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ACS Chemical Neuroscience Jun 2023Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new...
Design, Synthesis, and Biological Evaluation of Piperazine and -Benzylpiperidine Hybrids of 5-Phenyl-1,3,4-oxadiazol-2-thiol as Potential Multitargeted Ligands for Alzheimer's Disease Therapy.
Our present work demonstrates the successful design and synthesis of a new class of compounds based upon a multitargeted directed ligand design approach to discover new agents for use in Alzheimer's disease (AD). All the compounds were tested for their in vitro inhibitory potential against human acetylcholinesterase (hAChE), human butylcholinesterase (hBChE), β-secretase-1 (hBACE-1), and amyloid β (Aβ) aggregation. Compounds and have shown hAChE and hBACE-1 inhibition comparable to donepezil, while hBChE inhibition was comparable to rivastigmine. Compounds and also demonstrated a significant reduction in the formation of Aβ aggregates through the thioflavin T assay and confocal, atomic force, and scanning electron microscopy studies and significantly displaced the total propidium iodide, that is, 54 and 51% at 50 μM concentrations, respectively. Compounds and were devoid of neurotoxic liabilities against RA/BDNF (RA = retinoic acid; BDNF = brain-derived neurotrophic factor)-differentiated SH-SY5Y neuroblastoma cell lines at 10-80 μM concentrations. In both the scopolamine- and Aβ-induced mouse models for AD, compounds and demonstrated significant restoration of learning and memory behaviors. A series of ex vivo studies of hippocampal and cortex brain homogenates showed that and elicit decreases in AChE, malondialdehyde, and nitric oxide levels, an increase in glutathione level, and reduced levels of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) mRNA. The histopathological examination of mice revealed normal neuronal appearance in the hippocampal and cortex regions of the brain. Western blot analysis of the same tissue indicated a reduction in Aβ, amyloid precursor protein (APP)/Aβ, BACE-1, and tau protein levels, which were non-significant compared to the sham group. The immunohistochemical analysis also showed significantly lower expression of BACE-1 and Aβ levels, which was comparable to donepezil-treated group. Compounds and represent new lead candidates for developing AD therapeutics.
Topics: Humans; Mice; Animals; Alzheimer Disease; Donepezil; Amyloid beta-Peptides; Ligands; Brain-Derived Neurotrophic Factor; Piperazine; Acetylcholinesterase; Neuroblastoma; Cholinesterase Inhibitors; Structure-Activity Relationship
PubMed: 37216500
DOI: 10.1021/acschemneuro.3c00245 -
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 -
Analytical Methods : Advancing Methods... Feb 2023Five fluorescent probes TP1-5 were demonstrated as two-input "AND" molecular logic gates for the detection of thiols and protons. The molecules were designed based on...
Five fluorescent probes TP1-5 were demonstrated as two-input "AND" molecular logic gates for the detection of thiols and protons. The molecules were designed based on "thiol receptor-spacer-fluorophore-spacer-proton receptor" mode. The logic gates were constructed by employing maleimide, naphthalimide and morpholine (TP1-3)/-methyl piperazine (TP4-5) as the thiol receptor, fluorophore and proton receptor, respectively. All probes show significant fluorescence enhancements upon addition of both protons and thiols. However, much weaker spectral responses were observed with the addition of only one single analyte. The fluorescence outputs, based on photoinduced electron transfer (PET) and (twisted) intramolecular charge transfer (TICT/ICT), were modulated by the proton receptor and linker. The length of spacer affects the responses toward thiols, whereas spacer influences the sensing performance toward protons. The difference between the p values of morpholine (∼5.80) and -methyl piperazine (∼7.10) enables us to detect thiols in divergent pH circumstances. TP1-3 exhibit an excellent "AND" logic function for simultaneous detection of protons and thiols as well as bioimaging thiols in weakly acidic living cells. However, TP4 and TP5 are not good candidates for executing "AND" logic operation possibly due to the stronger electron donating properties and steric effect of -methyl piperazine.
Topics: Protons; Sulfhydryl Compounds; Fluorescent Dyes; Spectrometry, Fluorescence; Piperazines
PubMed: 36722868
DOI: 10.1039/d2ay01742c -
Journal of Pharmaceutical and... Jan 2022Ziprasidone hydrochloride is a second-generation antipsychotic drug employed for the treatment of schizophrenia and acute mania or mixed episodes associated with bipolar...
Ziprasidone hydrochloride is a second-generation antipsychotic drug employed for the treatment of schizophrenia and acute mania or mixed episodes associated with bipolar disorder. During the scale-up of ziprasidone hydrochloride, an unknown impurity was observed in the batches ranging from 0.10% to 0.15% by HPLC-UV analysis. The structure of an unknown impurity was proposed as 3,3'-methylenebis(5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one) which is named as methylene ziprasidone dimer (MZD impurity). It was isolated from an enriched sample by preparative HPLC, and its structure was elucidated by comprehensive analysis of HRMS, 1D NMR (H, C), DEPT-135, 2D NMR (COSY, HSQC, HMBC) spectroscopy. A plausible mechanism for the formation of isolated impurity is proposed.
Topics: Chromatography, High Pressure Liquid; Drug Contamination; Piperazines; Thiazoles
PubMed: 34678557
DOI: 10.1016/j.jpba.2021.114416 -
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 -
Journal of Natural Products Apr 2020Nine new epipoly(thiodioxopiperazine) (ETP) analogues, chetocochliodins AI (-), along with two known ones, chetoseminudins E and C ( and ), were purified from the fungus...
Nine new epipoly(thiodioxopiperazine) (ETP) analogues, chetocochliodins AI (-), along with two known ones, chetoseminudins E and C ( and ), were purified from the fungus . The planar structures and absolute configurations of these new compounds were determined by extensive NMR spectroscopic analysis, CD spectra, and chemical reactions. Shielding effects from the indole on the 3-SCH/3-OCH/3-OCH- groups facilitated the determination of relative configuration of the analogues. Compound was cytotoxic, suggesting the importance of the sulfide bridge for the diketopiperazine bioactivities.
Topics: Chaetomium; Circular Dichroism; Fermentation; Indole Alkaloids; Magnetic Resonance Spectroscopy; Molecular Structure; Piperazines; Sulfides; X-Ray Diffraction
PubMed: 32115958
DOI: 10.1021/acs.jnatprod.9b00239