoted the synthesis of cycloalkyl amine substituted isoindoline-1,3-dione-4-aminoquinolines was urbanized for evaluating their antiplasmodial activities. Compound with the optimum combination of propyl chain length and hydroxyethyl piperazine proved to be the most potent among the synthesized scaffolds against chloroquine-resistant W2 strain of Plasmodium falciparum with an IC50 value of 0.006 μM. Heme-binding along with density functional theory studies were further carried out in order to delineate the mechanism of action of the most active compound. Conclusion: The synthesized scaffold can act as a therapeutic template for further synthetic modifications toward the search for a new antimalarial agent.

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7

Stucchi, Mattia, Silvia Cairati, Rengul Cetin-Atalay, Michael S. Christodoulou, Giovanni Grazioso, Gennaro Pescitelli, Alessandra Silvani, Deniz Cansen Yildirim, and Giordano Lesma. "Application of the Ugi reaction with multiple amino acid-derived components: synthesis and conformational evaluation of piperazine-based minimalist peptidomimetics." Organic & Biomolecular Chemistry 13, no. 17 (2015): 4993–5005. http://dx.doi.org/10.1039/c5ob00218d.

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8

Okitsu, Takashi, Arisa Horike, Natsumi Shimazawa, and Akimori Wada. "A dearomative ipso-iodocyclization/desymmetrization sequence leading to optically active tricyclic piperazine scaffolds." Organic & Biomolecular Chemistry 18, no. 18 (2020): 3501–11. http://dx.doi.org/10.1039/d0ob00510j.

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9

Darapaneni, Chandra Mohan, Prathap Jeya Kaniraj, and Galia Maayan. "Water soluble hydrophobic peptoids via a minor backbone modification." Organic & Biomolecular Chemistry 16, no. 9 (2018): 1480–88. http://dx.doi.org/10.1039/c7ob02928d.

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10

Derbyshire, Emily R., Jaeki Min, W. Armand Guiguemde, Julie A. Clark, Michele C. Connelly, Andreia D. Magalhães, R. Kiplin Guy, and Jon Clardy. "Dihydroquinazolinone Inhibitors of Proliferation of Blood and Liver Stage Malaria Parasites." Antimicrobial Agents and Chemotherapy 58, no. 3 (December 23, 2013): 1516–22. http://dx.doi.org/10.1128/aac.02148-13.

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ABSTRACTDrugs that target both the liver and blood stages of malaria will be needed to reduce the disease's substantial worldwide morbidity and mortality. Evaluation of a 259-member library of compounds that block proliferation of the blood stage of malaria revealed several scaffolds—dihydroquinazolinones, phenyldiazenylpyridines, piperazinyl methyl quinolones, and bis-benzimidazoles—with promising activity against the liver stage. Focused structure-activity studies on the dihydroquinazolinone scaffold revealed several molecules with excellent potency against both blood and liver stages. One promising early lead with dual activity is 2-(p-bromophenyl)-3-(2-(diethylamino)ethyl)-2,3-dihydroquinazolin-4(1H)-one with 50% effective concentrations (EC50s) of 0.46 μM and 0.34 μM against liver stagePlasmodium bergheiANKA and blood stagePlasmodium falciparum3D7 parasites, respectively. Structure-activity relationships revealed that liver stage activity for this compound class requires a 3-dialkyl amino ethyl group and is abolished by substitution at theortho-position of the phenyl moiety. These compounds have minimal toxicity to mammalian cells and are thus attractive compounds for further development.

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11

James, Thomas, Paul MacLellan, George M. Burslem, Iain Simpson, J. Andrew Grant, Stuart Warriner, Visuvanathar Sridharan, and Adam Nelson. "A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds." Org. Biomol. Chem. 12, no. 16 (2014): 2584–91. http://dx.doi.org/10.1039/c3ob42512f.

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A modular synthetic approach is described in which combinations of cyclic sulfamidate and hydroxy sulfonamide building blocks may be converted into piperazine, 1,4-diazepine and 1,5-diazocane scaffolds.

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12

Sharma, Anjali, Sharad Wakode, Faizana Fayaz, Shaik Khasimbi, Faheem H. Pottoo, and Avneet Kaur. "An Overview of Piperazine Scaffold as Promising Nucleus for Different Therapeutic Targets." Current Pharmaceutical Design 26, no. 35 (October 16, 2020): 4373–85. http://dx.doi.org/10.2174/1381612826666200417154810.

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Piperazine scaffolds are a group of heterocyclic atoms having pharmacological values and showing significant results in pharmaceutical chemistry. Piperazine has a flexible core structure for the design and synthesis of new bioactive compounds. These flexible heterogenous compounds exhibit various biological roles, primarily anticancer, antioxidant, cognition enhancers, antimicrobial, antibacterial, antiviral, antifungal, antiinflammatory, anti-HIV-1 inhibitors, antidiabetic, antimalarial, antidepressant, antianxiety and anticonvulsant activities, etc. In the past few years, researchers focused on the therapeutic profile of piperazine synthons for different biological targets. The present review highlights the development in designing pharmacological activities of nitrogen-containing piperazine moiety as a therapeutic agent. The extensive popularity of piperazine as a drug of abuse and their vast heterogeneity research efforts over the last years motivated the new investigators to further explore this area.

