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1.
J Med Chem ; 64(2): 1170-1179, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33426889

RESUMO

Ifenprodil (1) is a potent GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonist that is used as a cerebral vasodilator and has been examined in clinical trials for the treatment of drug addiction, idiopathic pulmonary fibrosis, and COVID-19. To correlate biological data with configuration, all four ifenprodil stereoisomers were prepared by diastereoselective reduction and subsequent separation of enantiomers by chiral HPLC. The absolute configuration of ifenprodil stereoisomers was determined by X-ray crystal structure analysis of (1R,2S)-1a and (1S,2S)-1d. GluN2B affinity, ion channel inhibitory activity, and selectivity over α, σ, and 5-HT receptors were evaluated. (1R,2R)-Ifenprodil ((1R,2R)-1c) showed the highest affinity toward GluN2B-NMDA receptors (Ki = 5.8 nM) and high inhibition of ion flux in two-electrode voltage clamp experiments (IC50 = 223 nM). Whereas the configuration did not influence considerably the GluN2B-NMDA receptor binding, (1R)-configuration is crucial for elevated inhibitory activity. (1R,2R)-Configured ifenprodil (1R,2R)-1c exhibited high selectivity for GluN2B-NMDA receptors over adrenergic, serotonergic, and σ1 receptors.


Assuntos
Antifibrinolíticos/química , Antifibrinolíticos/farmacologia , Antivirais/química , Antivirais/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antifibrinolíticos/síntese química , Antivirais/síntese química , /metabolismo , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Modelos Moleculares , Estrutura Molecular , Piperidinas/química , Receptores de N-Metil-D-Aspartato/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
2.
Yakugaku Zasshi ; 140(9): 1087-1094, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879240

RESUMO

This review, based on my research work, introduces and summarizes the synthesis and characterization of novel cyclic compounds containing aminobenzenesulfonamide. The review discusses the (1) development of sequential Nicholas and Pauson-Khand reactions for the synthesis of unique polyheterocyclic compounds, (2) production of 2-aminobenzenesulfonamide-containing cyclononyne (ABSACN) as a multifunctional click cycloalkyne agent, and (3) improvement of the intramolecular Pauson-Khand reaction of the nitroarene-enyne substrate for the synthesis of cyclopenta[c]piperidine alkaloids. This research work will facilitate the discovery of sulfonamide or sultam-based functional molecules and pharmaceuticals. Thus, I believe that aminobenzenesulfonamide derivatives are versatile and valuable chemical moieties not only in organic syntheses but also in the pharmaceutical industry. If you are interested in the details of this topic, please refer to the original papers.


Assuntos
Sulfonamidas/síntese química , Ciclização , Cicloparafinas/síntese química , Fenômenos de Química Orgânica , Piperidinas/síntese química , Sulfonamidas/química
3.
PLoS One ; 15(7): e0235483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697773

RESUMO

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.


Assuntos
Inibidores Enzimáticos/química , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Piperidinas/farmacologia , Cristalografia por Raios X , Darunavir/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Infecções por HIV/virologia , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/química , HIV-1/patogenicidade , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
4.
Eur J Med Chem ; 197: 112282, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380361

RESUMO

Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC50 = 7.31 µM), BChE (IC50 = 0.56 µM) and MAO-B (IC50 = 26.1 µM) inhibitor 10, dual AChE (IC50 = 2.25 µM) and BChE (IC50 = 0.81 µM) inhibitor 22, selective BChE (IC50 = 0.06 µM) inhibitor 13, and selective MAO-B (IC50 = 0.18 µM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid ß1-42 (Aß1-42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aß1-42 anti-aggregation effects.


