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1.
Molecules ; 29(13)2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38998996

RESUMO

Diabetes mellitus is a severe endocrine disease that affects more and more people every year. Modern medical chemistry sets itself the task of finding effective and safe drugs against diabetes. This review provides an overview of potential antidiabetic drugs based on three heterocyclic compounds, namely morpholine, piperazine, and piperidine. Studies have shown that compounds containing their moieties can be quite effective in vitro and in vivo for the treatment of diabetes and its consequences.


Assuntos
Hipoglicemiantes , Morfolinas , Piperazina , Piperidinas , Humanos , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Morfolinas/química , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Piperazina/química , Piperazina/farmacologia , Animais , Piperazinas/química , Piperazinas/farmacologia , Piperazinas/síntese química , Piperazinas/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Relação Estrutura-Atividade
2.
Toxicon ; 246: 107795, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-38849008

RESUMO

Amphotericin B (AmB) induced liver and kidney injury is often responsible for hepatic and renal dysfunction. Therefore, the protection strategy on liver and renal functions in patients treated with AmB should be emphasized. In this paper, diammonium glycyrrhizinate (DG) and piperazine ferulate (PF) were taken as the research object to study its hepatoprotective and neuroprotective effect on AmB-induced liver and kidney damage in vitro and in vivo. The microplate method and ELISA kits were employed for the biochemical detection in the serum and urine of mice. Flow cytometric analysis and western blotting analysis were conducted to study the mechanism of DG and PF. Our results confirmed the prevention capacity of DG and PF on AmB-induced liver and kidney injury through the alleviation of pathological changes and enzyme reducing action. Furthermore, DG and PF suppressed ROS-mediated mitochondrial apoptosis in AmB-treated mice and cells through Caspase pathway and Caspase-independent AIF pathway. In summary, DG and PF could protect AmB-induced hepatotoxicity and nephrotoxicity by disrupting oxidative stress and apoptosis.


Assuntos
Anfotericina B , Apoptose , Doença Hepática Induzida por Substâncias e Drogas , Ácido Glicirrízico , Fármacos Neuroprotetores , Animais , Apoptose/efeitos dos fármacos , Camundongos , Ácido Glicirrízico/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Anfotericina B/toxicidade , Masculino , Fígado/efeitos dos fármacos , Fígado/patologia , Rim/efeitos dos fármacos , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/farmacologia , Piperazina/farmacologia , Substâncias Protetoras/farmacologia
3.
Eur J Med Chem ; 272: 116497, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38759453

RESUMO

A series of combretastatin A-4 (CA-4) derivatives were designed and synthesized, which contain stilbene core structure with different linker, predominantly piperazine derivatives. These compounds were evaluated for their cytotoxic activities against four cancer cell lines, HCT116, A549, AGS, and SK-MES-1. Among them, compound 13 displayed the best effectiveness with IC50 values of 0.227 µM and 0.253 µM against HCT116 and A549 cells, respectively, showing low toxicity to normal cells. Mechanistic studies showed that 13 inhibited HCT116 proliferation via arresting cell cycle at the G2/M phase through disrupting the microtubule network and inducing autophagy in HCT116 cells by regulating the expression levels of autophagy-related proteins. In addition, 13 displayed antiproliferative activities against A549 cells through blocking the cell cycle and inducing A549 cells apoptosis. Because of the poor water solubility of 13, four carbohydrate conjugates were synthesized which exhibited better water solubility. Further investigations revealed that 13 showed positive effects in vivo anticancer study with HCT116 xenograft models. These data suggest that 13 could be served as a promising lead compound for further development of anti-colon carcinoma agent.


