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1.
J Med Chem ; 63(9): 4978-4996, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32369358

RESUMO

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-ßR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a-c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.


Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Benzamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Receptores de Ativinas Tipo I/genética , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Feminino , Células HEK293 , Humanos , Masculino , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Mutação , Piperazinas/síntese química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Relação Estrutura-Atividade
2.
Nat Protoc ; 15(4): 1525-1541, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32111986

RESUMO

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., 18F). In recent years, new reactions have appeared for the 18F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring 18F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel 18F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [18F]olaparib. First, we established a robust manual protocol to prepare [18F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (Am) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated 18F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [18F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with Am up to 319 GBq/µmol.


Assuntos
Técnicas de Química Sintética/métodos , Cobre/química , Radioisótopos de Flúor/química , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases , Automação , Ftalazinas/síntese química , Ftalazinas/química , Piperazinas/síntese química , Piperazinas/química , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
3.
Chem Pharm Bull (Tokyo) ; 68(2): 117-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009078

RESUMO

The total syntheses of dimeric indole alkaloids, haplophytine, and T988s are described. These dimeric compounds comprising two structurally different indole units are ubiquitous in nature, and many possess pharmaceutically important activities. To realize an efficient chemical synthesis of these dimeric indole alkaloids, the establishment of convergent synthetic strategies and development of new coupling methods are indispensable. The linkage of two highly functionalized units at a late stage of the synthesis frequently induces synthetic problems such as chemoselectivity and steric repulsion. Moreover, although transition metal-catalyzed reactions are usually an effective method for the cross-coupling of two units, the application of these cross-coupling reactions to bond formation involving a sterically hindered C(sp3) is often difficult. Thus, even with precise modern synthetic methods, it is currently difficult to realize convergent syntheses of dimeric indole alkaloids possessing a quaternary carbon linking two units. To combat these synthetic problems, we developed a synthetic method to link two indole units using an Ag-mediated nucleophilic substitution reaction. In this review, we provide a detailed discussion of convergent synthetic strategies and coupling methods for dimeric indole alkaloids.


Assuntos
Técnicas de Química Sintética/métodos , Alcaloides Indólicos/síntese química , Dimerização , Alcaloides Indólicos/química , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo
4.
J Med Chem ; 63(9): 4468-4483, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32023060

RESUMO

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Quinazolinas/uso terapêutico , Quinolonas/uso terapêutico , Regulação Alostérica , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Células CACO-2 , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Camundongos Nus , Conformação Molecular , Mutação , Piperazinas/síntese química , Piperazinas/farmacocinética , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinolonas/síntese química , Quinolonas/farmacocinética , Ratos Wistar , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Org Biomol Chem ; 18(8): 1577-1581, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32039416

RESUMO

Functionalized 2-piperazinones play essential roles as conformationally-constrained peptidomimetics by mimicking inverse γ-turns in peptides. Here, we describe an efficient, scalable, stereoselective, modular, and chemoselective annulation protocol between a novel N-trifluoroacetyl anhydride and several reactive partners, including lactim ethers, imidoyl chlorides, aryl aldimines, and 1,3-azadienes, leading to vicinally functionalized (bicyclic) 2-piperazinones.


Assuntos
Anidridos/química , Piperazinas/química , Compostos Heterocíclicos/química , Conformação Molecular , Peptidomiméticos/química , Piperazinas/síntese química
6.
Eur J Med Chem ; 191: 112140, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088494

RESUMO

2,3-Dihydro-5,6-dimethoxy-2-[4-(4-alkyl-4-methylpiperazinium-1-yl)benzylidine]-1H-inden-1-one halide salt derivatives as a novel donepezil hybrid analogs with the property of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme inhibition were designed and synthesized via N-alkylation reaction of 2,3-dihydro-5,6-dimethoxy-2-[4-(4-methylpiperazin-1-yl)benzylidene]-1H-inden-1-one with some alkyl halides. Biological tests demonstrated that most of the synthesized compounds have moderate to good inhibitory activities effect on cholinesterase enzymes. Among them, 10e showed the best profile as a selected compound for inhibition of hAChE (IC50 = 0.32) and hBuChE (IC50 = 0.43 µM) enzymes. Kinetic analysis and molecular docking led to a better understanding of this compound. Kinetic studies disclosed that 10e inhibited acetylcholinesterase in mixed-type and butyrylcholinesterase in non-competitive type. The toxicity results showed that 10e is less toxic than donepezil and has better inhibitory activity against hBuChE when compared to donepezil or Galantamine. Other performed experiments revealed that 10e has an anti-ß amyloid effect which is capable of reducing ROS, LDH and MDA also possing positive effect on TAC. On the other hand, it has shown a good anti-inflammation effect.