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13

Dömling, Alexander, and Yijun Huang. "Piperazine Scaffolds via Isocyanide-Based Multicomponent Reactions." Synthesis 2010, no. 17 (July 30, 2010): 2859–83. http://dx.doi.org/10.1055/s-0030-1257906.

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14

An, Haoyun, Becky D. Haly, and P. Dan Cook. "New piperazinyl polyazacyclophane scaffolds, libraries and biological activities." Bioorganic & Medicinal Chemistry Letters 8, no. 17 (September 1998): 2345–50. http://dx.doi.org/10.1016/s0960-894x(98)00424-7.

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15

Szczepanska, Katarzyna, Kamil Kuder, and Katarzyna Kiec-Kononowicz. "Histamine H3 Receptor Ligands in the Group of (Homo)piperazine Derivatives." Current Medicinal Chemistry 25, no. 14 (May 7, 2018): 1609–26. http://dx.doi.org/10.2174/0929867325666171123203550.

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Since its discovery in 1983, followed by gene cloning in 1999, the histamine H3 receptor served as an outstanding target for drug discovery. The wide spectrum of possible therapeutic implications makes H3R's one of the most researched areas in the vast GPCR ligands field - started from imidazole containing ligands, through various successful imidazole replacements, with recent introduction of Wakix® to pharmaceutical market. One such replacement is piperazine moiety, a significant versatile scaffold in rational drug design for most of the GPCR ligands. Therefore, herein, we review ligands built on piperazine, as well as its seven membered analogue azepine, that target H3R’s and their potential therapeutical applications, in order to elucidate the current state of the art in this vast field. Due to a high level of structural divergence among compounds described herein, we decided to divide them into groups, where the key division element was the position of nitrogen basicity decreasing moieties in (homo)piperazine ring. Paying attention to a number of published structures and their overall high biological activity, one can realize that the (homo)piperazine scaffold bids a versatile template also for histamine H3 receptor ligands. With two possible substitution sites and therefore a number of possible structural combinations, piperazine derivatives stand as one of the largest group of high importance among H3R ligands.

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16

Brindisi, Margherita, Simone Brogi, Samuele Maramai, Alessandro Grillo, Giuseppe Borrelli, Stefania Butini, Ettore Novellino, et al. "Harnessing the pyrroloquinoxaline scaffold for FAAH and MAGL interaction: definition of the structural determinants for enzyme inhibition." RSC Advances 6, no. 69 (2016): 64651–64. http://dx.doi.org/10.1039/c6ra12524g.

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The pharmacogenic pyrroloquinoxaline scaffold has been exploited for developing piperazine and 4-aminopiperidine carboxamides/carbamates as inhibitors of the endocannabinoids’ catabolic enzymes fatty acid amide hydrolase and monoacylglycerol lipase.

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17

Afshar, Sepideh Saberi, Ghodsi Mohammadi Ziarani, Fatemeh Mohajer, Alireza Badiei, Siavash Iravani, and Rajender S. Varma. "Synthesis of Fumed-Pr-Pi-TCT as a Fluorescent Chemosensor for the Detection of Cyanide Ions in Aqueous Media." Water 14, no. 24 (December 19, 2022): 4137. http://dx.doi.org/10.3390/w14244137.

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In this research, fumed silica scaffolds modified via treatment with (3-chloropropyl)-triethoxysilane, piperazine, and trichlorotriazine groups were deployed for the specific detection of cyanide ions, thus paving the way for the detection of environmental hazards and pollutants with high specificity. Fumed-propyl -piperazine-trichlorotriazine (fumed-Pr-Pi-TCT) was synthesized in three steps starting from fume silica. It was functionalized subsequently using 3-(choloropropyl)-trimethoxysilane, piperazine, and trichlorotriazine, and then, the product was characterized through several methods including Fourier-transform infrared spectroscopy (FTIR) spectrum, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). Fumed-Pr-Pi-TCT was exposed as a nanoparticle sensor to a range of different anions in aqueous media. This novel sensor could detect cyanide ions as a hazardous material, with the limit of detection being 0.82 × 10−4 M.

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18

Boyom, Fabrice F., Patrick V. T. Fokou, Lauve R. Y. Tchokouaha, Thomas Spangenberg, Alvine N. Mfopa, Ruffin M. T. Kouipou, Cedric J. Mbouna, Valerie F. Donkeng Donfack, and Paul H. A. Zollo. "Repurposing the Open Access Malaria Box To Discover Potent Inhibitors of Toxoplasma gondii and Entamoeba histolytica." Antimicrobial Agents and Chemotherapy 58, no. 10 (July 21, 2014): 5848–54. http://dx.doi.org/10.1128/aac.02541-14.