Assuntos
Antineoplásicos , Autofagia , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Polimerização , Estilbenos , Tubulina (Proteína) , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estilbenos/farmacologia , Estilbenos/química , Estilbenos/síntese química , Tubulina (Proteína)/metabolismo , Animais , Polimerização/efeitos dos fármacos , Estrutura Molecular , Células HCT116 , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Camundongos , Relação Dose-Resposta a Droga , Apoptose/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Camundongos Nus , Piperazina/química , Piperazina/farmacologia , Piperazina/síntese química , Camundongos Endogâmicos BALB C
4.
J Agric Food Chem ; 72(20): 11360-11368, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38720533

RESUMO

In this study, a series of acrylamide derivatives containing trifluoromethylpyridine or piperazine fragments were rationally designed and synthesized. Subsequently, the in vitro antifungal activities of all of the synthesized compounds were evaluated. The findings revealed that compounds 6b, 6c, and 7e exhibited >80% antifungal activity against Phomopsis sp. (Ps) at the concentration of 50 µg/mL. Furthermore, the EC50 values for compounds 6b, 6c, and 7e against Ps were determined to be 4.49, 6.47, and 8.68 µg/mL, respectively, which were better than the positive control with azoxystrobin (24.83 µg/mL). At the concentration of 200 µg/mL, the protective activity of compound 6b against Ps reached 65%, which was comparable to that of azoxystrobin (60.9%). Comprehensive mechanistic studies, including morphological studies with fluorescence microscopy (FM), cytoplasmic leakage, and enzyme activity assays, indicated that compound 6b disrupts cell membrane integrity and induces the accumulation of defense enzyme activity, thereby inhibiting mycelial growth. Therefore, compound 6b serves as a valuable candidate for the development of novel fungicides for plant protection.


Assuntos
Acrilamida , Desenho de Fármacos , Fungicidas Industriais , Piridinas , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Acrilamida/química , Piridinas/química , Piridinas/farmacologia , Piridinas/síntese química , Relação Estrutura-Atividade , Ascomicetos/efeitos dos fármacos , Ascomicetos/crescimento & desenvolvimento , Piperazina/química , Piperazina/farmacologia , Piperazinas/farmacologia , Piperazinas/química , Piperazinas/síntese química , Estrutura Molecular , Testes de Sensibilidade Microbiana , Doenças das Plantas/microbiologia
5.
J Pharm Biomed Anal ; 246: 116202, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38820833

RESUMO

Recently, pharmaceutical research has been focused on the design of new antibacterial drugs with higher selectivity towards several strains. Major issues concern the possibility to obtain compounds with fewer side effects, at the same time effectively overcoming the problem of antimicrobial resistance. Several solutions include the synthesis of new pharmacophores starting from piperazine or morpholine core units. Mass spectrometry-based techniques offer important support for the structural characterization of newly synthesized compounds to design safer and more effective drugs for various medical conditions. Here, two new piperazine derivatives and four new morpholine derivatives were synthesized and structurally characterized through a combined approach of Fourier transform-ion cyclotron resonance (FT-ICR) and Linear Trap Quadrupole (LTQ) mass spectrometry. The support of both high-resolution and low-resolution mass spectrometric data namely accurate mass measurements, isotopic distribution and MSn spectra, was crucial to confirm the success of the synthesis. These compounds were further evaluated for inhibitory activity against a total of twenty-nine Gram-positive and Gram-negative bacteria to determine the action spectrum and the antimicrobial effectiveness. Results demonstrated compounds' antimicrobial activity against many tested bacterial species, providing an inhibitory effect linked to different chemical structure and suggesting that the new-synthesized derivatives could be considered as promising antimicrobial agents.


Assuntos
Antibacterianos , Bactérias Gram-Negativas , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Morfolinas , Piperazinas , Morfolinas/farmacologia , Morfolinas/química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/análise , Antibacterianos/síntese química , Testes de Sensibilidade Microbiana/métodos , Piperazinas/farmacologia , Piperazinas/química , Bactérias Gram-Negativas/efeitos dos fármacos , Espectrometria de Massas/métodos , Bactérias Gram-Positivas/efeitos dos fármacos , Relação Estrutura-Atividade , Piperazina/farmacologia , Piperazina/química
6.
Molecules ; 29(8)2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38675529