Assuntos
Carbamatos/farmacologia , Inibidores da Colinesterase/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Butirilcolinesterase/metabolismo , Carbamatos/síntese química , Carbamatos/toxicidade , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/toxicidade , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/toxicidade , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/toxicidade , Fragmentos de Peptídeos/metabolismo , Piperidinas/síntese química , Piperidinas/toxicidade , Multimerização Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
5.
Eur J Med Chem ; 193: 112214, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32182489

RESUMO

Schizophrenia is a chronic, disabling mental disorder that affects about one percent of world's population. Drugs acting on multiple targets have been demonstrated to provide superior efficacy in schizophrenia than agents acting on single target. In this study, based on FW01, a selective potent 5-HT1A receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D2 and 5-HT2A receptors. The optimized compound 9f was found to show dual potent D2 and 5-HT2A receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t1/2 of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with Kp value of 4.03. These results demonstrated that the dual D2 and 5-HT1A receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents.


Assuntos
Antipsicóticos/farmacologia , Descoberta de Drogas , Piperidinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Antagonistas da Serotonina/farmacologia , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade
6.
Eur J Med Chem ; 194: 112223, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32220685

RESUMO

The influenza virus hemagglutinin (HA) is an attractive target for antiviral therapy due to its essential role in mediating virus entry into the host cell. We here report the identification of a class of N-benzyl-4,4,-disubstituted piperidines as influenza A virus fusion inhibitors with specific activity against the H1N1 subtype. Using the highly efficient one-step Ugi four-component reaction, diverse library of piperidine-based analogues was synthesized and evaluated to explore the structure-activity relationships (SAR). Mechanistic studies, including resistance selection with the most active compound (2) demonstrated that it acts as an inhibitor of the low pH-induced HA-mediated membrane fusion process. Computational studies identified an as yet unrecognized fusion inhibitor binding site, which is located at the bottom of the HA2 stem in close proximity to the fusion peptide. A direct π-stacking interaction between the N-benzylpiperidine moiety of 2 and F9HA2 of the fusion peptide, reinforced with an additional π-stacking interaction with Y119HA2, and a salt bridge of the protonated piperidine nitrogen with E120HA2, were identified as important interactions to mediate ligand binding. This site rationalized the observed SAR and provided a structural explanation for the H1N1-specific activity of our inhibitors. Furthermore, the HA1-S326V mutation resulting in resistance to 2 is close to the proposed new binding pocket. Our findings point to the N-benzyl-4,4,-disubstituted piperidines as an interesting class of influenza virus inhibitors, representing the first example of fusion peptide binders with great potential for anti-influenza drug development.


Assuntos
Antivirais/farmacologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Piperidinas/farmacologia , Animais , Antivirais/síntese química , Antivirais/química , Cães , Relação Dose-Resposta a Droga , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Humanos , Vírus da Influenza A Subtipo H1N1/metabolismo , Células Madin Darby de Rim Canino/efeitos dos fármacos , Células Madin Darby de Rim Canino/virologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade
7.
J Med Chem ; 63(9): 4617-4627, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32105467

RESUMO

Selective inhibitors of gut bacterial ß-glucuronidases (GUSs) are of particular interest in the prevention of xenobiotic-induced toxicities. This study reports the first structure-activity relationships on potency and selectivity of several iminocyclitols (2-7) for the GUSs. Complex structures of Ruminococcus gnavus GUS with 2-7 explained how charge, conformation, and substituent of iminocyclitols affect their potency and selectivity. N1 of uronic isofagomine (2) made strong electrostatic interactions with two catalytic glutamates of GUSs, resulting in the most potent inhibition (Ki ≥ 11 nM). C6-propyl analogue of 2 (6) displayed 700-fold selectivity for opportunistic bacterial GUSs (Ki = 74 nM for E. coli GUS and 51.8 µM for RgGUS). In comparison with 2, there was 200-fold enhancement in the selectivity, which was attributed to differential interactions between the propyl group and loop 5 residues of the GUSs. The results provide useful insights to develop potent and selective inhibitors for undesired GUSs.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Ciclitóis/química , Microbioma Gastrointestinal/efeitos dos fármacos , Glucuronidase/antagonistas & inibidores , Piperidinas/química , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Bovinos , Clostridiales/enzimologia , Clostridium perfringens/enzimologia , Cristalografia por Raios X , Ciclitóis/síntese química , Ciclitóis/metabolismo , Ensaios Enzimáticos , Escherichia coli/enzimologia , Glucuronidase/química , Glucuronidase/metabolismo , Conformação Molecular , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Relação Estrutura-Atividade
8.
J Med Chem ; 63(6): 3120-3130, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32069052

