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Journal of Natural Products Jan 2022We have previously reported that neoechinulin B (), a prenylated indole diketopiperazine alkaloid, shows antiviral activities against hepatitis C virus (HCV) via the...
We have previously reported that neoechinulin B (), a prenylated indole diketopiperazine alkaloid, shows antiviral activities against hepatitis C virus (HCV) via the inactivation of the liver X receptors (LXRs) and the resultant disruption of double-membrane vesicles. In this study, a two-step synthesis of the diketopiperazine scaffold of was achieved by the base-induced coupling of 1,4-diacetyl-3-{[-butyldimethylsilyl)oxy]methyl}piperazine-2,5-dione with aldehydes, followed by the treatment of the resultant coupling products with tetra--butylammonium fluoride. Compound and its 16 derivatives - were prepared using this method. Furthermore, variecolorin H, a related alkaloid, was obtained by the acid treatment of in MeOH. The antiviral evaluation of and its derivatives revealed that , , , , , , and exhibited both anti-HCV and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activities. The results of this study indicate that the exomethylene moiety on the diketopiperazine ring is important for the antiviral activities. The antiviral compounds can inhibit the production of HCV and SARS-CoV-2 by inactivating LXRs.
Topics: Alkaloids; Antiviral Agents; Cell Line, Tumor; Diketopiperazines; Hepacivirus; Humans; Liver X Receptors; Molecular Structure; Piperazines; SARS-CoV-2; Structure-Activity Relationship; Transcription, Genetic
PubMed: 34967639
DOI: 10.1021/acs.jnatprod.1c01120 -
European Journal of Pharmaceutical... Nov 2020Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates...
Mitoxantrone, pixantrone and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia.
Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions. In this study, a library of 140 000 compounds was virtually screened and a resulting hit-list of 1000 compounds was tested using a cellular reporter system. The topoisomerase II inhibitor mitoxantrone and its analogues pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were identified as inhibitors of TLR4 and NF-κB activation. Mitoxantrone was shown to bind directly to the TLR4, and pixantrone and mitoxantrone (2-hydroxyethyl)piperazine were shown to inhibit the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNFα) in primary microglia. The inhibitory effect on NF-κB activation or on TNFα production was not mediated through cytotoxity at ≤ 1 µM concentration for pixantrone and mitoxantrone (2-hydroxyethyl)piperazine treated cells, as assessed by ATP counts. This study thus identifies a new mechanism of action for mitoxantrone, pixantrone, and mitoxantrone (2-hydroxyethyl)piperazine through the TLR4.
Topics: Isoquinolines; Microglia; Mitoxantrone; NF-kappa B; Piperazine; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha
PubMed: 32730846
DOI: 10.1016/j.ejps.2020.105493 -
Tijdschrift Voor Psychiatrie 2019Since 2018, cariprazine has been available for the treatment of schizophrenia on the Dutch and Belgian markets.
AIM: To give an overview of the indications,... (Review)Review
Since 2018, cariprazine has been available for the treatment of schizophrenia on the Dutch and Belgian markets.
AIM: To give an overview of the indications, effectiveness and side effects of cariprazine. To make an inventory of the advantages and disadvantages of this new antipsychotic drug.
METHOD: A clinically oriented literature review of published clinical studies and pharmacodynamic and -kinetic publications.
RESULTS: Cariprazine is unique because of its preferential D3 receptor partial agonist affinity and has, in theory, a beneficial effect on negative symptoms. The antipsychotic has two active metabolites: desmethylcariprazine and didesmethylcariprazine. The long half-life of cariprazine indicates that, in theory, the drug should not be given daily. Cariprazine is metabolized by cyp3a4 and to a lesser extent by cyp2d6 enzymes. Extrapyramidal symptoms and akathisia are relatively frequent side effects. In contrast, metabolic side effects and weight gain have been reported rarely.
CONCLUSION: Cariprazine can be an effective treatment option for schizophrenia. The final positioning of this antipsychotic drug will have to be based on future research.Topics: Antipsychotic Agents; Dopamine Agonists; Humans; Piperazines; Schizophrenia; Treatment Outcome
PubMed: 31907914
DOI: No ID Found -
Molecules (Basel, Switzerland) Dec 2023The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the... (Review)
Review
The piperazine moiety is often found in drugs or in bioactive molecules. This widespread presence is due to different possible roles depending on the position in the molecule and on the therapeutic class, but it also depends on the chemical reactivity of piperazine-based synthons, which facilitate its insertion into the molecule. In this paper, we take into consideration the piperazine-containing drugs approved by the Food and Drug Administration between January 2011 and June 2023, and the synthetic methodologies used to prepare the compounds in the discovery and process chemistry are reviewed.