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ABSTRACTToxoplasmosis and amebiasis are important public health concerns worldwide. The drugs currently available to control these diseases have proven limitations. Therefore, innovative approaches should be adopted to identify and develop new leads from novel scaffolds exhibiting novel modes of action. In this paper, we describe results from the screening of compounds in the Medicines for Malaria Venture (MMV) open access Malaria Box in a search for new anti-Toxoplasmaand anti-Entamoebaagents. Standardin vitrophenotypic screening procedures were adopted to assess their biological activities. Seven anti-Toxoplasmacompounds with a 50% inhibitory concentration (IC50) of <5 μM and selectivity indexes (SI) of >6 were identified. The most interesting compound was MMV007791, a piperazine acetamide, which has an IC50of 0.19 μM and a selectivity index of >157. Also, we identified two compounds, MMV666600 and MMV006861, with modest activities againstEntamoeba histolytica, with IC50s of 10.66 μM and 15.58 μM, respectively. The anti-Toxoplasmacompounds identified in this study belong to scaffold types different from those of currently used drugs, underscoring their novelty and potential as starting points for the development of new antitoxoplasmosis drugs with novel modes of action.

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19

Leeza Zaidi, Saadia, Subhash M. Agarwal, Porntip Chavalitshewinkoon-Petmitr, Thidarat Suksangpleng, Kamal Ahmad, Fernando Avecilla, and Amir Azam. "Thienopyrimidine sulphonamide hybrids: design, synthesis, antiprotozoal activity and molecular docking studies." RSC Advances 6, no. 93 (2016): 90371–83. http://dx.doi.org/10.1039/c6ra15181g.

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A series of hybrid compounds containing the thienopyrimidine scaffold with sulphonamide piperazine skeleton were synthesized and evaluated against K1 strain of Plasmodium falciparum and the HM1:1MSS strain of Entamoeba histolytica, respectively

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20

Thirunarayanan, Ayyavu, Sivasamy Selvarani, Gracia Francisco, and Perumal Rajakumar. "Efficient Straightforward Synthesis of Amidopiperazinophanes as Versatile Novel Supramolecular Scaffolds." SynOpen 03, no. 04 (October 2019): 157–63. http://dx.doi.org/10.1055/s-0039-1690333.

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A simple one-pot synthesis of amidopiperazinophanes with a combination of electron-deficient amide groups and electron-rich alkyne and piperazine functionalities has been achieved by using multicomponent reaction (MCR) methodology with the Mannich reaction. Herein, we demonstrate the synthesis of macrocyclic amide structures in good yields. These macrocycles, with electron donor/acceptor sites, are versatile molecules for host–guest and binding.

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21

Fjellaksel, Richard, Marc Boomgaren, Rune Sundset, Ira H. Haraldsen, Jørn H. Hansen, and Patrick J. Riss. "Small molecule piperazinyl-benzimidazole antagonists of the gonadotropin-releasing hormone (GnRH) receptor." MedChemComm 8, no. 10 (2017): 1965–69. http://dx.doi.org/10.1039/c7md00320j.

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In this communication, we report the synthesis and characterization of a library of small molecule antagonists of the human gonadotropin releasing hormone receptor based upon the 2-(4-tert-butylphenyl)-4-piperazinyl-benzimidazole scaffold via Cu-catalysed azide alkyne cycloaddition.

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22

Doemling, Alexander, and Yijun Huang. "ChemInform Abstract: Piperazine Scaffolds via Isocyanide-Based Multicomponent Reactions." ChemInform 41, no. 50 (November 18, 2010): no. http://dx.doi.org/10.1002/chin.201050239.

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23

Kraft, Oliver, Ann-Kathrin Hartmann, Sophie Hoenke, Immo Serbian, and René Csuk. "Madecassic Acid—A New Scaffold for Highly Cytotoxic Agents." International Journal of Molecular Sciences 23, no. 8 (April 14, 2022): 4362. http://dx.doi.org/10.3390/ijms23084362.

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Due to their manifold biological activities, natural products such as triterpenoids have advanced to represent excellent leading structures for the development of new drugs. For this reason, we focused on the syntheses and cytotoxic evaluation of derivatives obtained from gypsogenin, hederagenin, and madecassic acid, cytotoxicity increased—by and large—from the parent compounds to their acetates. Another increase in cytotoxicity was observed for the acetylated amides (phenyl, benzyl, piperazinyl, and homopiperazinyl), but a superior cytotoxicity was observed for the corresponding rhodamine B conjugates derived from the (homo)-piperazinyl amides. In particular, a madecassic acid homopiperazinyl rhodamine B conjugate 24 held excellent cytotoxicity and selectivity for several human tumor cell lines. Thus, this compound was more than 10,000 times more cytotoxic than parent madecassic acid for A2780 ovarian cancer cells. We assume that the presence of an additional hydroxyl group at position C–6 in derivatives of madecassic, as well as the (2α, 3β) configuration of the acetates in ring A, had a beneficial effect onto the cytotoxicity of the conjugates, as well as onto tumor/non-tumor cell selectivity.