RESUMO

Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for the acute treatment of influenza infections to control this virus and prevent epidemics/pandemics from developing. We have discovered fast-acting, orally bioavailable acylated 4-aminopiperidines with an effective mechanism of action targeting viral hemagglutinin (HA). Our data show that these compounds are potent entry inhibitors of influenza A viruses. We present docking studies that suggest an HA binding site for these inhibitors on H5N1. Compound 16 displayed a significant decrease of viral titer when evaluated in the infectious assays with influenza virus H1N1 (A/Puerto Rico/8/1934) or H5N1 (A/Vietnam/1203/2004) strains and the oseltamivir-resistant strain with the most common H274Y mutation. In addition, compound 16 showed significant synergistic activity with oseltamivir in vitro.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Oseltamivir/farmacologia , Piperidinas/farmacologia , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/metabolismo , Sítios de Ligação , Cães , Sinergismo Farmacológico , Hemaglutininas Virais/química , Hemaglutininas Virais/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/química , Virus da Influenza A Subtipo H5N1/química , Células Madin Darby de Rim Canino , Camundongos , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade
9.
J Med Chem ; 63(3): 1361-1387, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31917923

RESUMO

The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis- and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Inibidores da Monoaminoxidase/uso terapêutico , Piperidinas/uso terapêutico , Estirenos/uso terapêutico , Animais , Antidepressivos/síntese química , Antidepressivos/metabolismo , Encéfalo , Domínio Catalítico , Humanos , Isoenzimas/antagonistas & inibidores , Cinética , Masculino , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Monoaminoxidase/química , Monoaminoxidase/classificação , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/metabolismo , Piperidinas/síntese química , Piperidinas/metabolismo , Ligação Proteica , Estereoisomerismo , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/metabolismo
10.
Molecules ; 25(2)2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940857

RESUMO

In order to prepare, at low cost, new compounds active against Plasmodium falciparum, and with a less side-effects, we have designed and synthesized a library of 1,4-disubstituted piperidine derivatives from 4-aminopiperidine derivatives 6. The resulting compound library has been evaluated against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) strains of P. falciparum. The most active molecules-compounds 12d (13.64 nM (3D7)), 13b (4.19 nM (3D7) and 13.30 nM (W2)), and 12a (11.6 nM (W2))-were comparable to chloroquine (22.38 nM (3D7) and 134.12 nM (W2)).


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Antimaláricos/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Piperidinas/química , Plasmodium falciparum/efeitos dos fármacos
11.
Eur J Med Chem ; 188: 112017, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31926470

RESUMO

A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD50 in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC50 4.9 µM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Piperidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Xantina/farmacologia , Animais , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade , Xantina/síntese química , Xantina/química
12.
Org Lett ; 22(2): 666-669, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31909622

RESUMO

A catalytic conjunctive cross-coupling reaction is developed that allows the construction of chiral organoboronic esters from alkylboron ate complexes and alkyl iodide electrophiles. The process occurs most efficiently with a Ni/Pybox-comprised catalyst and with an acenapthoquinone-derived boron ligand. Because of the broad functional group tolerance of this reaction, it can be a versatile tool for organic synthesis. Applications to the construction of (R)-coniine and (-)-indolizidine 209D are described.