Topics: United States; Piperazine; United States Food and Drug Administration
PubMed: 38202651
DOI: 10.3390/molecules29010068 -
Bioorganic & Medicinal Chemistry May 2018Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the...
Proliferating cells, including cancer cells, obtain serine both exogenously and via the metabolism of glucose. By catalyzing the first, rate-limiting step in the synthesis of serine from glucose, phosphoglycerate dehydrogenase (PHGDH) controls flux through the biosynthetic pathway for this important amino acid and represents a putative target in oncology. To discover inhibitors of PHGDH, a coupled biochemical assay was developed and optimized to enable high-throughput screening for inhibitors of human PHGDH. Feedback inhibition was minimized by coupling PHGDH activity to two downstream enzymes (PSAT1 and PSPH), providing a marked improvement in enzymatic turnover. Further coupling of NADH to a diaphorase/resazurin system enabled a red-shifted detection readout, minimizing interference due to compound autofluorescence. With this protocol, over 400,000 small molecules were screened for PHGDH inhibition, and following hit validation and triage work, a piperazine-1-thiourea was identified. Following rounds of medicinal chemistry and SAR exploration, two probes (NCT-502 and NCT-503) were identified. These molecules demonstrated improved target activity and encouraging ADME properties, enabling in vitro assessment of the biological importance of PHGDH, and its role in the fate of serine in PHGDH-dependent cancer cells. This manuscript reports the assay development and medicinal chemistry leading to the development of NCT-502 and -503 reported in Pacold et al. (2016).
Topics: Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; High-Throughput Screening Assays; Humans; Molecular Structure; Phosphoglycerate Dehydrogenase; Piperazines; Structure-Activity Relationship; Thiourea
PubMed: 29555419
DOI: 10.1016/j.bmc.2018.02.016 -
Journal of Enzyme Inhibition and... Dec 2021Piperazine moiety is a cyclic molecule containing two nitrogen atoms in positions 1 and 4, as well as four carbon atoms. Piperazine is one of the most sought... (Review)
Review
Piperazine moiety is a cyclic molecule containing two nitrogen atoms in positions 1 and 4, as well as four carbon atoms. Piperazine is one of the most sought heterocyclics for the development of new drug candidates with a wide range of applications. Over 100 molecules with a broad range of bioactivities, including antitumor, antibacterial, anti-inflammatory, antioxidant, and other activities, were reviewed. This article reviewed investigations regarding piperazine groups for the modification of natural product derivatives in the last decade, highlighting parameters that affect their biological activity.
Topics: Anti-Bacterial Agents; Biological Products; Drug Screening Assays, Antitumor; Piperazines; Structure-Activity Relationship
PubMed: 34080510
DOI: 10.1080/14756366.2021.1931861 -
PloS One 2017The Antibiogram properties of 1-chloro-2-isocyanatoethane derivatives of thiomorpholine (CTC), piperazine (CPC) and morpholine (CMC) were evaluated by the approved agar...
The Antibiogram properties of 1-chloro-2-isocyanatoethane derivatives of thiomorpholine (CTC), piperazine (CPC) and morpholine (CMC) were evaluated by the approved agar well diffusion, the minimum inhibitory concentration (MIC) and in silico techniques. A total of fourteen microbial cultures consisting of ten bacteria and four yeast strains were used in the biological study while affinity of the compounds for DNA gyrase, a validated antibacterial drug target, was investigated by docking method. Results indicate that both thiomorpholine and piperazine had zero activity against the Gram negative organisms tested. With morpholine, similar result was obtained except that cultures of Escherichia coli (ATCC 15442) and Salmonella typhi (ATCC 6539) presented with weak sensitivity (7-8 mm) as shown by the inhibition zone diameter (IZD) measurement. The Gram positive organisms were more sensitive to morpholine than the other compounds. The highest IZD values of 15-18 mm were achieved except for Streptococcus pneumoniae (ATCC 49619) in which mobility of the compound stopped after 12 mm. S. pneumoniae was resistant to both thiomorpholine and piperazine. The yeast strains were not sensitive to any of the studied compounds investigated. The MIC tests evaluated against a reference antibiotic show that while morpholine was most active at 4 μg.ml-1 against both B. cereus ATCC (14579) and B. subtilis, the least active compound was thiomorpholine which inhibited S. aureus (ATCC 25923) at 64 μg.ml-1. The three compounds demonstrated high affinity for the target protein (DNA gyrase) ranging from -4.63 to -5.64 Kcal/mol and even showed better ligand efficiencies than three known antibiotics; chlorobiocin, ciprofloxacin and tetracycline. This study identified the studied compounds as potential antibiotic leads with acceptable physicochemical properties and gave the molecular basis for the observed interactions between the compounds and the target protein which can be harnessed in structural optimization process.