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Gupta, Sonal, Deepti Pandey, Dhanaraju Mandalapu, Veenu Bala, Vikas Sharma, Mahendra Shukla, Santosh K. Yadav, et al. "Design, synthesis and biological profiling of aryl piperazine based scaffolds for the management of androgen sensitive prostatic disorders." MedChemComm 7, no. 11 (2016): 2111–21. http://dx.doi.org/10.1039/c6md00426a.

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25

Opatz, Till. "Synthesis of two Conformationally Restricted Piperazine Scaffolds for Combinatorial Chemistry." European Journal of Organic Chemistry 2004, no. 20 (October 2004): 4113–18. http://dx.doi.org/10.1002/ejoc.200400358.

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26

Narczyk, Aleksandra, and Sebastian Stecko. "An entry to non-racemic β-tertiary-β-amino alcohols, building blocks for the synthesis of aziridine, piperazine, and morpholine scaffolds." Organic & Biomolecular Chemistry 18, no. 30 (2020): 5972–81. http://dx.doi.org/10.1039/d0ob01315c.

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The synthesis of α-dialkyl-substituted non-racemic allyl alcohols and their transformation into enantiomerically enriched 1,1-dialkylated 1,2-aminoalcohols, aziridines, morpholines and piperazines is reported.

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27

Ruan, Changshun, Nan Hu, Yang Hu, Lixin Jiang, Qingqing Cai, Huaiyu Wang, Haobo Pan, William W. Lu, and Yuanliang Wang. "Piperazine-based polyurethane-ureas with controllable degradation as potential bone scaffolds." Polymer 55, no. 4 (February 2014): 1020–27. http://dx.doi.org/10.1016/j.polymer.2014.01.011.

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28

Sabino, Marcos Antonio, Maria Gabriela Carrero, and Carlos Julio Rodriguez. "Intelligent copolymers based on poly (N-isopropilacrylamide). Part ii: Grafts polysaccharide to obtain new biomaterials for biomedical and pharmacological applications." International Journal of Advances in Medical Biotechnology - IJAMB 2, no. 1 (March 1, 2019): 17. http://dx.doi.org/10.25061/2595-3931/ijamb/2019.v2i1.31.

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Biopolymers such as polysaccharides are compounds that have functional groups and they are very susceptible to be used in chemical modifications and also allows them to synthesizer of new copolymers (used as graft-like chains). Poly (N-Isopropylacrylamide) PNIPAm, is a thermosensitive synthetic polymer widely used in the preparation of intelligent gels for the biomedical field, but have some limitations in use as biodegradable matrix or scaffolds. In this research wered the synthesis and characterization of copolymers their PNIPAm grafted with the polysaccharides: chitosan (CS) or hyaluronic acid (HA), were performed to obtain new biodegradable and biocompatible biomaterials that conserve the intelligent character (thermosensitivity).The PNIPAm was in first chemically modified with 3-butenoic acid in order to generate carboxyl end groups on the graft-polymer chain (PNIPAm-co-COOH) which serve as anchor points and then covalently graft the polysaccharides. For the specific case of grafting with hyaluronic acid, it was necessary to perform a second modification using piperazine (PIP) and obtain the graft-polymers PNIPAm-co-COO-g-PIP. All this modification process was previously reported (Carrero et al, 2018). In this case, the polysaccharides used as grafts-like chains were: (1) chitosan oligomers obtained by acid degradation and (2) hyaluronic acid. The characterization of all copolymers obtained was follow by infrared spectroscopic (FT-IR); the differential scanning calorimetric (DSC) technique was used to determine the lower critical solution transition temperature (LCST), resulting in the range of 29-34 °C. Its morphology was studied using scanning electron microscopy (SEM), but previously was simulate an inject process, for the reversible gel character presented by these novel copolymers; resulting a high porosity and interconnection between pores (scaffold-like micrometric structures). Hemocompatibility assays were performed on agar/blood systems, showing non cytotoxicity. All these results give these graftcopolymers a high potentiality of use as scaffolds in tissue engineering and also for pharmacological applications.

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29

Zaharani, Lia, Nader Ghaffari Khaligh, Taraneh Mihankhah, and Mohd Rafie Johan. "1H,4H-Piperazine-diium Dichlorosulfonate: Structure Elucidation and its Dual Solvent–Catalyst Activity for the Synthesis of New Dihydro-[1,2,4]triazolo[1,5-a]pyrimidine Scaffolds." Australian Journal of Chemistry 73, no. 11 (2020): 1118. http://dx.doi.org/10.1071/ch20022.