Assuntos
Alcaloides/síntese química , Ácidos Borônicos/síntese química , Ésteres/síntese química , Indolizinas/síntese química , Níquel/química , Piperidinas/síntese química , Alcaloides/química , Ácidos Borônicos/química , Catálise , Ésteres/química , Indolizinas/química , Estrutura Molecular , Piperidinas/química
13.
Eur J Med Chem ; 185: 111785, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669851

RESUMO

Multi-target-directed ligands seem to be an interesting approach to the treatment of complex disorders such as Alzheimer's disease. The aim of the present study was to find novel multifunctional compounds in a non-imidazole histamine H3 receptor ligand library. Docking-based virtual screening was applied for selection of twenty-six hits which were subsequently evaluated in Ellman's assay for the inhibitory potency toward acetyl- (AChE) and butyrylcholinesterase (BuChE). The virtual screening with high success ratio enabled to choose multi-target-directed ligands. Based on docking results, all selected ligands were able to bind both catalytic and peripheral sites of AChE and BuChE. The most promising derivatives combined the flavone moiety via a six carbon atom linker with a heterocyclic moiety, such as azepane, piperidine or 3-methylpiperidine. They showed the highest inhibitory activities toward cholinesterases as well as well-balanced potencies against H3R and both enzymes. Two derivatives were chosen - 5 (IC50 = 0.46 µM (AChE); 0.44 µM (BuChE); Ki = 159.8 nM (H3R)) and 17 (IC50 = 0.50 µM (AChE); 0.76 µM (BuChE); Ki = 228.2 nM (H3R)), and their inhibition mechanism was evaluated in kinetic studies. Both compounds displayed non-competitive mode of AChE and BuChE inhibition. Compounds 5 and 17 might serve as good lead structures for further optimization and development of novel multi-target anti-Alzheimer's agents.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores Histamínicos H3/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Benzopiranos/síntese química , Benzopiranos/química , Benzopiranos/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/química , Cavalos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 185: 111770, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711793

RESUMO

Piperine has been associated with neuroprotective effects and monoamine oxidase (MAO) inhibition, thus being an attractive scaffold to develop new antiparkinsonian agents. Accordingly, we prepared a small library of piperine derivatives and screened the inhibitory activities towards human MAO isoforms (hMAO-A and hMAO-B). Structure-activity relationship (SAR) studies pointed out that the combination of α-cyano and benzyl ester groups increased both potency and selectivity towards hMAO-B. Kinetic experiments with compounds 7, 10 and 15 indicated a competitive hMAO-B inhibition mechanism. Compounds 15 and 16, at 10 µM, caused a small but significant decrease in P-gp efflux activity in Caco-2 cells. Compound 15 stands out as the most potent piperine-based hMAO-B inhibitor (IC50 = 47.4 nM), displaying favourable drug-like properties and a broad safety window. Compound 15 is thus a suitable candidate for lead optimization and the development of multitarget-directed ligands.


Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , Desenho de Fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Benzodioxóis/síntese química , Benzodioxóis/química , Células CACO-2 , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/síntese química , Piperidinas/química , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
15.
Eur J Med Chem ; 186: 111864, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31767136

RESUMO

A series of indazolyl-substituted piperidin-4-yl-aminopyrimidines (IPAPYs) were designed from two potent HIV-1 NNRTIs piperidin-4-yl-aminopyrimidine 3c and diaryl ether 4 as the lead compounds by molecular hybridization strategy. The target molecules 5a-q were synthesized and evaluated for their anti-HIV activities and cytotoxicities in MT-4 cells. 5a-q displayed moderate to excellent activities against wild-type (WT) HIV-1 with EC50 values ranging from 1.5 to 0.0064 µM. Among them, 5q was regarded as the most excellent compound against WT HIV-1 (EC50 = 6.4 nM, SI = 2500). And also, it displayed potent activities against K103 N (EC50 = 0.077 µM), Y181C (EC50 = 0.11 µM), E138K (EC50 = 0.057 µM), and moderate activity against double mutants RES056 (EC50 = 8.7 µM). Moreover, the structure-activity relationships (SARs) were summarized, and the molecular docking was performed to investigate the binding mode of IPAPYs and HIV-1 reverse transcriptase.


Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV/efeitos dos fármacos , Indazóis/farmacologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Humanos , Indazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
16.
Curr Top Med Chem ; 20(2): 132-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31880262

RESUMO

BACKGROUND: Since the influenza virus is the main cause of acute seasonal respiratory infections and pandemic outbreaks, antiviral drugs are critical to mitigate infections and impair chain of transmission. Neuraminidase inhibitors (NAIs) are the main class of anti-influenza drugs in clinical use. Nevertheless, resistance to oseltamivir (OST), the most used NAI, has been detected in circulating strains of the influenza virus. Therefore, novel compounds with anti-influenza activity are necessary. OBJECTIVE: To verify whether the NA from influenza A and B virus is susceptible to the compound 4-(4- phenyl-1H-1,2,3-triazol-1-yl)-2,2,6,6-tetramethylpiperidine-1-oxyl (Tritempo). METHODS: Cell-free neuraminidase inhibition assays were performed with Tritempo, using wild-type (WT) and OST-resistant influenza strains. Cell-based assays in MDCKs were performed to confirm Tritempo`s antiviral activity and cytotoxicity. Multiple passages of the influenza virus in increasing concentrations of our compound, followed by the sequencing of NA gene and molecular docking, were used to identify our Tritempo's target. RESULTS AND DISCUSSION: Indeed, Tritempo inhibited the neuraminidase activity of WT and OSTresistant strains of influenza A and B, at the nanomolar range. Tritempo bound to WT and OST-resistant influenza NA isoforms at the sialic acid binding site with low free binding energies. Cell-free assays were confirmed using a prototypic influenza A infection assay in MDCK cells, in which we found an EC50 of 0.38 µM, along with very low cytotoxicity, CC50 > 2,000 µM. When we passaged the influenza A virus in the presence of Tritempo, a mutant virus with the G248P change in the NA was detected. This mutant was resistant to Tritempo but remained sensitive to OST, indicating no cross-resistance between the studied and reference drugs. CONCLUSION: Our results suggest that Tritempo's chemical structure is a promising one for the development of novel antivirals against influenza.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Piperidinas/farmacologia , Tiazóis/farmacologia , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Vírus da Influenza A/enzimologia , Vírus da Influenza B/enzimologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
17.
Sci Rep ; 9(1): 19344, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852967

RESUMO

The non-selective activation of central and peripheral opioid receptors is a major shortcoming of currently available opioids. Targeting peripheral opioid receptors is a promising strategy to preclude side effects. Recently, we showed that fentanyl-derived µ-opioid receptor (MOR) agonists with reduced acid dissociation constants (pKa) due to introducing single fluorine atoms produced injury-restricted antinociception in rat models of inflammatory, postoperative and neuropathic pain. Here, we report that a new double-fluorinated compound (FF6) and fentanyl show similar pKa, MOR affinity and [35S]-GTPγS binding at low and physiological pH values. In vivo, FF6 produced antinociception in injured and non-injured tissue, and induced sedation and constipation. The comparison of several fentanyl derivatives revealed a correlation between pKa values and pH-dependent MOR activation, antinociception and side effects. An opioid ligand's pKa value may be used as discriminating factor to design safer analgesics.