Assuntos
Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Indenos/farmacologia , Piperazinas/farmacologia , Acetilcolinesterase/genética , Algoritmos , Butirilcolinesterase/genética , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Indenos/síntese química , Indenos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Sais/síntese química , Sais/química , Sais/farmacologia , Relação Estrutura-Atividade
7.
Nat Prod Res ; 34(9): 1282-1287, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30698024

RESUMO

Phenazine-1-carboxylic acid (PCA) as a natural product which has significant inhibition effects against many soil-borne fungal phytopathogens in agricultural application and has been registered in China as the fungicide against rice sheath blight. In order to find new higher fungicidal activities lead compounds and develop new eco-friendly agrochemicals, we introduced substructure piperazines which also have high biological activity into PCA, designed and synthesized a series of phenazine-1-carboxylic piperazine derivatives, and their structures were confirmed by 1H NMR and HRMS. Most compounds exhibited certain in vitro fungicidal activities. In particular, Compounds 5r exhibited the activity against all the tested pathogenic fungi, such as Rhizoctonia solani, Alternaria solani, Fusarium oxysporum, Fusarium graminearum, Pyricularia oryzac Cavgra, with the EC50 value of 24.6µM, 42.9µM, 73.7µM, 73.8µM, 34.2µM, respectively, more potent activities than PCA (33.2µM, 81.5µM, 186.5µM, 176.4µM, 37.3µM). This result provided a highly active lead compound for the further structure optimization design.


Assuntos
Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Alternaria/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Fusarium/efeitos dos fármacos , Espectrometria de Massas , Estrutura Molecular , Fenazinas/síntese química , Fenazinas/química , Piperazinas/síntese química , Rhizoctonia/efeitos dos fármacos , Relação Estrutura-Atividade
8.
J Enzyme Inhib Med Chem ; 35(1): 96-108, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31690133

RESUMO

A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.


Assuntos
Indóis/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Lipase Lipoproteica/metabolismo , Linfócitos/efeitos dos fármacos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
9.
Eur J Med Chem ; 185: 111840, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711794

RESUMO

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 µM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs.


Assuntos
Adenovírus Humanos/efeitos dos fármacos , Antivirais/farmacologia , Piperazinas/farmacologia , Ureia/farmacologia , Células A549 , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
10.
Eur J Med Chem ; 186: 111905, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785819

RESUMO

Farnesyl pyrophosphate synthase (FPPS) is known to participate in a variety of disease-related cell signaling pathway and bisphosphonates (BPs) are served as FPPS inhibitors. However, the high polarity of BPs often induces a series of side effects, limiting their applications. In the present study, novel non-BP FPPS inhibitors were discovered by in silico screening and experimental validation. From the structure-based virtual screening (SBVS) strategy combining molecular docking, pharmacophore and binding affinity prediction, 10 hits with novel scaffolds were filtered. The inhibition activity of hits against FPPS was identified and 7 hits showed comparable or higher inhibition activity than Zoledronate. The hit VS-4 with higher lipophilicity (XlogP = 1.81) and binding affinity (KD = 14.3 ± 2.63 µM) to FPPS was selected for further study on cancer cells with different FPPS expression level. Experimental results revealed that VS-4 could better target the FPPS high-expressing colon LoVo and HCT116 cancer cell lines with IC50 of 51.772 ± 0.473 and 43.553 ± 1.027 µM, respectively, whereas the IC50 value against FPPS low expressing MDA-MB-231 cells was >100 µM. The mechanism of VS-4 against colon cancer cells was investigated by flow cytometry and the results indicated that VS-4 induced cell apoptosis by increasing the intracellular reactive oxygen species (ROS) level. Taken together, the SBVS strategy could be used to discover promising non-BP FPPS inhibitors and the lead compound VS-4 might shed a light on designing more potent inhibitors as novel anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Geraniltranstransferase/antagonistas & inibidores , Piperazinas/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Geraniltranstransferase/metabolismo , Células HCT116 , Humanos , Células MCF-7 , Estrutura Molecular , Piperazinas/líquido cefalorraquidiano , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade , Sulfonamidas/líquido cefalorraquidiano , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas
11.
Int J Pharm ; 575: 118953, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31843548