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A new ionic liquid containing a 1H,4H-piperazine-diium ring and chlorosulfonate as a 1,4-dicationic core and counter ion, respectively, was designed and synthesised. The structure elucidation of this ionic liquid was conducted by 1D and 2D NMR, FT-IR, Raman, and mass spectrum analysis. The physical properties of this ionic liquid were determined and reported. Furthermore, the dual solvent–catalyst activity of piperazine-1,4-diium dichlorosulfonate was investigated for the synthesis of new dihydro[1,2,4]triazolo[1,5-a]pyrimidines through a one-pot three-component reaction. The ionic liquid was retrieved and reused several times without reducing its catalytic efficiency.

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James, Thomas, Iain Simpson, J. Andrew Grant, Visuvanathar Sridharan, and Adam Nelson. "Modular, Gold-Catalyzed Approach to the Synthesis of Lead-like Piperazine Scaffolds." Organic Letters 15, no. 23 (November 12, 2013): 6094–97. http://dx.doi.org/10.1021/ol402988s.

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Reilly, Sean W., and Robert H. Mach. "Pd-Catalyzed Synthesis of Piperazine Scaffolds Under Aerobic and Solvent-Free Conditions." Organic Letters 18, no. 20 (October 13, 2016): 5272–75. http://dx.doi.org/10.1021/acs.orglett.6b02591.

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Shaquiquzzaman, Mohammad, Garima Verma, Akranth Marella, Mymoona Akhter, Wasim Akhtar, Mohemmed Faraz Khan, Sharba Tasneem, and Mohammad Mumtaz Alam. "Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents." European Journal of Medicinal Chemistry 102 (September 2015): 487–529. http://dx.doi.org/10.1016/j.ejmech.2015.07.026.

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Sandanayaka, Vincent, Bjorn Mamat, Nikhil Bhagat, Louis Bedell, Gudrun Halldorsdottir, Heida Sigthorsdottir, Þorkell Andrésson, Alex Kiselyov, Mark Gurney, and Jasbir Singh. "Discovery of novel leukotriene A4 hydrolase inhibitors based on piperidine and piperazine scaffolds." Bioorganic & Medicinal Chemistry Letters 20, no. 9 (May 2010): 2851–54. http://dx.doi.org/10.1016/j.bmcl.2010.03.047.

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Borzenko, Andrey, Hassan Pajouhesh, Jerrie-Lynn Morrison, Elizabeth Tringham, Terrance P. Snutch, and Laurel L. Schafer. "Modular, efficient synthesis of asymmetrically substituted piperazine scaffolds as potent calcium channel blockers." Bioorganic & Medicinal Chemistry Letters 23, no. 11 (June 2013): 3257–61. http://dx.doi.org/10.1016/j.bmcl.2013.03.114.

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Zhao, Jun, Li Na Yu, Xiong Li, Yin Yang, and Xue Fen Wang. "Bioenabled Interfacial Polymerized on Nanofibrous Scaffold as Composite Nanofiltration Membrane." Advanced Materials Research 482-484 (February 2012): 565–68. http://dx.doi.org/10.4028/www.scientific.net/amr.482-484.565.

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Thin-film nanofiltration composite (TFNFC) membrane consisting of polyethersulfone (PES) nanofibrous support layer modified by 3, 4-dihydroxy-phenethylamine (dopamine) and interfacial polymerization (IFP) polyamide selective barrier layer was obtained in this study. The hydrophilicity of PES nanofibrous membrane was tremendously improved as the water static contact angle changed from 81.6° to 26.83° by dopamine modification. An ultrathin selective layer was produced by IFP reaction between solutions of piperazine (PIP) and trimesoyl chloride (TMC) on the dopamine modified porous PES membrane. The TFNFC membrane presented relatively high permeate flux (~59.9 L/m2h) and high salt rejection (~98.9%) to divalent anion solutions (1000mg/L, Na2SO4) at a low pressure of 0.6 MPa. It could be believed that dopamine modification would be very efficient to fabricate the composite membranes with stable structure and high filtration performance.

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Alagöz, Mehmet Abdullah, Zeynep Özdemir, Mehtap Uysal, Simone Carradori, Marialucia Gallorini, Alessia Ricci, Susi Zara, and Bijo Mathew. "Synthesis, Cytotoxicity and Anti-Proliferative Activity against AGS Cells of New 3(2H)-Pyridazinone Derivatives Endowed with a Piperazinyl Linker." Pharmaceuticals 14, no. 3 (February 25, 2021): 183. http://dx.doi.org/10.3390/ph14030183.

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Novel twenty-three 3(2H)-pyridazinone derivatives were designed and synthesized based on the chemical requirements related to the anti-proliferative effects previously demonstrated within this scaffold. The introduction of a piperazinyl linker between the pyridazinone nucleus and the additional (un)substituted phenyl group led to some compounds endowed with a limited cytotoxicity against human gingival fibroblasts (HGFs) and good anti-proliferative effects against gastric adenocarcinoma cells (AGS) as evaluated by MTT and LDH assays, using doxorubicin as a positive control. Successive analyses revealed that the two most promising representative compounds (12 and 22) could exert their effects by inducing oxidative stress as demonstrated by the hydrogen peroxide release and the morphological changes (cell blebbing) revealed by light microscopy analysis after the haematoxylin-eosin staining. Moreover, to further assess the apoptotic process induced by compounds 12 and 22, Bax expression was measured by flow cytometry. These findings enlarged our knowledge of the structural requirements in this scaffold to display valuable biological effects against cancerous cell lines.