RESUMO

It is well known that daidzein has various significant medicinal values and health benefits, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, cholesterol lowering, neuroprotective, cardioprotective and so on. To our disappointment, poor solubility, low permeability and inferior bioavailability seriously limit its clinical application and market development. To optimize the solubility, permeability and bioavailability of daidzein, the cocrystal of daidzein and piperazine was prepared through a scientific and reasonable design, which was thoroughly characterized by single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. Combining single-crystal X-ray diffraction analysis with theoretical calculation, detailed structural information on the cocrystal was clarified and validated. In addition, a series of evaluations on the pharmacogenetic properties of the cocrystal were investigated. The results indicated that the cocrystal of daidzein and piperazine possessed the favorable stability, increased solubility, improved permeability and optimized bioavailability of daidzein. Compared with the parent drug, the formation of cocrystal, respectively, resulted in 3.9-, 3.1-, 4.9- and 60.8-fold enhancement in the solubility in four different media, 4.8-fold elevation in the permeability and 3.2-fold in the bioavailability of daidzein. Targeting the pharmaceutical defects of daidzein, the surprising elevation in the solubility, permeability and bioavailability of daidzein was realized by a clever cocrystal strategy, which not only devoted assistance to the market development and clinical application of daidzein but also paved a new path to address the drug-forming defects of insoluble drugs.


Assuntos
Disponibilidade Biológica , Isoflavonas , Permeabilidade , Piperazina , Solubilidade , Isoflavonas/química , Isoflavonas/farmacocinética , Piperazina/química , Cristalização , Difração de Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Animais , Cristalografia por Raios X , Varredura Diferencial de Calorimetria , Humanos
7.
Biomed Pharmacother ; 174: 116484, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38565058

RESUMO

A novel small molecule based on benzothiazole-piperazine has been identified as an effective multi-target-directed ligand (MTDL) against Alzheimer's disease (AD). Employing a medicinal chemistry approach, combined with molecular docking, MD simulation, and binding free energy estimation, compound 1 emerged as a potent MTDL against AD. Notably, compound 1 demonstrated efficient binding to both AChE and Aß1-42, involving crucial molecular interactions within their active sites. It displayed a binding free energy (ΔGbind) -18.64± 0.16 and -16.10 ± 0.18 kcal/mol against AChE and Aß1-42, respectively. In-silico findings were substantiated through rigorous in vitro and in vivo studies. In vitro analysis confirmed compound 1 (IC50=0.42 µM) as an effective, mixed-type, and selective AChE inhibitor, binding at both the enzyme's catalytic and peripheral anionic sites. Furthermore, compound 1 demonstrated a remarkable ability to reduce the aggregation propensity of Aß, as evidenced by Confocal laser scanning microscopy and TEM studies. Remarkably, in vivo studies exhibited the promising therapeutic potential of compound 1. In a scopolamine-induced memory deficit mouse model of AD, compound 1 showed significantly improved spatial memory and cognition. These findings collectively underscore the potential of compound 1 as a promising therapeutic candidate for the treatment of AD.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Peptídeos beta-Amiloides , Benzotiazóis , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Benzotiazóis/farmacologia , Benzotiazóis/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Peptídeos beta-Amiloides/metabolismo , Acetilcolinesterase/metabolismo , Camundongos , Masculino , Humanos , Piperazinas/farmacologia , Piperazinas/química , Escopolamina , Piperazina/farmacologia , Piperazina/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacologia , Simulação de Dinâmica Molecular , Simulação por Computador , Modelos Animais de Doenças , Aprendizagem em Labirinto/efeitos dos fármacos
8.
Chem Biol Drug Des ; 103(3): e14499, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38444047

RESUMO

In this paper, we report the synthesis of quinoxaline-isoxazole-piperazine conjugates. The anticancer activity was evaluated against three human cancer cell lines, including MCF-7 (breast), HepG-2 (liver), and HCT-116 (colorectal). The outcomes of the tested compounds 5d, 5e, and 5f have shown more potent activity when compared to the standard drug erlotinib. In a cell survivability test (MCF-10A), three potent compounds (5d, 5e, and 5f) were evaluated against the normal breast cell line, although neither of them displayed any significant cytotoxicity with IC50 values greater than 84 µM. Furthermore, the compounds 5d, 5e, and 5f were tested for tyrosine kinase EGFR inhibitory action using erlotinib as the reference drug and compound 5e was shown to be more potent in inhibiting the tyrosine kinase EGFR than sorafenib. In addition to this, molecular docking studies of compounds 5d, 5e, and 5f demonstrated that these compounds had more EGFR-binding interactions. The potent compounds 5d, 5e, and 5f were subjected to in silico pharmacokinetic assessment by SWISS, ADME, and pkCSM. While the compounds 5d, 5e, and 5f followed Lipinski, Veber, Egan, and Muegge rules without any deviation.


