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1.
Int J Mol Sci ; 23(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36555144

RESUMO

Fatty acid amide hydrolase (FAAH) plays a key role in the control of cannabinoid signaling and it represents a promising therapeutic strategy for the treatment of a wide range of diseases, including neuropathic pain and chronic inflammation. Starting from kinetics experiments carried out in our previous work for the most potent inhibitor 2-amino-3-chloropyridine amide (TPA14), we have investigated its non-competitive mechanism of action using molecular dynamics, thermodynamic integration and QM-MM/GBSA calculations. The computational studies highlighted the impact of mutations on the receptor binding pockets and elucidated the molecular basis of the non-competitive inhibition mechanism of TPA14, which prevents the endocannabinoid anandamide (AEA) from reaching its pro-active conformation. Our study provides a rationale for the design of non-competitive potent FAAH inhibitors for the treatment of neuropathic pain and chronic inflammation.


Assuntos
Endocanabinoides , Neuralgia , Humanos , Endocanabinoides/metabolismo , Neuralgia/tratamento farmacológico , Amidoidrolases/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Inflamação/tratamento farmacológico , Simulação de Dinâmica Molecular
2.
Molecules ; 28(1)2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36615285

RESUMO

A small series of hydrazonobenzenesulfonamides was designed, synthesized and studied for their human carbonic anhydrase (hCA) inhibitory activity. The synthesized compounds were evaluated against hCA I, II, IX and XII isoforms using acetazolamide (AAZ) as the standard inhibitor. Various hydrazonosulfonamide derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The most potent and selective hydrazones 8, 9, 10, 11, 19 and 24 were docked into isoforms I, II, IX and XII to better understand their activity and selectivity for the different CA isoforms.


Assuntos
Anidrase Carbônica I , Anidrases Carbônicas , Humanos , Anidrases Carbônicas/metabolismo , Relação Estrutura-Atividade , Inibidores da Anidrase Carbônica/farmacologia , Anidrase Carbônica IX , Antígenos de Neoplasias , Isoformas de Proteínas , Estrutura Molecular
3.
Molecules ; 27(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36080139

RESUMO

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms.


Assuntos
Anidrase Carbônica I , Anidrases Carbônicas , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Humanos , Estrutura Molecular , Isoformas de Proteínas , Relação Estrutura-Atividade , Sulfanilamida , Sulfonamidas/farmacologia , Tioureia/farmacologia , Ureia
4.
Molecules ; 27(24)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36558029

RESUMO

A series of 6- and 6,8-halocoumarin derivatives have been investigated as potential antiproliferative compounds against a panel of tumor and normal cell lines. Cytotoxic effects were determined by the MTT method. To investigate the potential molecular mechanism involved in the cytotoxic effect, apoptosis assay, cell cycle analysis, reactive oxygen species (ROS), and reduced glutathione analysis were performed. Among the screened compounds, coumarins 6,8-dibromo-2-oxo-2H-chromene-3-carbonitrile 2h and 6,8-diiodo-2-oxo-2H-chromene-3-carbonitrile 2k exhibited the most antiproliferative effect in thyroid cancer-derived cells TPC-1. The apoptosis assay showed that both 2h and 2k induced apoptosis in TPC-1 thyroid cancer cells. According to these experiments, both coumarins induced a slight increase in TPC-1 cells in the G2/M phase and a decrease in the S phase. A significant increase in ROS levels was observed in TPC-1 treated with diiodocoumarin 2k, while the dibromocoumarin 2h induced a decrease in ROS in a dose and time-dependent manner.


Assuntos
Antineoplásicos , Neoplasias da Glândula Tireoide , Humanos , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Cumarínicos/farmacologia , Antineoplásicos/farmacologia , Neoplasias da Glândula Tireoide/patologia , Apoptose , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais
5.
J Enzyme Inhib Med Chem ; 36(1): 940-953, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33896320

RESUMO

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.


Assuntos
Amidas/farmacologia , Amidoidrolases/antagonistas & inibidores , Analgésicos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/farmacologia , Flurbiprofeno/farmacologia , Amidas/síntese química , Amidas/química , Amidoidrolases/metabolismo , Analgésicos/síntese química , Analgésicos/química , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flurbiprofeno/síntese química , Flurbiprofeno/química , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Eletricidade Estática , Relação Estrutura-Atividade
6.
Bioorg Chem ; 101: 104034, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32599361