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Gao, Donglin, Christian Penno, and Bernhard Wünsch. "Rigid Scaffolds: Synthesis of 2,6‐Bridged Piperazines with Functional Groups in all three Bridges." ChemistryOpen 9, no. 8 (August 2020): 874–89. http://dx.doi.org/10.1002/open.202000188.

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Sureshkumar, Kempahanumakkagari, Thippeswamy Ramakrishnappa, and Devarmane Samrat. "Piperazine appended napthalimide scaffold as turn on fluorescent probe for hydrogen sulfide." Microchemical Journal 157 (September 2020): 105019. http://dx.doi.org/10.1016/j.microc.2020.105019.

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Moisan, Lionel, Severin Odermatt, Naran Gombosuren, Alexandre Carella, and Julius Rebek. "Synthesis of an Oxazole–Pyrrole–Piperazine Scaffold as an α-Helix Mimetic." European Journal of Organic Chemistry 2008, no. 10 (April 2008): 1673–76. http://dx.doi.org/10.1002/ejoc.200701164.

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40

James, Thomas, Iain Simpson, J. Andrew Grant, Visuvanathar Sridharan, and Adam Nelson. "ChemInform Abstract: Modular, Gold-Catalyzed Approach to the Synthesis of Lead-Like Piperazine Scaffolds." ChemInform 45, no. 19 (April 23, 2014): no. http://dx.doi.org/10.1002/chin.201419178.

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41

Márquez-Domínguez, Luis, Julio Reyes-Leyva, Irma Herrera-Camacho, Gerardo Santos-López, and Thomas Scior. "Five Novel Non-Sialic Acid-Like Scaffolds Inhibit In Vitro H1N1 and H5N2 Neuraminidase Activity of Influenza a Virus." Molecules 25, no. 18 (September 16, 2020): 4248. http://dx.doi.org/10.3390/molecules25184248.

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Neuraminidase (NA) of influenza viruses enables the virus to access the cell membrane. It degrades the sialic acid contained in extracellular mucin. Later, it is responsible for releasing newly formed virions from the membrane of infected cells. Both processes become key functions within the viral cycle. Therefore, it is a therapeutic target for research of the new antiviral agents. Structure–activity relationships studies have revealed which are the important functional groups for the receptor–ligand interaction. Influenza virus type A NA activity was inhibited by five scaffolds without structural resemblance to sialic acid. Intending small organic compound repositioning along with drug repurposing, this study combined in silico simulations of ligand docking into the known binding site of NA, along with in vitro bioassays. The five proposed scaffolds are N-acetylphenylalanylmethionine, propanoic 3-[(2,5-dimethylphenyl) carbamoyl]-2-(piperazin-1-yl) acid, 3-(propylaminosulfonyl)-4-chlorobenzoic acid, ascorbic acid (vitamin C), and 4-(dipropylsulfamoyl) benzoic acid (probenecid). Their half maximal inhibitory concentration (IC50) was determined through fluorometry. An acidic reagent 2′-O-(4-methylumbelliferyl)-α-dN-acetylneuraminic acid (MUNANA) was used as substrate for viruses of human influenza H1N1 or avian influenza H5N2. Inhibition was observed in millimolar ranges in a concentration-dependent manner. The IC50 values of the five proposed scaffolds ranged from 6.4 to 73 mM. The values reflect a significant affinity difference with respect to the reference drug zanamivir (p < 0.001). Two compounds (N-acetyl dipeptide and 4-substituted benzoic acid) clearly showed competitive mechanisms, whereas ascorbic acid reflected non-competitive kinetics. The five small organic molecules constitute five different scaffolds with moderate NA affinities. They are proposed as lead compounds for developing new NA inhibitors which are not analogous to sialic acid.

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42

Shakil, Shazi, Adel M. Abuzenadah, Suzan M. Attar, Omar Fathaldin, Rajaa Al-Raddadi, and Mansour I. Sulaiman. "Identification of a putative anti-rheumatoid arthritis molecule by virtual screening." Tropical Journal of Pharmaceutical Research 19, no. 6 (November 13, 2020): 1255–61. http://dx.doi.org/10.4314/tjpr.v19i6.21.