Assuntos
Antineoplásicos , Quinoxalinas , Humanos , Simulação de Acoplamento Molecular , Cloridrato de Erlotinib/farmacologia , Quinoxalinas/farmacologia , Antineoplásicos/farmacologia , Isoxazóis , Piperazina , Proteínas Tirosina Quinases , Receptores ErbB
9.
Chemosphere ; 355: 141763, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38522672

RESUMO

The fluoroquinolones ciprofloxacin, danofloxacin, enoxacin, levofloxacin and lomefloxacin, occur in water bodies worldwide and therefore pose a threat to the aquatic environment. Advanced purification procedures, such as electrochemical oxidation, may act as a remedy since they contribute to eliminating contaminants and prevent micropollutants from entering open water bodies. By electrochemical treatment in a micro-flow reactor equipped with a boron-doped diamond (BDD) electrode, the fluoroquinolones were efficiently degraded. A total of 15 new products were identified using high-performance high-resolution chromatography coupled with high-resolution multifragmentation mass spectrometry. The ecotoxicity of the emerging transformation products was estimated through in silico quantitative structure activity relationship analysis. Almost all transformation products were predicted less ecotoxic than the initial compounds. The fluoroquinolone degradation followed three major mechanisms depending on the voltage during the electrochemical oxidation. At approximately 1 V, the reactions started with the elimination of molecular hydrogen from the piperazine moiety. At approx. 1.25 V, methyl and methylene groups were eliminated. At 1.5 V, hydroxyl radicals, generated at the BDD electrode, led to substitution at the piperazine ring. This novel finding of the three reactions depending on voltage contributes to the mechanistic understanding of electrochemical oxidation as potential remedy against fluoroquinolones in the aquatic environment.


Assuntos
Ciprofloxacina , Poluentes Químicos da Água , Ciprofloxacina/química , Levofloxacino/análise , Enoxacino/análise , Diamante/química , Fluoroquinolonas/análise , Piperazina , Oxirredução , Eletrodos , Água , Poluentes Químicos da Água/análise
10.
Bioorg Med Chem ; 104: 117698, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38552597

RESUMO

Serotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC50 of 1.9 nM), all of which were significantly elevated compared to 1. In particular, compound 5a showed weaker inhibitory activity against hERG than 1, and demonstrated good stability in liver microsomes in vitro. The preliminary screening using FST indicated that orally administered 5a, at a high dose, could reduce immobility time in mice markedly, indicating potential antidepressant activity.


Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Camundongos , Animais , Piperazina/farmacologia , Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Piperidinas/farmacologia , Piperazinas/química , Receptor 5-HT1A de Serotonina
11.
Angew Chem Int Ed Engl ; 63(20): e202401324, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38499463

RESUMO

We report the discovery and biosynthesis of new piperazine alkaloids-arizonamides, and their derived compounds-arizolidines, featuring heterobicyclic and spirocyclic isoquinolone skeletons, respectively. Their biosynthetic pathway involves two crucial non-heme iron enzymes, ParF and ParG, for core skeleton construction. ParF has a dual function facilitating 2,3-alkene formation of helvamide, as a substrate for ParG, and oxidative cleavage of piperazine. Notably, ParG exhibits catalytic versatility in multiple oxidative reactions, including cyclization and ring reconstruction. A key amino acid residue Phe67 was characterized to control the formation of the constrained arizonamide B backbone by ParG.


Assuntos
Alcaloides , Alcaloides/química , Alcaloides/metabolismo , Alcaloides/biossíntese , Piperazinas/química , Piperazinas/metabolismo , Ferro/química , Ferro/metabolismo , Ciclização , Biocatálise , Estrutura Molecular , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Oxirredução , Piperazina/química , Piperazina/metabolismo
12.
J Am Chem Soc ; 146(8): 5204-5214, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38358897