RESUMO

In this study, we report the relationship between structure, self-assembly behavior and antimicrobial activity of multicationic gemini surfactants and their successful use as stabilizers of a new liposomal formulation for transdermal drug delivery. New surfactants containing natural moiety 1,4-diazabicyclo[2.2.2]octane with four charges and two hydrophobic chains (n-Dabco-s-Dabco-n, where s = 2, 6, 12 and n = 12, 14, 16, 18) were synthesized. A linear dependence of the CMC decrease, with the increase of the number of carbon atoms in alkyl groups (slope 0.23) was shown. The aggregation numbers of n-Dabco-2-Dabco-n are smaller than 30 and they decrease with increasing alkyl chain length. This is in compliance with the larger surface area per n-Dabco-2-Dabco-n molecule. New liposomal formulations loading Rhodamine B phosphatidylcholine (with mean size about 100 nm and increased zeta potential from -7 ± 2 mV to +55 ± 2 mV) have been successfully stabilized by n-Dabco-s-Dabco-n surfactants. These formulations were designed to improve the bioavailability and skin permeation of loaded compound. The antibacterial activity of Dabco-surfactants was shown to be strongly affected by their structure (alkyl chain length and number of charged nitrogen). 12-Dabco-2-Dabco-12 was the most active (MIC = 0.48, 0.98 and 15.6 µg/mL against S. aureus, B. cereus and E. coli, respectively) without hemolytic activity at 3.1 µg/mL concentration. PC/14-Dabco-2-Dabco-14-liposomes were shown to be the best formulation, with the highest antibacterial activity against Sa (MIC = 7.8 µg‧mL-1) and lowest cytotoxicity (IC50 > 125). The modification of liposomes by Dabco-surfactants stabilizes the membrane of the vesicles, preventing the release of rhodamine B and impairing the penetration of the dye across Strat-M® membrane. Cellular uptake of rhodamine B-loaded PC/12-Dabco-2-Dabco-12-liposomes was also reported. This is the first example of cationic mixed liposomes containing Dabco-surfactants of potential interest for transdermal drug delivery.


Assuntos
Antibacterianos/farmacologia , Lipossomos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Tecnologia Farmacêutica/métodos , Administração Cutânea , Antibacterianos/farmacocinética , Compostos Aza/química , Proteínas da Membrana Bacteriana Externa , Linhagem Celular , Sobrevivência Celular , Ciclo-Octanos/química , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/química , Lipossomos/farmacocinética , Micelas , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Piperazinas/síntese química , Piperazinas/farmacocinética , Pele/efeitos dos fármacos , Relação Estrutura-Atividade , Tensoativos/química , Tensoativos/farmacologia
12.
Eur J Med Chem ; 187: 111970, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881454

RESUMO

Amongst the fluoroquinolone antibacterials, the 7-piperazinyl containing chemotypes such as norfloxacin, enoxacin, ciprofloxacin, pefloxacin, lomefloxacin, enrofloxacin, ofloxacin, levofloxacin, gatifloxacin and sparfloxacin have been shown to possess non-classical activities including cytotoxicity against different cancer cell lines, induction of apoptosis, and cell cycle arrest at the S/G2 stage. Additionally, piperazinylquinolones (PQs) have enough flexibility for chemical modification via their N-4 of piperazine ring and carboxylic acid at C-3. Therefore, PQs have been considered as a starting point for design and development of new anticancer agents. This review has focused on the recent synthetic modifications of PQs which led to N-substituted and/or C-3 modified PQs with potential anticancer activity.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bactérias/efeitos dos fármacos , Piperazinas/farmacologia , Quinolonas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Piperazinas/síntese química , Piperazinas/química , Quinolonas/síntese química , Quinolonas/química
13.
Eur J Med Chem ; 186: 111878, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757524

RESUMO

We have previously disclosed compound 3 (CZh-226), a potent and selective PAK4 inhibitor, but its development was delayed due to poor oral pharmacokinetics. In an attempt to improve this issue, we synthesised a series of prodrugs by masking its terminal nitrogen of the piperazine moiety. Most synthesised prodrugs of 3 have low or no inhibition of PAK4 activity. The stability of synthetic prodrugs was evaluated in PBS, SGF, SIF, rat plasma and liver S9 fraction. Of these, prodrug 19 was not only stable under both acidic and neutral conditions but also could be quickly converted to parent drug 3 in rat plasma and liver S9 fraction. Such effective conversion into parent drug 3 was observed in rats, providing higher exposure of 3 compared to its direct administration. When given via oral route at daily doses of 25 and 50 mg/kg, the prodrug 19 was effective and well tolerated in mouse model of HCT-116 and B16F10.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Pró-Fármacos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Fígado/química , Fígado/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Piperazinas/síntese química , Piperazinas/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
14.
Eur J Med Chem ; 187: 111912, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31812034

