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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 Pharmaceutical Sciences Oct 2022Piperazine (PIP) is a pharmaceutically acceptable molecule and a good co-conformer in crystallographic engineering. Most of the non-steroidal anti-inflammatory drugs...
Piperazine (PIP) is a pharmaceutically acceptable molecule and a good co-conformer in crystallographic engineering. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) have poor aqueous solubility, which hinders their clinical application. The reports show that the solubility of many insoluble drugs can be significantly improved through salt formation with the PIP. In this work, we obtained a series of NSAIDs-PIP salts, such as ibuprofen-piperazine (IBU-0.5PIP) salt, indomethacin-piperazine (IND-0.5PIP) salt, sulindac-piperazine (SUL-0.5PIP) salt, phenylbutazone-piperazine (PBZ-0.5PIP) salt, ketoprofen-piperazine (KPF-0.5PIP) salt and flurbiprofen-piperazine (FLB-0.5PIP) salt. The spatial structure, arrangement, interaction and associations were expatiated by single crystal X-ray diffraction. Powder X-ray diffraction, Fourier transform infrared, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the novel salts. The six new salts had more than 10 folds of solubility and a faster dissolution rate improved corresponding to the bulk drugs in pure water, and the significant improvement of solubility is closely related to the structure of salts.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Calorimetry, Differential Scanning; Flurbiprofen; Ibuprofen; Indomethacin; Ketoprofen; Phenylbutazone; Piperazine; Powders; Salts; Solubility; Spectroscopy, Fourier Transform Infrared; Sulindac; Water; X-Ray Diffraction
PubMed: 35580691
DOI: 10.1016/j.xphs.2022.05.009 -
Phytochemistry Jun 2021Four undescribed piperazine-2,5-dione derivatives designated janthinolides C-F, and an α-pyrone-containing polyketide namely trichopyrone C, were isolated from the...
Four undescribed piperazine-2,5-dione derivatives designated janthinolides C-F, and an α-pyrone-containing polyketide namely trichopyrone C, were isolated from the extract of the fungus Penicillium griseofulvum along with four known products. Among them, janthinolide C represents the first naturally occured piperazine-2,5-dione analogue featuring a cleavaged piperazinedione ring with an oxime group, while the structure of janthinolide D possesses a rare N-methoxy group in natural products. Their structures and absolute stereochemistry were elucidated based on spectroscopic data, theoretical NMR and ECD calculations, Snatzke's method, and modified Mosher's method. All compounds were evaluated for in vitro immunosuppression activity in murine splenocytes stimulated by anti-CD3/anti-CD28 mAbs, of which janthinolides B and C showed potential inhibitory activity with IC values at 9.3 and 1.3 μM, respectively.
Topics: Animals; Immunosuppression Therapy; Mice; Molecular Structure; Penicillium; Piperazine; Polyketides; Pyrones
PubMed: 33857795
DOI: 10.1016/j.phytochem.2021.112708 -
International Journal of Molecular... Aug 2023The oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform was designed based on branched... (Review)
Review
The oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform was designed based on branched piperazine-2,5-diones for creating orally available biologically active peptidomimetics. The platform includes a bio-carrier with "built-in" functionally active peptide fragments or bioactive molecules that are covalently attached via linkers. The developed platform allows for a small peptide to be taken with a particular biological activity and to be transformed into an orally stable compound displaying the same activity. Based on this approach, various peptidomimetics exhibiting hemostimulating, hemosuppressing, and adjuvant activity were prepared. In addition, new examples of a rare phenomenon when enantiomeric molecules demonstrate reciprocal biological activity are presented. Finally, the review summarizes the evolutionary approach of the short peptide pharmaceutical development from the immunocompetent organ separation to orally active cyclopeptides and peptidomimetics.
Topics: Peptides, Cyclic; Pharmaceutical Preparations; Peptidomimetics; Peptides; Piperazine
PubMed: 37686336
DOI: 10.3390/ijms241713534 -
Bioorganic Chemistry Jul 2023Piperazine derivatives have been of great interest to medicinal chemists in the development of antidepressant drugs due to their distinct molecular and structural...
Piperazine derivatives have been of great interest to medicinal chemists in the development of antidepressant drugs due to their distinct molecular and structural features along with their pharmacological profile. In this study, we have designed and synthesized a series of 10 compounds of piperazine clubbed oxadiazole derivatives (5a-j) and screened for their MAO inhibitory activity. Compound 5f and 5 g were found to be the most potent MAO-A inhibitors of the series with IC values of 0.96 ± 0.04 µM µM and 0.81 ± 0.03 µM, respectively with a selectivity index of 18-folds and 9-folds over MAO-B isoform. The compounds were found to be reversible inhibitors of MAO-A with no cytotoxicity against SH-SY5Y neuronal cells. The compounds also displayed good antioxidant activity. Further, in vivo TST studies revealed that both the compounds 5f and 5 g possessed good anti-depressant-like activity and reduced the immobility time significantly although were found inactive in FST studies. The molecular docking studies revealed that both compounds fit well at the active site of MAO-A enzyme as similar to clorgyline and form a stable complex. The results were confirmed via molecular dynamic studies which demonstrate the stable complex formation between MAO-A and 5f & 5 g. The appropriate drug-like characteristics with favourable ADMET profile, these molecules presented this piperazine clubbed oxadiazole structural framework as a key pharmacophore for the development of new antidepressant molecules along with strong candidature for further clinical investigations.