RESUMO

We report piperazine-fused six-membered-cyclic disulfides as redox substrates that unlock best-in-class bioreduction probes for live cell biology, since their self-immolation after reduction is unprecedentedly rapid. We develop scalable, diastereomerically pure, six-step syntheses that access four key cis- and trans-piperazine-fused cyclic dichalcogenides without chromatography. Fluorogenic redox probes using the disulfide piperazines are activated >100-fold faster than the prior art monoamines, allowing us to deconvolute reduction and cyclization rates during activation. The cis- and trans-fused diastereomers have remarkably different reductant specificities, which we trace back to piperazine boat/chair conformation effects: the cis-fused disulfide C-DiThia is activated only by strong vicinal dithiol reductants, but the trans-disulfide T-DiThia is activated even by moderate concentrations of monothiols such as GSH. Thus, in cellular applications, cis-disulfide probes selectively report on the reductive activity of the powerful thioredoxin proteins, while trans-disulfides are rapidly but promiscuously reactive. Finally, we showcase late-stage diversifications of the piperazine-disulfides, promising their broad applicability as redox-cleavable cores for probes and prodrugs that interface powerfully with cellular thiol/disulfide redox biology, for solid phase synthesis and purification, and for stimulus-responsive linkers in bifunctional reagents and antibody-drug conjugates - in addition to their dithiols' potential as high-performance reducing agents.


Assuntos
Dissulfetos , Compostos de Sulfidrila , Dissulfetos/química , Compostos de Sulfidrila/química , Reagentes de Ligações Cruzadas , Piperazina , Tiorredoxinas/metabolismo , Oxirredução , Biologia
13.
Drug Dev Res ; 85(1): e22153, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38349258

RESUMO

An innovative series of N-substituted piperazine-linked imidazothiazole derivatives 7(a-x) were synthesized, and their antitubercular effectiveness was evaluated. A three-step reaction sequence involving the condensation of 1,3-dichloroacetone and thiourea, coupling with substituted piperazines to give the intermediates 5(a-d) and cyclization with substituted α-bromoacetophenones produced the desired imidazothiazole derivatives 7(a-x) in excellent yields. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv resulted in 7k (minimum inhibitory concentration [MIC]: 0.78 µg/mL) and 7g and 7h (MIC: 1.56 µg/mL) as potent hit compounds. Further, the docking studies of the promising compounds 7k, 7g, and 7h revealed that the best molecular interactions are with the DprE1 in complex with sulfonyl PBTZ of M. tuberculosis as the target protein (PDB ID: 6G83).


Assuntos
Mycobacterium tuberculosis , Piperazina/farmacologia , Piperazinas/farmacologia , Antituberculosos/farmacologia , Tiazóis/farmacologia
14.
Int J Biol Macromol ; 261(Pt 2): 129689, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38272428

RESUMO

Piperazine functionalized Schiff bases 4(a-c) were synthesized by a condensation reaction which were thoroughly characterized by using various spectroscopic techniques like 1H NMR, 13C NMR, IR and mass spectrometry. X-ray crystallography was used to analyse synthesized compound 4b. The sensing capability of 4b was investigated towards the tetravalent form of the zirconium ion among other metal ions. The limit of detection and the association constant, were calculated to be 56.4 × 10-8 M and 5.36 × 105 M-1 respectively. The inclusion of additional metal ions had no effect on the selectivity of sensor 4b. The binding mechanism was clarified using 1HNMR spectroscopy, which was further verified computationally, using DFT. Also, the seed germination experiments were performed and effect of compound 4b was analyzed on the seedlings of Zea Mays. An investigation into molecular docking study using (5HQX) protein revealed that it had inhibitory effects on cytokinin oxidase. The protein and ligand effectively associate, as indicated by the lower binding energy of -9.69 kcal/mol. Therefore, compound 4b can act as a good, powerful inhibitor against cytokinin oxidase.


Assuntos
Antioxidantes , Zea mays , Piperazina , Simulação de Acoplamento Molecular , Antioxidantes/farmacologia , Cobre/química , Bases de Schiff/química , Íons
15.
Bioorg Chem ; 143: 107082, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38199142