RESUMO

A family of 12 triazolo-pyridazine-6-yl-substituted piperazines (5a-l) was synthesized and evaluated for their Dipeptidyl peptidase-4 (DPP-4) inhibition potentials in order to develop them as anti-diabetic medications. In the two-step synthesis process, 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine was synthesized with one-pot mode using pyridine, 3,6-dichloropyridazine 5-(3-methyl-phenyl)tetrazole in toluene. Conjugating corresponding 2° amines with 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine afforded the target triazolo-pyridazine-6-yl-substituted piperazines (5a-l). DPP-4 inhibition potential of these compounds was testified in silico and in nitro along with their insulinotropic activities in 832/13 INS-1 cells. H2O2 radical scavenging assay and MTT assay were conducted to assess the antioxidant and cytotoxicity of these compounds respectively. Molecular docking and ELISA based enzyme inhibition assay results revealed the strong inhibition potential of the target compounds. MTT assay results indicated a maximum dose of 2.5 nM (IC50 1.25 nM) could be used and above this level vital for the cells. Compounds 5a, 5c, 5g and 5i were found with excellent antioxidant and insulinotropic activity up to 99%.


Assuntos
Diabetes Mellitus/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Piperazinas/farmacologia , Diabetes Mellitus/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Piridazinas/química , Piridazinas/farmacologia , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia
15.
ChemMedChem ; 14(24): 2052-2060, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31674147

RESUMO

Molecular hybridization approach is a promising structural modification tool to design new chemical entities (NCEs) by mimicking two different pharmacophoric units into one scaffold to enhance the biological properties. With this aim, combretastatin-A4 acids were integrated with sulfonyl piperazine scaffolds as a one molecular platform and evaluated for their in vitro antiproliferative activity against a panel of human cancer lines cell lines namely, lung (A549), mouse melanoma (B16F10), breast (MDA MB-231and MCF-7) and colon (HCT-15) by MTT assay. Amongst which the compound (E)-3-(4-Chlorophenyl)-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (5 ab) displayed significant IC50 values in the range of 0.36 to 7.08 µm against the selected cancer cell lines. Moreover, 5 ab was found to be the most potent member of this series with IC50 0.36±0.02 µm. Further investigations revealed that the compound 5 ab displayed significant inhibition of tubulin assembly with IC50 5.24±0.06 µm and molecular docking studies also disclosed the binding of 5 ab effectively in CA4 binding space at the colchicine binding site. The flow cytometric analysis demonstrated that the compound 5 ab caused cell cycle arrest at G2/M phase in A549 cells. Compound 5 ab induced apoptosis in A549 cells which was further evaluated by different staining assays such as DAPI and AO which undoubtedly speculated, the induction of apoptosis. To study the anti-migration with 5 ab, cell migration/scratch wound assay was performed and the extent of apoptosis was studied by Annexin-V, including mitochondrial potential by JC-1 staining.


Assuntos
Antineoplásicos/farmacologia , Piperazinas/farmacologia , Estilbenos/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Polimerização/efeitos dos fármacos , Estilbenos/síntese química , Estilbenos/química , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
16.
Drug Des Devel Ther ; 13: 3539-3550, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31631978

RESUMO

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer which is associated with poor patient outcome and lack of targeted therapy. Our laboratory has synthesized a series of indole-2-carboxamide derivatives. Among this series, compound LG25 showed a favorable pharmacological profile against sepsis and inflammatory diseases. In the present study, we investigated the chemotherapeutic potential of LG25 against TNBC utilizing in vitro and in vivo models. Methods: Changes in cell viability, cell cycle phases and apoptosis were analyzed using MTT, clonogenic assay, FACS and Western blotting assays. The anti-cancer effects of LG25 were further determined in a xenograft mouse model. Results: Our findings reveal that LG25 reduced TNBC viability in a dose-dependent manner. Flow cytometric and Western blot analyses showed that LG25 enhances G2/M cell cycle arrest and induced cell apoptosis. In addition, LG25 treatment significantly inhibited Akt/mTOR phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB). These inhibitory activities of LG25 were confirmed in mice implanted MDA-MB-231 TNBC cells. Conclusion: Our studies provide experimental evidence that indole-2-carboxamide derivative LG25 effectively targeted TNBC in preclinical models by inducing cell cycle arrest and apoptosis, through suppressing Akt/mTOR/NF-κB signaling pathway.