RESUMO

In experimental animals, inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents that act by inhibition of cyclooxygenase (COX). This suggests that compounds able to inhibit both enzymes may be potentially useful therapeutic agents. In the present study, we have investigated eight novel amide analogues of carprofen, ketoprofen and fenoprofen as potential FAAH/COX dual action inhibitors. Carpro-AM1 (2-(6-Chloro-9H-carbazol-2-yl)-N-(3-methylpyridin-2-yl)propenamide) and Carpro-AM6 (2-(6-Chloro-9H-carbazol-2-yl)-N-(3-chloropyridin-2-yl)propenamide) were found to be fully reversible inhibitors of the hydrolysis of 0.5 µM [3H]anandamide in rat brain homogenates with IC50 values of 94 and 23 nM, respectively, i.e. 2-3 orders of magnitude more potent than carprofen in this respect. Both compounds inhibited the cyclooxygenation of arachidonic acid by ovine COX-1, and were more potent inhibitors of human recombinant COX-2 when 2-arachidonoylglycerol was used as substrate than when arachidonic acid was used. It is concluded that Carpro-AM1 and Carpro-AM6 are dual-acting FAAH/substrate-selective COX inhibitors.


Assuntos
Amidoidrolases/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Carbazóis/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Amidoidrolases/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Carbazóis/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Humanos , Camundongos
7.
Bioorg Chem ; 98: 103728, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32182519

RESUMO

Herein we report on a new series of hydrazidoureidobenzensulfonamides investigated as inhibitors of the cytosolic human (h) hCA I and II isoforms, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The reported derivatives contain a 4-substituted piperidine fragment in which the hydrazidoureido linker has been involved as spacer between the benzenesulfonamide fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Depending on the substitution pattern at the piperidine ring, low nanomolar inhibitors were detected against hCA II, hCA IX and hCA XII, making the new class of sulfonamides of interest for various pharmacologic applications.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Hidrazinas/farmacologia , Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Hidrazinas/química , Estrutura Molecular , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Benzenossulfonamidas
8.
Bioorg Chem ; 94: 103396, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31677860

RESUMO

Three series of arylbenzimidazole derivatives 3-40, 45 have been simply synthesized and tested for their antioxidant capacity. The 2-arylbenzimidazoles were tested against various radicals by the DPPH, FRAP and ORAC tests and showed different activity profiles. It has been observed that the number and position of the hydroxy groups on the 2-aryl portion and the presence of a diethylamino group or a 2-styryl group are related to a good antioxidant capacity. Furthermore, benzimidazoles showed satisfactory SPF values ​​in vitro compared to the commercial PBSA filter, proving to have a good photoprotective profile. In particular, 2-arylbenzimidazole-5-sulphonic acids 15 and 38, the 2-styryl-benzimidazole 45 showed broad spectrum solar protection against UVA and UVB rays. The antiproliferative effect of the benzimidazoles was tested on human skin melanoma Colo-38 cells. The styrylbenzimidazole 45 exhibited antiproliferative effect at low micromolar concentration against Colo-38 cells and very low antiproliferative activity on normal HaCat keratinocyte cells.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Benzimidazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Benzimidazóis/síntese química , Benzimidazóis/química , Compostos de Bifenilo/antagonistas & inibidores , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Picratos/antagonistas & inibidores , Relação Estrutura-Atividade
9.
J Enzyme Inhib Med Chem ; 35(1): 815-823, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32200655

RESUMO

Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)-2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.


Assuntos
Amidas/farmacologia , Amidoidrolases/antagonistas & inibidores , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/farmacologia , Ibuprofeno/farmacologia , Amidas/síntese química , Amidas/química , Amidoidrolases/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Ibuprofeno/síntese química , Ibuprofeno/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade
10.
Molecules ; 25(6)2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32183488

RESUMO

The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by circulating variants resistant to non-nucleoside inhibitors, and the RNase H function interacting with conserved regions within the RNase H domain. Proving compound 21 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects.


Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Replicação Viral/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Linhagem Celular Tumoral , Transcriptase Reversa do HIV/metabolismo , Humanos , Ribonuclease H/metabolismo
11.
Molecules ; 25(9)2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384805

RESUMO

Induction of apoptosis is a common chemotherapeutic mechanism to kill cancer cells The thiazole system has been reported over the past decades as a building block for the preparation of anticancer agents. A novel series of 2-arylalkylamino-4-amino-5-(3',4',5'-trimethoxybenzoyl)-thiazole derivatives designed as dual inhibitors of tubulin and cyclin-dependent kinases (CDKs) were synthesized and evaluated for their antiproliferative activity in vitro against two cancer cell lines and, for selected highly active compounds, for interactions with tubulin and cyclin-dependent kinases and for cell cycle and apoptosis effects. Structure-activity relationships were elucidated for various substituents at the 2-position of the thiazole skeleton. Among the synthesized compounds, the most active analogues were found to be the p-chlorobenzylamino derivative 8e as well as the p-chloro and p-methoxyphenethylamino analogues 8f and 8k, respectively, which inhibited the growth of U-937 and SK-MEL-1 cancer cell lines with IC50 values ranging from 5.7 to 12.2 µM. On U-937 cells, the tested compounds 8f and 8k induced apoptosis in a time and concentration dependent manner. These two latter molecules did not affect tubulin polymerization (IC50 > 20 µM) nor CDK activity at a single concentration of 10 µM, suggesting alternative targets than tubulin and CDK for the compounds.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Tiazóis/síntese química , Tiazóis/farmacologia , Tubulina (Proteína)/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
12.
J Neuroinflammation ; 16(1): 89, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995914

