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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 -
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 -
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 -
Journal of Inorganic Biochemistry Apr 2023Rigidification of the ligand scaffolds has been a particular mechanism of interest employed to achieve properties suitable for MRI contrast, catalysis, or other...
Rigidification of the ligand scaffolds has been a particular mechanism of interest employed to achieve properties suitable for MRI contrast, catalysis, or other applications of metal complexes. Towards the goal of targeting a 15-anePyNPip type ligand, a serendipitous isolation of a 30-anePyNPip aza-macrocycle was achieved, instead. X-ray diffraction and determination of pK events were carried out and compared to 17-anePyNPip. Furthermore, the X-ray diffraction of the Cu(II) and Zn(II) complexes of 17-anePyNPip was achieved and compared to previous reports of other first-row transition metal derivatives of this ligand. Determination of the log β with both 30-anePyNPip and 17-anePyNPip with the divalent MnZn metal-ion series was used to demonstrate the impact that the piperazine ring plays compared to other, less rigid macrocycles reported to date.
Topics: Coordination Complexes; Piperazine; Ligands; Molecular Structure; Transition Elements
PubMed: 36652846
DOI: 10.1016/j.jinorgbio.2023.112124 -
Bioorganic Chemistry Sep 2020The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel...
The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the crystal structure of Klebsiella pneumoniae LpxH in complex with 1 (AZ1), a sulfonyl piperazine LpxH inhibitor. The analysis of the LpxH-AZ1 co-crystal structure and ligand dynamics led to the design of 2 (JH-LPH-28) and 3 (JH-LPH-33) with enhanced LpxH inhibition. In order to harness our recent findings, we prepared and evaluated a series of sulfonyl piperazine analogs with modifications in the phenyl and N-acetyl groups of 3. Herein, we describe the synthesis and structure-activity relationship of sulfonyl piperazine LpxH inhibitors. We also report the structural analysis of an extended N-acyl chain analog 27b (JH-LPH-41) in complex with K. pneumoniae LpxH, revealing that 27b reaches an untapped polar pocket near the di-manganese cluster in the active site of K. pneumoniae LpxH. We expect that our findings will provide designing principles for new LpxH inhibitors and establish important frameworks for the future development of antibiotics against multidrug-resistant Gram-negative pathogens.
Topics: Antinematodal Agents; Enzyme Inhibitors; Humans; Piperazine; Structure-Activity Relationship
PubMed: 32663666
DOI: 10.1016/j.bioorg.2020.104055 -
International Journal of Molecular... May 2023Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor...
Fibroblast activation proteins (FAP) are overexpressed in the tumor stroma and have received attention as target molecules for radionuclide therapy. The FAP inhibitor (FAPI) is used as a probe to deliver nuclides to cancer tissues. In this study, we designed and synthesized four novel At-FAPI(s) possessing polyethylene glycol (PEG) linkers between the FAP-targeting and At-attaching moieties. At-FAPI(s) and piperazine (PIP) linker FAPI exhibited distinct FAP selectivity and uptake in FAPII-overexpressing HEK293 cells and the lung cancer cell line A549. The complexity of the PEG linker did not significantly affect selectivity. The efficiencies of both linkers were almost the same. Comparing the two nuclides, At was superior to I in tumor accumulation. In the mouse model, the antitumor effects of the PEG and PIP linkers were almost the same. Most of the currently synthesized FAPI(s) contain PIP linkers; however, in our study, we found that PEG linkers exhibit equivalent performance. If the PIP linker is inconvenient, a PEG linker is expected to be an alternative.
Topics: Humans; Animals; Mice; HEK293 Cells; Piperazine; Polyethylene Glycols; Fibroblasts; Positron Emission Tomography Computed Tomography; Gallium Radioisotopes
PubMed: 37240044
DOI: 10.3390/ijms24108701 -
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 -
International Journal of Molecular... May 2024Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations... (Review)
Review
Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients' bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients' bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.
Topics: Humans; Antipsychotic Agents; Piperazines; Receptors, Dopamine D3; Schizophrenia; Animals; Bipolar Disorder; Drug Development
PubMed: 38891871
DOI: 10.3390/ijms25115682 -
Fa Yi Xue Za Zhi Dec 2017As a new hypnotic, zopiclone is widely used in clinical treatment. There are many methods for determination of zopiclone, including spectrophotometry, chromatography and... (Review)
Review
As a new hypnotic, zopiclone is widely used in clinical treatment. There are many methods for determination of zopiclone, including spectrophotometry, chromatography and chromatography mass spectrum, etc. Present paper reviews different kinds of biological samples associated with zopiclone, extraction and purification methods, and determination and analysis methods, which aims to provide references for the relevant research and practice.
Topics: Azabicyclo Compounds; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Humans; Hypnotics and Sedatives; Mass Spectrometry; Piperazines; Tandem Mass Spectrometry
PubMed: 29441774
DOI: 10.3969/j.issn.1004-5619.2017.06.014 -
Upsala Journal of Medical Sciences 2022The small tyrosine kinase (TK) inhibitor imatinib mesylate (Gleevec, STI571) protects against both type 1 and type 2 diabetes, but as it inhibits many TKs and other... (Review)
Review
The small tyrosine kinase (TK) inhibitor imatinib mesylate (Gleevec, STI571) protects against both type 1 and type 2 diabetes, but as it inhibits many TKs and other proteins, it is not clear by which mechanisms it acts. This present review will focus on the possibility that imatinib acts, at least in part, by improving beta-cell function and survival via off-target effects on beta-cell signaling/metabolic flow events. Particular attention will be given to the possibility that imatinib and other TK inhibitors function as inhibitors of mitochondrial respiration. A better understanding of how imatinib counteracts diabetes will possibly help to clarify the pathogenic role of beta-cell signaling events and mitochondrial function, and hopefully leading to improved treatment of the disease.
Topics: Benzamides; Diabetes Mellitus, Type 2; Humans; Imatinib Mesylate; Piperazines; Protein-Tyrosine Kinases; Pyrimidines
PubMed: 36187072
DOI: 10.48101/ujms.v127.8841