Assuntos
Antineoplásicos/farmacologia , Indóis/farmacologia , NF-kappa B/antagonistas & inibidores , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/síntese química , Indóis/química , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , NF-kappa B/metabolismo , Piperazinas/síntese química , Piperazinas/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
17.
Assay Drug Dev Technol ; 17(7): 298-309, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31634019

RESUMO

Multidrug resistance (MDR) is a major health issue for the treatment of infectious diseases throughout the world. Staphylococcus aureus (S. aureus) is a Gram-positive bacteria, responsible for various local and systemic infections in humans. The continuous and abrupt use of antibiotics against bacteria such as S. aureus results in the development of resistant strains. Presently, mupirocin (MUP) is the drug of choice against S. aureus and MDR (methicillin-resistant). However, S. aureus has acquired resistance against MUP as well due to isoleucyl-tRNA synthetase (IleS) mutation at sites 588 and 631. Thus, the aim of the present study was to discover novel bioactives against MUP-resistant S. aureus using in silico drug repurposing approaches. In silico drug repurposing techniques were used to obtain suitable bioactive lead molecules such as buclizine, tasosartan, emetine, medrysone, and so on. These lead molecules might be able to resolve this issue. These leads were obtained through molecular docking simulation based virtual screening, which could be promising for the treatment of MUP-resistant S. aureus. The findings of the present work need to be validated further through in vitro and in vivo studies for their clinical application.


Assuntos
Antibacterianos/farmacologia , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Simulação de Acoplamento Molecular , Antibacterianos/síntese química , Antibacterianos/química , Emetina/síntese química , Emetina/química , Emetina/farmacologia , Humanos , Isoleucina-tRNA Ligase/antagonistas & inibidores , Isoleucina-tRNA Ligase/metabolismo , Staphylococcus aureus Resistente à Meticilina/enzimologia , Testes de Sensibilidade Microbiana , Piperazinas/síntese química , Piperazinas/química , Piperazinas/farmacologia , Pregnenodionas/síntese química , Pregnenodionas/química , Pregnenodionas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Tetrazóis/síntese química , Tetrazóis/química , Tetrazóis/farmacologia
18.
Bioorg Med Chem Lett ; 29(21): 126679, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31537425

RESUMO

Searching for CNS active cyclic amines derivatives containing heterocyclic xanthone core we designed and synthesized a set of fourteen novel 2- or 4-methylxanthone substituted by alkyl- or aryl-piperazine moieties. The compounds were evaluated in vivo for their potential antidepressant-like activity (in the forced swim test) and anxiolytic-like activity (four-plate test) and their inhibitory effect against rat 5-HT2 receptor was checked. The pharmacokinetic analysis of active compounds done by a non-compartmental approach have shown a rapid absorption of all studied molecules from intraperitoneal cavity and good penetration the blood-brain barrier after i.p. administration with brain to plasma ratios varied from 2.8 to 31.6. Genotoxicity and biotransformation of active compounds were studied. Compound 19 interactions with major classes of GPCRs, uptake systems and ion channels were tested and results indicated that it binds to 5-HT2A, 5-HT2B receptors and sodium channels.


Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Sistema Nervoso Central/metabolismo , Piperazinas/síntese química , Xantonas/síntese química , Animais , Ansiolíticos/farmacocinética , Antidepressivos/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Ligantes , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Piperazina/química , Piperazinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Xantonas/farmacocinética
19.
Bioorg Med Chem Lett ; 29(22): 126620, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31537423

RESUMO

Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R1 and R4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R6 substituents and iterative R1, R4 and R6 substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility.


Assuntos
Antivirais/farmacologia , Arenavirus/efeitos dos fármacos , Piperazinas/farmacologia , Proteínas do Envelope Viral/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Arenavirus/metabolismo , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade , Proteínas do Envelope Viral/metabolismo
20.
Bioorg Med Chem Lett ; 29(18): 2690-2694, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31387791

RESUMO

As part of our on-going effort to explore the role of dopamine receptors in drug addiction and identify potential novel therapies for this condition, we have a identified a series of N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide D3 ligands. Members of this class are highly selective for D3 versus D2, and we have identified two compounds (13g and 13r) whose rat in vivo IV pharmacokinetic properties that indicate that they are suitable for assessment in in vivo efficacy models of substance use disorders.


Assuntos
Benzamidas/farmacologia , Desenho de Fármacos , Piperazinas/farmacologia , Receptores de Dopamina D3/metabolismo , Animais , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Ligantes , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Ratos , Relação Estrutura-Atividade
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