Topics: Humans; Monoamine Oxidase Inhibitors; Molecular Docking Simulation; Structure-Activity Relationship; Neuroblastoma; Antidepressive Agents; Monoamine Oxidase; Piperazine; Molecular Structure
PubMed: 37116324
DOI: 10.1016/j.bioorg.2023.106544 -
ACS Chemical Neuroscience Jan 2022In an attempt to extend recent studies showing that some clinically evaluated histamine H receptor (HR) antagonists possess nanomolar affinity at sigma-1 receptors...
In an attempt to extend recent studies showing that some clinically evaluated histamine H receptor (HR) antagonists possess nanomolar affinity at sigma-1 receptors (σR), we selected 20 representative structures among our previously reported HR ligands to investigate their affinity at σRs. Most of the tested compounds interact with both sigma receptors to different degrees. However, only six of them showed higher affinity toward σR than σR with the highest binding preference to σR for compounds , , and . Moreover, all these ligands share a common structural feature: the piperidine moiety as the fundamental part of the molecule. It is most likely a critical structural element for dual H/σ receptor activity as can be seen by comparing the data for compounds and (hHR = 3.17 and 7.70 nM, σR = 1531 and 3.64 nM, respectively), where piperidine is replaced by piperazine. We identified the putative protein-ligand interactions responsible for their high affinity using molecular modeling techniques and selected compounds and as lead structures for further evaluation. Interestingly, both ligands turned out to be high-affinity histamine H and σ receptor antagonists with negligible affinity at the other histamine receptor subtypes and promising antinociceptive activity . Considering that many literature data clearly indicate high preclinical efficacy of individual selective σ or HR ligands in various pain models, our research might be a breakthrough in the search for novel, dual-acting compounds that can improve existing pain therapies. Determining whether such ligands are more effective than single-selective drugs will be the subject of our future studies.
Topics: Analgesics; Histamine; Histamine Antagonists; Histamine H3 Antagonists; Ligands; Piperazine; Piperidines; Receptors, Histamine H3; Receptors, sigma; Structure-Activity Relationship; Sigma-1 Receptor
PubMed: 34908391
DOI: 10.1021/acschemneuro.1c00435 -
European Journal of Medicinal Chemistry Oct 2021JNJ4796, a small molecule fuse inhibitor targeting the conserved stem region of hemagglutinin, effectively neutralized a broad spectrum of group 1 influenza A virus...
JNJ4796, a small molecule fuse inhibitor targeting the conserved stem region of hemagglutinin, effectively neutralized a broad spectrum of group 1 influenza A virus (IAV), and protected mice against lethal and sublethal influenza challenge after oral administration. In this study, we reported the modification and structure-activity relationship (SAR) of C (piperazine ring) and E (phenyl ring) rings of JNJ4796. Compound (R)-2c was identified to show excellent in vitro activity against IAV H1N1 and Oseltamivir-resistant IAV H1N1 stains (IC: 0.03-0.06 μM), low cytotoxicity (CC > 200 μM), accepted oral PK profiles and low inhibition rate of hERG (13.2%, at 10 μM). Evaluation for the in vivo anti-IAV efficacy of (R)-2c will begin soon.
Topics: Antiviral Agents; Dose-Response Relationship, Drug; Influenza A Virus, H1N1 Subtype; Microbial Sensitivity Tests; Molecular Structure; Piperazine; Piperazines; Pyridines; Structure-Activity Relationship; Tetrazoles
PubMed: 34126455
DOI: 10.1016/j.ejmech.2021.113591 -
Emergencias : Revista de La Sociedad... Jun 2022To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency... (Observational Study)
Observational Study
OBJECTIVES
To detect the presence of unsuspected and/or undeclared cathinone and piperazine-type designer drugs in methamphetamine (METH) and amphetamine users treated in emergency departments, and to compare clinical and toxicologic profiles.
MATERIAL AND METHODS
Retrospective observational study of emergency department patients treated for confirmed acute intoxication by recreational drugs (METH and amphetamines) between March 2019 and December 2020. We ordered high-performance liquid chromatography with tandem mass spectrometry to detect cathinones (methylone, fluoromethcathinone, mexedrone, fluoromethamphetamine, mephedrone, methylenedioxypyrovalerone) and synthetic piperazines (meta-chlorophenylpiperazine and trifluoromethylphenylpiperazine). Demographic, clinical, and toxicologic variables were analyzed with SPSS software (version 23).
RESULTS
Thirty-nine patients were included: 24 (61.5%) had used METH and 15 (38.5%) an amphetamine. Synthetic cathinones were detected in samples from 11 patients (28.2%), 10 (90.9%) in the METH group and 1 (9.1%) in the amphetamine group (P = .028). The METH users had taken mephedrone (8 patients) or methylone (2 patients); the amphetamine user had taken mephedrone. None of the patients had declared use of a cathinone; nor was use suspected. The mean (SD) number of substances involved was higher among users of cathinones (3.5 [1.13] vs 2.5 [1.40] in those who took no cathinones; P = .036). Among the cathinone users, 90.9% were men, 90.9% had used METH, and 45.5% had practiced chemsex. HIV positivity was significantly associated with cathinone use (in 45.5% vs 10.7% of those not using cathinones; P = .028). All 5 of the patients who had taken cathinones and also practiced chemsex were HIV positive. Significantly more patients who had taken cathinones presented with anxiety (72.7% vs 21.43%; P = .007). No differences in clinical management were found.
CONCLUSION
Detection of METH in intoxicated patients should raise suspicion of probable use of a synthetic cathinone. Patients in whom new psychoactive substances are detected should be kept under observation, and clinical protocols should include referring them to addiction treatment centers.
Topics: Alkaloids; Amphetamine; Emergency Service, Hospital; Female; Humans; Male; Methamphetamine; Piperazine; Piperazines
PubMed: 35736521
DOI: No ID Found