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Purpose: To propose an improved chemical skeleton whose scaffolds could be used for the design of future thymidylate synthase (TS)-inhibitors against rheumatoid arthritis. Methods: The drug discovery platform, ‘MCULE’, was employed for inhibitor-screening. The ‘methotrexate-interaction site’ in the crystal (PDB ID 5X66) was used as a target. One ‘RO5 violation’ was permitted. A maximum of ‘10 rotatable bonds’ and ‘100 diverse molecules’ were also allowed in the protocol. The ‘threshold similarity cut off’ was 0.7. The input values describing the remaining parameters were kept as ‘default’. The ‘Open Babel Linear Fingerprint’ was used for the analyses of molecular descriptors, followed by ADME-check. Results: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidine corresponding to the MCULE ID-7590816301-0-93 exhibited the overall best binding with TS. The free energy of binding was -8.6 kcal/mol. A total of 17 amino acid residues were significant for the binding interactions. Importantly, 9 residues were common to methotrexate binding. It satisfied pertinent ADME conditions. Conclusion: 4-(4-Methyl-1-piperazinyl)-2-phenyl[1]benzofuro[3,2-d]pyrimidinemay emerge as a potent seed molecule for TS-inhibitor design in the context of rheumatoid arthritis. It has satisfied pertinent ADME features. However, there is need for further wet laboratory validation. Keywords: Anti-rheumatoid arthritis, Inhibitor design, Methotrexate, Seed molecule, Thymidylate synthase, Virtual screening

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Vanguru, Sowmya, Lavanya Jilla, Yasodakrishna Sajja, Rajashaker Bantu, Lingaiah Nagarapu, Jagadeesh Babu Nanubolu, Bala Bhaskar, Nishant Jain, Sreekanth Sivan, and Vijjulatha Manga. "A novel piperazine linked β -amino alcohols bearing a benzosuberone scaffolds as anti-proliferative agents." Bioorganic & Medicinal Chemistry Letters 27, no. 4 (February 2017): 792–96. http://dx.doi.org/10.1016/j.bmcl.2017.01.031.

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44

Alexopoulos, Kostas, Panagiotis Fatseas, Efi Melissari, Demetrios Vlahakos, Julian Smith, Thomas Mavromoustakos, Mahmoud Saifeddine, Graham Moore, Morley Hollenberg, and John Matsoukas. "Design and synthesis of thrombin receptor-derived nonpeptide mimetics utilizing a piperazine scaffold." Bioorganic & Medicinal Chemistry 7, no. 6 (June 1999): 1033–41. http://dx.doi.org/10.1016/s0968-0896(99)00017-6.

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45

Shaquiquzzaman, Mohammad, Garima Verma, Akranth Marella, Mymoona Akhter, Wasim Akhtar, Mohemmed Faraz Khan, Sharba Tasneem, and Mohammad Mumtaz Alam. "ChemInform Abstract: Piperazine Scaffold: A Remarkable Tool in Generation of Diverse Pharmacological Agents." ChemInform 46, no. 45 (October 22, 2015): no. http://dx.doi.org/10.1002/chin.201545235.

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46

Kim, Seong Heon, Gopinadhan N. Anilkumar, Lisa Guise Zawacki, Qingbei Zeng, De-Yi Yang, Yuefei Shao, Guizhen Dong, et al. "III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl–piperazinyl–piperidine scaffold." Bioorganic & Medicinal Chemistry Letters 21, no. 23 (December 2011): 6982–86. http://dx.doi.org/10.1016/j.bmcl.2011.09.120.

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47

Yalcinkaya, Baturalp, Fatma Yalcinkaya, and Jiri Chaloupek. "Thin Film Nanofibrous Composite Membrane for Dead-End Seawater Desalination." Journal of Nanomaterials 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/2694373.

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The aim of the study was to prepare a thin film nanofibrous composite membrane utilized for nanofiltration technologies. The composite membrane consists of a three-layer system including a nonwoven part as the supporting material, a nanofibrous scaffold as the porous surface, and an active layer. The nonwoven part and the nanofibrous scaffold were laminated together to improve the mechanical properties of the complete membrane. Active layer formations were done successfully via interfacial polymerization. A filtration test was carried out using solutions of MgSO4, NaCl, Na2SO4, CaCl2, and real seawater using the dead-end filtration method. The results indicated that the piperazine-based membrane exhibited higher rejection of divalent salt ions (>98%) with high flux. In addition, them-phenylenediamine-based membrane exhibited higher rejection of divalent and monovalent salt ions (>98% divalent and >96% monovalent) with reasonable flux. The desalination of real seawater results showed that thin film nanofibrous composite membranes were able to retain 98% of salt ions from highly saline seawater without showing any fouling. The electrospun nanofibrous materials proved to be an alternative functional supporting material instead of the polymeric phase-inverted support layer in liquid filtration.

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Lorca, Valdes, Chung, Romero-Parra, Pessoa-Mahana, and Mella. "Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR) on a Series of Piperazine-Carboxamides Fatty Acid Amide Hydrolase (FAAH) Inhibitors as a Useful Tool for the Design of New Cannabinoid Ligands." International Journal of Molecular Sciences 20, no. 10 (May 21, 2019): 2510. http://dx.doi.org/10.3390/ijms20102510.