RESUMO

BACKGROUND: Neuropathy is a dose-limiting side effect of many chemotherapeutics, including bortezomib. The mechanisms underlying this condition are not fully elucidated even if a contribution of neuroinflammation was suggested. Here, we investigated the role of a chemokine family, the prokineticins (PKs), in the development of bortezomib-induced peripheral neuropathy (BIPN), and we used a PK receptor antagonist to counteract the development and progression of the pathology. METHODS: Neuropathy was induced in male C57BL/6J mice by using a protocol capable to induce a detectable neuropathic phenotype limiting systemic side effects. The presence of allodynia (both mechanical and thermal) and thermal hyperalgesia was monitored over time. Mice were sacrificed at two different time points: 14 and 28 days after the first bortezomib (BTZ) injection. At these times, PK system activation (PK2 and PK-Rs), macrophage and glial activation markers, and cytokine production were evaluated in the main station involved in pain transmission (sciatic nerve, DRG, and spinal cord), and the effect of a PK receptors antagonist (PC1) on the same behavioral and biochemical parameters was assessed. Structural damage of DRG during BTZ treatment and an eventual protective effect of PC1 were also evaluated. RESULTS: BTZ induces in mice a dose-related allodynia and hyperalgesia and a progressive structural damage to the DRG. We observed a precocious increase of macrophage activation markers and unbalance of pro- and anti-inflammatory cytokines in sciatic nerve and DRG together with an upregulation of GFAP in the spinal cord. At higher BTZ cumulative dose PK2 and PK receptors are upregulated in the PNS and in the spinal cord. The therapeutic treatment with the PK-R antagonist PC1 counteracts the development of allodynia and hyperalgesia, ameliorates the structural damage in the PNS, decreases the levels of activated macrophage markers, and prevents full neuroimmune activation in the spinal cord. CONCLUSIONS: PK system may be a strategical pharmacological target to counteract BTZ-induced peripheral neuropathy. Blocking PK2 activity reduces progressive BTZ toxicity in the DRG, reducing neuroinflammation and structural damage to DRG, and it may prevent spinal cord sensitization.


Assuntos
Antineoplásicos/toxicidade , Bortezomib/toxicidade , Hormônios Gastrointestinais/metabolismo , Neuropeptídeos/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Modelos Animais de Doenças , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/metabolismo
13.
Bioorg Chem ; 85: 568-576, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30825715

RESUMO

Two series of indole derivatives 4-17, 20-22 were easily prepared and assayed for their radical-scavenging ability. Arylidene-1H-indole-2-carbohydrazones showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety as well as to the presence of methoxy or 4-(diethylamino) group. On the contrary low antioxidant activity is showed by the isomeric 1H-indol-2-yl(methylene)-benzohydrazides. Furthermore, hydrazones 4-17 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The indole 16 and 17, showing the best antioxidant and photoprotective profile, were included in different formulation and their topical release was evaluated. Varying the formulation composition, it was possible to optimize skin adsorption and solubility of the active indole in the formulation. The antiproliferative effect of the hydrazones 4-17 was tested on human erythroleukemia K562 and melanoma Colo-38 cells. Hydrazones 11, 16 and 17 showed growth inhibition at sub micromolar concentrations on both cell lines. These results indicate indole hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 16 and 17 correlated to their high antiproliferative activity.


Assuntos
Antineoplásicos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Hidrazonas/farmacologia , Indóis/farmacologia , Protetores Solares/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/química , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Indóis/síntese química , Indóis/química , Estrutura Molecular , Relação Estrutura-Atividade , Protetores Solares/síntese química , Protetores Solares/química
14.
J Enzyme Inhib Med Chem ; 34(1): 562-576, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30688118

RESUMO

Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.