RESUMO

The multi-target directed ligand (MTDL) discovery has been gaining immense attention in the development of therapeutics for Alzheimer's disease (AD). The strategy has been evolved as an auspicious approach suitable to combat the heterogeneity and the multifactorial nature of AD. Therefore, multi-targetable chalcone derivatives bearing N-aryl piperazine moiety were designed, synthesized, and evaluated for the treatment of AD. All the synthesized compounds were screened for thein vitro activityagainst acetylcholinesterase (AChE), butylcholinesterase (BuChE), ß-secretase-1 (BACE-1), and inhibition of amyloid ß (Aß) aggregation. Amongst all the tested derivatives, compound 41bearing unsubstituted benzylpiperazine fragment and para-bromo substitution at the chalcone scaffold exhibited balanced inhibitory profile against the selected targets. Compound 41 elicited favourable permeation across the blood-brain barrier in the PAMPA assay. The molecular docking and dynamics simulation studies revealed the binding mode analysis and protein-ligand stability ofthe compound with AChE and BACE-1. Furthermore,itameliorated cognitive dysfunctions and signified memory improvement in thein-vivobehavioural studies (scopolamine-induced amnesia model). Theex vivobiochemical analysis of mice brain homogenates established the reduced AChE and increased ACh levels. The antioxidant activity of compound 41 was accessed with the determination of catalase (CAT) and malondialdehyde (MDA) levels. The findings suggested thatcompound 41, containing a privileged chalcone scaffold, can act as a lead molecule for developing AD therapeutics.


Assuntos
Doença de Alzheimer , Chalcona , Chalconas , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Chalconas/química , Acetilcolinesterase/metabolismo , Piperazina/farmacologia , Simulação de Acoplamento Molecular , Ligantes , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Piperazinas/farmacologia , Relação Estrutura-Atividade , Desenho de Fármacos
16.
Int J Mol Sci ; 25(2)2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38256142

RESUMO

To reduce the mortality and morbidity associated with cancer, new cancer theranostics are in high demand and are an emerging area of research. To achieve this goal, we report the synthesis and characterization of piperazine-linked 1,8-naphthalimide-arylsulfonyl derivatives (SA1-SA7). These compounds were synthesized in good yields following a two-step protocol and characterized using multiple analytical techniques. In vitro cytotoxicity and fluorescent cellular imaging of the compounds were assessed against non-cancerous fibroblast (3T3) and breast cancer (4T1) cell lines. Although the former study indicated the safe nature of the compounds (viability = 82-95% at 1 µg/mL), imaging studies revealed that the designed probes had good membrane permeability and could disperse in the whole cell cytoplasm. In silico studies, including molecular docking, molecular dynamics (MD) simulation, and ADME/Tox results, indicated that the compounds had the ability to target CAIX-expressing cancers. These findings suggest that piperazine-linked 1,8-naphthalimide-arylsulfonyl derivatives are potential candidates for cancer theranostics and a valuable backbone for future research.


Assuntos
Naftalimidas , Neoplasias , Humanos , Simulação de Acoplamento Molecular , Piperazina , Imagem Molecular
17.
Bioorg Med Chem ; 98: 117562, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38184947

RESUMO

In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity as compared to the simple and N-benzyl indole-piperazine derivatives. In addition, the observed activity profile of indole-piperazines was similar to standard anti-TB drugs (isoniazid and pyrazinamide) against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains, demonstrating the compounds' selectivity towards the Mycobacterium tuberculosis H37Rv strain. All the active anti-TB compounds are proved to be non-toxic (with IC50 > 300 µg/mL) as verified through the toxicity evaluation against VERO cell lines. Additionally, molecular docking studies against two target enzymes (Inh A and CYP121) were performed to validate the activity profile of indole-piperazine derivatives. Further, in silico-ADME prediction and pharmacokinetic parameters indicated that these compounds have good oral bioavailability.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Antituberculosos/farmacologia , Simulação de Acoplamento Molecular , Isoniazida/farmacologia , Pirazinamida , Piperazinas/farmacologia , Triazóis/farmacologia , Triazóis/metabolismo , Piperazina , Relação Estrutura-Atividade , Mycobacterium tuberculosis/metabolismo , Indóis/farmacologia , Testes de Sensibilidade Microbiana
18.
Bioorg Med Chem Lett ; 100: 129620, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38280655

RESUMO

Six amino derivatives of xanthone were obtained via chemical synthesis. Biochemical studies revealed their SIRT2 inhibitory activity ranging from 48.5 % (compound 4, 5-chloro-2-((4-(3-methoxyphenyl)piperazin-1-yl)methyl)-9H-xanthen-9-one hydrochloride) to 93.2 % (compound 3, 5-chloro-2-(((2-methoxyphenethyl)amino)methyl)-9H-xanthen-9-one hydrochloride). The structure-activity analysis showed favourable properties of secondary amines relative to tertiary piperazine derivatives. The tested compounds do not possess additional SIRT1 activating activity and no antioxidant activity (DPPH in vitro assay). Comprehensive analysis of the lipophilicity of the obtained compounds was also performed. For compound 3 potential molecular targets and similar active compounds were predicted in order to facilitate further research in this group of compounds.