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Fatty Acid Amide Hydrolase (FAAH) is one of the main enzymes responsible for endocannabinoid metabolism. Inhibition of FAAH increases endogenous levels of fatty acid ethanolamides such as anandamide (AEA) and thus consitutes an indirect strategy that can be used to modulate endocannabinoid tone. In the present work, we present a three-dimensional quantitative structure-activity relationships/comparative molecular similarity indices analysis (3D-QSAR/CoMSIA) study on a series of 90 reported irreversible inhibitors of FAAH sharing a piperazine-carboxamide scaffold. The model obtained was extensively validated (q2 = 0.734; r2 = 0.966; r2m = 0.723). Finally, based on the information derived from the contour maps we designed a series of 10 new compounds with high predicted FAAH inhibition (predicted pIC50 of the best-proposed compounds = 12.196; 12.416).

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Padalino, Gilda, Iain W. Chalmers, Andrea Brancale, and Karl F. Hoffmann. "Identification of 6-(piperazin-1-yl)-1,3,5-triazine as a chemical scaffold with broad anti-schistosomal activities." Wellcome Open Research 5 (July 17, 2020): 169. http://dx.doi.org/10.12688/wellcomeopenres.16069.1.

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Background: Schistosomiasis, caused by infection with blood fluke schistosomes, is a neglected tropical disease of considerable importance in resource-poor communities throughout the developing world. In the absence of an immunoprophylactic vaccine and due to over-reliance on a single chemotherapy (praziquantel), schistosomiasis control is at risk should drug insensitive schistosomes develop. In this context, application of in silico virtual screening on validated schistosome targets has proven successful in the identification of novel small molecules with anti-schistosomal activity. Methods: Focusing on the Schistosoma mansoni histone methylation machinery, we herein have used RNA interference (RNAi), ELISA-mediated detection of H3K4 methylation, homology modelling and in silico virtual screening to identify a small collection of small molecules for anti-schistosomal testing. A combination of low to high-throughput whole organism assays were subsequently used to assess these compounds’ activities on miracidia to sporocyst transformation, schistosomula phenotype/motility metrics and adult worm motility/oviposition readouts. Results: RNAi-mediated knockdown of smp_138030/smmll-1 (encoding a histone methyltransferase, HMT) in adult worms (~60%) reduced parasite motility and egg production. Moreover, in silico docking of compounds into Smp_138030/SmMLL-1’s homology model highlighted competitive substrate pocket inhibitors, some of which demonstrated significant activity on miracidia, schistosomula and adult worm lifecycle stages together with variable effects on HepG2 cells. Particularly, the effect of compounds containing a 6-(piperazin-1-yl)-1,3,5-triazine core on adult schistosomes recapitulated the results of the smp_138030/smmll-1 RNAi screens. Conclusions: The biological data and the structure-activity relationship presented in this study define the 6-(piperazin-1-yl)-1,3,5-triazine core as a promising starting point in ongoing efforts to develop new urgently needed schistosomicides.

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50

Padalino, Gilda, Iain W. Chalmers, Andrea Brancale, and Karl F. Hoffmann. "Identification of 6-(piperazin-1-yl)-1,3,5-triazine as a chemical scaffold with broad anti-schistosomal activities." Wellcome Open Research 5 (November 13, 2020): 169. http://dx.doi.org/10.12688/wellcomeopenres.16069.2.

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Background: Schistosomiasis, caused by infection with blood fluke schistosomes, is a neglected tropical disease of considerable importance in resource-poor communities throughout the developing world. In the absence of an immunoprophylactic vaccine and due to over-reliance on a single chemotherapy (praziquantel), schistosomiasis control is at risk should drug insensitive schistosomes develop. In this context, application of in silico virtual screening on validated schistosome targets has proven successful in the identification of novel small molecules with anti-schistosomal activity. Methods: Focusing on the Schistosoma mansoni histone methylation machinery, we herein have used RNA interference (RNAi), ELISA-mediated detection of H3K4 methylation, homology modelling and in silico virtual screening to identify a small collection of small molecules for anti-schistosomal testing. A combination of low to high-throughput whole organism assays were subsequently used to assess these compounds’ activities on miracidia to sporocyst transformation, schistosomula phenotype/motility metrics and adult worm motility/oviposition readouts. Results: RNAi-mediated knockdown of smp_138030/smmll-1 (encoding a histone methyltransferase, HMT) in adult worms (~60%) reduced parasite motility and egg production. Moreover, in silico docking of compounds into Smp_138030/SmMLL-1’s homology model highlighted competitive substrate pocket inhibitors, some of which demonstrated significant activity on miracidia, schistosomula and adult worm lifecycle stages together with variable effects on HepG2 cells. Particularly, the effect of compounds containing a 6-(piperazin-1-yl)-1,3,5-triazine core on adult schistosomes recapitulated the results of the smp_138030/smmll-1 RNAi screens. Conclusions: The biological data and the structure-activity relationship presented in this study define the 6-(piperazin-1-yl)-1,3,5-triazine core as a promising starting point in ongoing efforts to develop new urgently needed schistosomicides.

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