Assuntos
Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Desenho de Fármacos , Células HEK293 , Humanos , Concentração de Íons de Hidrogênio , Ligantes , Masculino , Nociceptividade/efeitos dos fármacos , Piperidinas/efeitos adversos , Piperidinas/síntese química , Piperidinas/química , Ratos Wistar , Receptores Opioides mu/metabolismo
18.
Bioorg Med Chem Lett ; 29(24): 126769, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31699607

RESUMO

A series of novel alkoxy-piperidine derivatives were synthesized and evaluated for their serotonin reuptake inhibitory and binding affinities for 5-HT1A/5-HT7 receptors. In vivo antidepressant activities of the selective compounds were explored using the forced swimming test (FST) and tail suspension test (TST) in mice. The results showed that compounds 7a (reuptake inhibition (RUI), IC50 = 177 nM; 5-HT1A, Ki = 12 nM; 5-HT7, Ki = 25 nM) and 15g (RUI, IC50 = 85 nM; 5-HT1A, Ki = 17 nM; 5-HT7, Ki = 35 nM) were potential antidepressant agents in animal behavioral models with high 5-HT1A/5-HT7 receptor affinities and moderate serotonin reuptake inhibition, and good metabolic stability in vitro.


Assuntos
Antidepressivos/uso terapêutico , Piperidinas/síntese química , Piperidinas/uso terapêutico , Inibidores de Captação de Serotonina/uso terapêutico , Antidepressivos/farmacologia , Humanos , Piperidinas/farmacologia , Inibidores de Captação de Serotonina/farmacologia
19.
Future Med Chem ; 11(19): 2547-2562, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31633399

RESUMO

Aim: The σ1 receptor is a druggable target involved in many physiological processes and diseases. To clarify its physiology and derive therapeutic benefit, nine analogs based on the σ1 antagonist PB212 were synthesized replacing the 4-methylpiperidine with basic moieties of varying size and degree of conformational freedom. Results & methodology: 3-Phenylpyrrolidine, 4-phenylpiperidine or granatane derivatives displayed the highest affinity (Ki.#x00A0;= 0.12, 0.31 or 1.03 nM). Calcium flux assays in MCF7σ1 cells indicated that the highest σ1 receptor affinity are σ1 antagonists. Molecular models provided a structural basis for understanding the σ1 affinity and functional activity of the analogs and incorporated Glennon's σ1 pharmacophore model. Conclusion: Herein, we identify new compounds exploitable as therapeutic drug leads or as tools to study σ1 receptor physiology.


Assuntos
Naftalenos/química , Naftalenos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptores sigma/antagonistas & inibidores , Receptores sigma/química , Humanos , Modelos Moleculares , Estrutura Molecular , Naftalenos/síntese química , Imagem Óptica , Piperidinas/síntese química , Receptores sigma/metabolismo , Células Tumorais Cultivadas
20.
J Am Chem Soc ; 141(44): 17937-17948, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31589820

RESUMO

Ni-catalyzed cross-electrophile coupling reactions have emerged as appealing methods to construct organic molecules without the use of stoichiometric organometallic reagents. The mechanisms are complex: plausible pathways, such as "radical chain" and "sequential reduction" mechanisms, are dependent on the sequence of the activation of electrophiles. A combination of kinetic, spectroscopic, and organometallic studies reveals that a Ni-catalyzed, reductive 1,2-dicarbofunctionalization of alkenes proceeds through a "sequential reduction" pathway. The reduction of Ni by Zn is the turnover-limiting step, consistent with Ni(II) intermediates as the catalyst resting-state. Zn is only sufficient to reduce (phen)Ni(II) to a Ni(I) species. As a result, commonly proposed Ni(0) intermediates are absent under these conditions. (Phen)Ni(I)-Br selectively activates aryl bromides via two-electron oxidation addition, whereas alkyl bromides are activated by (phen)Ni(I)-Ar through single-electron activation to afford radicals. These findings could provide insight into achieving selectivity between different electrophiles.


Assuntos
Alcenos/química , Níquel/química , Catálise , Ciclização , Ciclopentanos/síntese química , Radicais Livres/química , Furanos/síntese química , Modelos Químicos , Oxirredução , Piperidinas/síntese química , Pirrolidinas/síntese química , Zinco/química
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