Assuntos
Sirtuína 2 , Xantonas , Piperazina , Xantonas/farmacologia , Xantonas/química , Relação Estrutura-Atividade
19.
Med Chem ; 20(1): 17-29, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37815177

RESUMO

Despite extensive research in the field of drug discovery and development, still there is a need to develop novel molecular entities. Literature reveals a substantial heterocyclic nucleus named, piperazine, which shows an immense therapeutic voyage. For several decades, molecules having the piperazine nucleus have entered the market as a drug exhibiting biological potential. It was known to possess antipsychotic, antihistamine, antianginal, antidepressant, anticancer, antiviral, cardioprotective, and anti-inflammatory activity with a specific basis for structural activity relationship. Thus, it is regarded as a key structural feature in most of the already available therapeutic drugs in the market. Reports also suggest that the extensive utilization of these currently available drugs having a piperazine nucleus shows increasing tolerance significantly day by day. In addition to this, various other factors like solubility, low bioavailability, cost-effectiveness, and imbalance between pharmacokinetics and pharmacodynamics profile limit their utilization. Focusing on that issues, various structural modification studies were performed on the piperazine moiety to develop new derivatives/analogs to overcome the problems associated with available marketed drugs. Thus, this review article aims to gain insight into the number of structural modifications at the N-1 and N-4 positions of the piperazine scaffold. This SAR approach may prove to be the best way to overcome the above-discussed drawbacks and lead to the design of drug molecules with better efficacy and affinity. Hence, there is an urgent need to focus on the structural features of this scaffold which paves further work for deeper exploration and may help medicinal chemists as well as pharmaceutical industries.


Assuntos
Descoberta de Drogas , Piperazina , Relação Estrutura-Atividade
20.
Pest Manag Sci ; 80(3): 1026-1038, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37842924

RESUMO

BACKGROUND: Plant bacterial infections and plant viruses seriously affect the yield and quality of crops. Based on the various activities of tryptanthrin, a series of tryptanthrin analogues bearing F and piperazine moieties were designed, synthesized, and evaluated for their biological activities against three plant bacteria and tobacco mosaic virus (TMV). RESULTS: Bioassay results indicated that compounds 6a-6l displayed excellent antibacterial activities in vitro and 6a-6c and 6g exhibited better antiviral activities against TMV than commercial ribavirin. In particular, 6b showed the most effect on Xanthomonas oryzae pv. oryzae (Xoo) with a half-maximal effective concentration (EC50 ) of 1.26 µg mL-1 , compared with the commercial pesticide bismerthiazol (BT; EC50 = 34.3 µg mL-1 ) and thiodiazole copper (TC; EC50 = 73.3 µg mL-1 ). Meanwhile, 6a also had the best antiviral activity at 500 µg mL-1 for curative, protection, and inactivation purposes, compared with ribavirin in vivo. CONCLUSION: Compound 6b could cause changes in bacterial morphology, induce the accumulation of reactive oxygen species, promote apoptosis of bacterial cells, inhibit the formation of biofilm, and block the growth of Xoo cells. Proteomic analysis revealed major differences in the bacterial secretory system pathways T2SS and T6SS, which inhibited membrane transport. Molecular docking revealed that 6a and 6g could interact with TMV coat protein preventing virus assembly. These results suggest that tryptanthrin analogues bearing F and piperazine moieties could be promising candidate agents for antibacterial and antiviral use in agricultural production. © 2023 Society of Chemical Industry.


Assuntos
Oryza , Quinazolinas , Vírus do Mosaico do Tabaco , Xanthomonas , Ribavirina/metabolismo , Ribavirina/farmacologia , Simulação de Acoplamento Molecular , Piperazina/metabolismo , Piperazina/farmacologia , Proteômica , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antivirais/farmacologia , Doenças das Plantas , Relação Estrutura-Atividade
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