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Journal of Medicinal Chemistry Dec 2023The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and...
Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability.
The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (M) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal demonstrated high enzyme-inhibitory potency (IC = 0.19 μM) and exhibited excellent antiviral activity (EC = 0.40 μM), reaching the same level as Nirmatrelvir (EC = 0.38 μM). Additionally, displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic M inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.
Topics: Humans; SARS-CoV-2; COVID-19; Molecular Docking Simulation; Protease Inhibitors; Antiviral Agents; Piperazines
PubMed: 37992202
DOI: 10.1021/acs.jmedchem.3c01876 -
Molecular Pharmaceutics Oct 2023Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical...
Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.
Topics: Piperazine; Salts; X-Ray Diffraction; Solubility
PubMed: 37677085
DOI: 10.1021/acs.molpharmaceut.3c00646 -
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 -
Journal of Natural Products Jul 2023Bioassay-guided fractionation of the essential oil of led to the identification of α-santalol () and β-santalol () as new chemotypes of cannabinoid receptor type II...
Bioassay-guided fractionation of the essential oil of led to the identification of α-santalol () and β-santalol () as new chemotypes of cannabinoid receptor type II (CB) ligands with values of 10.49 and 8.19 μM, respectively. Nine structurally new α-santalol derivatives (- and ) were synthesized to identify more selective and potent CB ligands. Compound with a piperazine structural moiety demonstrated a value of 0.99 μM against CB receptor and did not show binding activity against cannabinoid receptor type I (CB) at 10 μM. Compounds , , and increased intracellular calcium influx in SH-SY5Y human neuroblastoma cells that were attenuated by CB antagonism or inverse agonism, supporting the results that these compounds are CB agonists. Molecular docking showed that and had similar binding poses, exhibiting a unique interaction with Thr114 within the CB receptor, and that the piperazine structural moiety is required for the binding affinity of . A 200 ns molecular dynamics simulation of CB complexed with confirmed the stability of the complex. This structural insight lays a foundation to further design and synthesize more potent and selective α-santalol-based CB ligands for drug discovery.
Topics: Humans; Molecular Docking Simulation; Ligands; Drug Inverse Agonism; Neuroblastoma; Receptors, Cannabinoid; Piperazines; Receptor, Cannabinoid, CB2; Receptor, Cannabinoid, CB1; Molecular Structure; Structure-Activity Relationship
PubMed: 37450763
DOI: 10.1021/acs.jnatprod.3c00282 -
Bioorganic Chemistry Jul 2021We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting...
We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC for AChE = 1.83 ± 0.03 μM (K = 1.50 ± 0.12 and αK = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pK values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.
Topics: Acetylcholinesterase; Alzheimer Disease; Aminoquinolines; Animals; Antioxidants; Benzothiazoles; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Horses; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Oxidative Stress; Piperazine; Structure-Activity Relationship; Sulfonic Acids
PubMed: 34029971
DOI: 10.1016/j.bioorg.2021.104974 -
Chembiochem : a European Journal of... Mar 2024Epidithiodioxopiperazine (ETP) alkaloids, featuring a 2,5-diketopiperazine core and transannular disulfide bridge, exhibit a broad spectrum of biological activities....
Epidithiodioxopiperazine (ETP) alkaloids, featuring a 2,5-diketopiperazine core and transannular disulfide bridge, exhibit a broad spectrum of biological activities. However, the structural complexity has prevented efficient chemical synthesis and further clinical research. In the past few decades, many achievements have been made in the biosynthesis of ETPs. Here, we discuss the biosynthetic progress and summarize them as two comprehensible metabolic principles for better understanding the complex pathways of α, α'- and α, β'-disulfide bridged ETPs. Specifically, we systematically outline the catalytic machineries to install α, α'- and α, β'-disulfide by flavin-containing oxygenases. This concept would contribute to the medical and industrial applications of ETPs.
Topics: Disulfides; Piperazines
PubMed: 38116907
DOI: 10.1002/cbic.202300770 -
Chemosphere Nov 2022Purification of Natural gas is vital for utilizing it as a source of energy harvesting for the world. Amine-based chemical absorption technique is the most utilized in...