Assuntos
Amidas/farmacologia , Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Ibuprofeno/farmacologia , Piperazina/farmacologia , Amidas/química , Amidoidrolases/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Ibuprofeno/síntese química , Ibuprofeno/química , Modelos Moleculares , Estrutura Molecular , Piperazina/química , Relação Estrutura-Atividade
15.
Bioorg Chem ; 77: 293-299, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29421705

RESUMO

Herein we report the synthesis of a new series of aromatic sulfamates investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IV, and IX. The reported derivatives, obtained by a sulfamoylation reaction of the corresponding phenolic precursors, bear arylthiazolin-4-one moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Thiazolin-4-ones are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. Phenolic precursors, also evaluated for CA inhibition, did not exhibit noteworthy efficacy in inhibiting the screened hCAs, whereas low nanomolar inhibitors were evidenced within the sulfamates subset mainly against hCA II (KIs in the range of 28.7-84.3 nM) and IX (KIs in the range of 17.6-73.3 nM). The variety of substituents appended at the outer aromatic portion almost generally reduced the inhibitory efficacy against isoforms II and IV, increasing instead that against the tumor-associated isoform IX.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Descoberta de Drogas , Ácidos Sulfônicos/farmacologia , Tiazóis/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IV/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ácidos Sulfônicos/química , Tiazóis/química
16.
Bioorg Chem ; 77: 633-639, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29502024

RESUMO

Herein we report the synthesis of a new series of aromatic sulfamates designed considering the sulfonamide COX-2 selective inhibitors celecoxib and valdecoxib as lead compounds. These latter were shown to possess important human carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties, with the inhibition of the tumor-associated isoform hCA IX likely being co-responsible of the celecoxib anti-tumor effects. Bioisosteric substitution of the pyrazole or isoxazole rings from these drugs with the pyrazoline one was considered owing to the multiple biological activities ascribed to this latter heterocycle and paired with the replacement of the sulfonamide of celecoxib and valdecoxib with its equally potent bioisoster sulfamate. The synthesized derivatives were screened for the inhibition of four human carbonic anhydrase isoforms, namely hCA I, II, IV, and IX. All screened sulfamates exhibited great potency enhancement in inhibiting isoform II and IV, widely involved in glaucoma (KIs in the range of 0.4-12.4 nM and 17.7 and 43.3 nM, respectively), compared to the lead compounds, whereas they affected the tumor-associated hCA IX as potently as celecoxib.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IV/antagonistas & inibidores , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Pirazóis/farmacologia , Ácidos Sulfônicos/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IV/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Pirazóis/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/química
17.
Bioorg Med Chem Lett ; 27(5): 1179-1185, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28189420

RESUMO

A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak AChE and strong BuChE inhibitory activities. In particular, compound 8b and 8d were the most active compounds in the series against BChE with IC50 values of 45nM and 62nM, as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound 8b and 8d bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with better interaction energy values than AChE, in agreement with our experimental data. Furthermore, the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding nature in kinetic studies.


Assuntos
Inibidores da Colinesterase/farmacologia , Quinazolinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Quinazolinas/uso terapêutico
19.
Pflugers Arch ; 468(2): 193-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26354962

RESUMO

T-type channels are important contributors to the initiation and the maintenance of chronic pain states. Blocking T-type channels is therefore a possible therapeutic strategy for relieving pain. Here, we report the Cav3.2 T-type channel blocking action of a previously reported small organic molecule, KYS-05090S. This compound was able to reduce transiently expressed Cav3.2 currents with low micromolar affinity and mediated a hyperpolarizing shift in half-inactivation potential. KYS-05090S was then tested in models of acute and neuropathic pain. KYS-05090S (10 µg/10 µl delivered intrathecally) significantly reduced acute pain induced by formalin in both the tonic and inflammatory phases. Its antinociceptive effect was not observed when delivered to Cav3.2 null-mice revealing a Cav3.2-dependent mechanism. KYS-05090S also reduced neuropathic pain in a model of partial sciatic nerve injury. Those results indicate that KYS-05090S mediates a potent analgesic effect in inflammatory and neuropathic pain through T-type channel modulation, suggesting that its scaffold could be explored as a new class of analgesic compounds.


Assuntos
Dor Aguda/tratamento farmacológico , Analgésicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Neuralgia/tratamento farmacológico , Quinazolinas/farmacologia , Potenciais de Ação , Analgésicos/uso terapêutico , Animais , Bloqueadores dos Canais de Cálcio/uso terapêutico , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade , Quinazolinas/uso terapêutico
20.
Molecules ; 21(5)2016 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-27144551

RESUMO

The synthesis and antiproliferative activity of new benzimidazole derivatives bearing an hydrazone mojety at the 2-position is described. The new N'-(4-arylidene)-1H-benzo[d]imidazole-2-carbohydrazides were evaluated for their cytostatic activity toward the murine leukemia (L1210), human T-cell leukemia (CEM), human cervix carcinoma (HeLa) and human pancreas carcinoma cells (Mia Paca-2). A preliminary structure-activity relationship could be defined. Some of the compounds possess encouraging and consistent antiproliferative activity, having IC50 values in the low micromolar range.


Assuntos
Antineoplásicos/síntese química , Benzimidazóis/síntese química , Proliferação de Células/efeitos dos fármacos , Hidrazonas/síntese química , Animais , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Hidrazonas/farmacologia , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
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