Topics: Anti-Bacterial Agents; Biological Availability; Computer Simulation; Gram-Negative Bacteria; Isocyanates; Microbial Sensitivity Tests; Molecular Docking Simulation; Morpholines; Piperazines
PubMed: 28107379
DOI: 10.1371/journal.pone.0170150 -
Journal of Enzyme Inhibition and... Dec 2021Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture...
Molecular hybridisation of four bioactive fragments piperazine, substituted-benzofuran, amino acids, and 2,4-dinitrobenzenesulfonamide as single molecular architecture was designed. A series of new hybrids were synthesised and subjected to evaluation for their inhibitory activity against () H37Rv. - and found to exhibit MIC as 1.56 µg/mL, equally active as ethambutol whereas displayed MIC 0.78 µg/mL were superior to ethambutol. Tested compounds demonstrated an excellent safety profile with very low toxicity, good selectivity index, and antioxidant properties. All the newly synthesised compounds were thoroughly characterised by analytical methods. The result was further supported by molecular modelling studies on the crystal structure of enoyl reductase.
Topics: Amides; Antitubercular Agents; Benzenesulfonates; Benzofurans; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Humans; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Piperazine; Spectrum Analysis
PubMed: 34325595
DOI: 10.1080/14756366.2021.1956914 -
International Journal of Molecular... Dec 2023Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal...
Thiazole and piperazine are two important heterocyclic rings that play a prominent role in nature and have a broad range of applications in agricultural and medicinal chemistry. Herein, we report the parallel synthesis of a library of diverse piperazine-tethered thiazole compounds. The reaction of piperazine with newly generated 4-chloromethyl-2-amino thiazoles led to the desired piperazine thiazole compounds with high purities and good overall yields. Using a variety of commercially available carboxylic acids, the parallel synthesis of a variety of disubstituted 4-(piperazin-1-ylmethyl)thiazol-2-amine derivatives is described. the screening of the compounds led to the identification of antiplasmodial compounds that exhibited interesting antimalarial activity, primarily against the chloroquine-resistant Dd2 strain. The hit compound demonstrated an antiplasmodial EC of 102 nM in the chloroquine-resistant Dd2 strain and a selectivity of over 140.
Topics: Antimalarials; Piperazine; Thiazoles; Chloroquine; Plasmodium falciparum
PubMed: 38139243
DOI: 10.3390/ijms242417414 -
ACS Chemical Biology Dec 2021The global rise of multidrug resistant infections poses an imminent, existential threat. Numerous pipelines have failed to convert biochemically active molecules into...
The global rise of multidrug resistant infections poses an imminent, existential threat. Numerous pipelines have failed to convert biochemically active molecules into bona fide antibacterials, owing to a lack of chemical material with antibacterial-like physical properties in high-throughput screening compound libraries. Here, we demonstrate scalable design and synthesis of an antibacterial-like solid-phase DNA-encoded library (DEL, 7488 members) and facile hit deconvolution from whole-cell and cytotoxicity screens. The screen output identified two low-micromolar inhibitors of growth and recapitulated known structure-activity relationships of the fluoroquinolone antibacterial class. This phenotypic DEL screening strategy is also potentially applicable to adherent cells and will broadly enable the discovery and optimization of cell-active molecules.
Topics: Anti-Bacterial Agents; Apoptosis; Bacillus subtilis; Ciprofloxacin; DNA; Drug Discovery; Escherichia coli; Gene Library; High-Throughput Screening Assays; Molecular Structure; Piperazine; Structure-Activity Relationship
PubMed: 34806373
DOI: 10.1021/acschembio.1c00714