Purification of Natural gas is vital for utilizing it as a source of energy harvesting for the world. Amine-based chemical absorption technique is the most utilized in the gas field for the purification of gas that ensures the purity of the sweet gas stream with the elimination of carbon dioxide. However, it is considered an energy-intensive process to deal with considerable energy loss and environmental damage to the ecosystem. Five cases have been developed in this study based on various blends comprising mono and tertiary amines in combination with piperazine with a focus on the use of Aqueous Monodiethanolamine (Aq. MDEA), Aqueous Monoethanolamine (Aq. MEA) and piperazine (Pz) for the CO sequestration from the sour natural gas extracted from the remote location located in the province of Baluchistan in Pakistan. The use of exergy, advanced exergy, and exergo environment for optimizing and selecting a suitable solvent combination that may result in an effective separation process has been proposed. Five cases have been developed based on various blends such as mono and tertiary amines combined with piperazine. From the results of all the studied scenarios, Case IV, based on the combination of Aqueous monoethanolamine and piperazine, provides reduced exergy destruction of 2551.7 KW. It was observed that the maximum removal of CO around 99.87 wt% is achieved in case IV. In addition, advance exergy analysis also highlights that case-IV has a venue of 25% exergy destruction avoidable, which would further enhance its performance. Nevertheless, still, case-IV has 75% exergy destruction unavoidable. The environmental factors show that Case-IV has a reduced exergy destruction factor of 0.96, a highly environmentally benign choice as a solvent with a high value of 1.03, and case-IV has the higher operational stability and higher exergy efficiency with an exergy stability value of 0.40. Therefore, monoethanolamine combined with piperazine to be an effective and efficient solvent blend that could be an energy-effective approach for sweetening the natural gas.
Topics: Amines; Carbon Dioxide; Ecosystem; Ethanolamine; Natural Gas; Piperazine; Solvents; Water
PubMed: 35987263
DOI: 10.1016/j.chemosphere.2022.136001 -
Environmental Science and Pollution... Jan 2022In this study, activated carbon and piperazine-modified activated carbon adsorbents were prepared and used for CO adsorption. The effect of various parameters including...
In this study, activated carbon and piperazine-modified activated carbon adsorbents were prepared and used for CO adsorption. The effect of various parameters including adsorbent particle size, adsorbent amount, piperazine weight percent, pressure, and temperature were investigated on the CO adsorption capacity. The adsorbents were characterized using nitrogen adsorption/desorption isotherms and FTIR analyses. The results showed that the adsorption capacity decreases with temperature increasing and increases with pressure increasing. In addition, the surface modification of activated carbon improved the CO adsorption capacity more than the unmodified adsorbent, and the highest CO adsorption was obtained 203.842 mg/g at 25 °C and 8 bar. Additionally, to determine the adsorbent behavior, CO adsorption experimental data were fitted by isotherm and kinetic models. CO adsorption isotherm modeling was studied up to 8 bar at 25 °C, and kinetic modeling was investigated up to 85 °C at 6 bar. The results show that Hill isotherm model and Elovich kinetic models have a good agreement with the adsorption data. Finally, thermodynamic modeling was carried out for modified and unmodified adsorbents, and enthalpy, entropy, and Gibbs free energy changes of adsorption for piperazine-modified activated carbon at 25 °C and 6 bar obtained 17.078 kJ/mol, - 0.039 kJ/mol.K, and - 5.318 kJ/mol, respectively.
Topics: Adsorption; Carbon Dioxide; Charcoal; Kinetics; Nitrogen; Piperazine; Thermodynamics
PubMed: 34417695
DOI: 10.1007/s11356-021-16040-5 -
Carbohydrate Research Jul 2023To imbibe the aim of synthesizing water-soluble and biocompatible motif, a click-inspired piperazine glycoconjugate has been devised up. In this report, we present a...
To imbibe the aim of synthesizing water-soluble and biocompatible motif, a click-inspired piperazine glycoconjugate has been devised up. In this report, we present a focused approach to design and synthesis of versatile sugar-appended triazoles through 'Click Chemistry' along with their pharmacological studies on cyclin-dependent kinases (CDKs) and cell cytotoxicity on cancer cells using in silico and in vitro approaches, respectively. The study has inclusively recognized the galactose- and mannose-derived piperazine conjugates as the promising motifs. The findings suggested that the galactosyl bis-triazolyl piperazine analogue 10b is the most CDK interactive derivative and also possess significant anticancer activity.
Topics: Piperazine; Sugars; Click Chemistry; Glycoconjugates; Galactose; Antineoplastic Agents
PubMed: 37245419
DOI: 10.1016/j.carres.2023.108846 -
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