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1.
Molecules ; 24(21)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683688

RESUMO

The Kinesins are proteins involved in several biological processes such as mitosis, intracellular transport, and microtubule movement. The mitotic process is allowed by the correct formation of the mitotic spindle which consists of microtubules originating from the spindle poles. In recent years, kinesin Eg5 inhibitors were studied as new chemotherapeutic drugs, due to the lack of side effects and resistance mechanisms. The aim of this work was to investigate the molecular signaling underlying the administration of novel kinesis Eg5 inhibitors in an in vitro model of gastric adenocarcinoma. Data obtained from analogues of K858 led us to select compounds 2 and 41, due to their lower IC50 values. The ability of kinesin inhibitors to induce apoptosis was investigated by evaluating Bax and Caspase-3 protein expression, evidencing that compound 41 and K858 markedly raise Bax expression, while only compounds 2 and 41 co-administrated with K858 trigger Caspase-3 activation. The inhibition of mitotic spindle was measured by ß-tubulin immunofluorescence analysis revealing monopolar spindles formation in gastric cancer cells treated with compounds 2, 41, and K858. Nitric Oxide Synthase (NOS-2) and Matrix Metalloproteinase 9 (MMP-9) expression levels were measured finding a NOS-2-mediated downregulation of MMP-9 when compound 41 and K858 are co-administered. However, this is in contrast to what was reported by migration assay in which both novel compounds and K858 in monotherapy markedly reduce cell migration. This work remarks the importance of understanding and exploring the biological effects of different novel Eg5 kinesin inhibitors administered in monotherapy and in combination with K858 as potential strategy to counteract gastric cancer.

2.
J Chromatogr A ; : 460572, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31606155

RESUMO

Recently it has been reported that immobilized chlorinated-type chiral stationary phases based on cellulose tris(3,5-dichlorophenylcarbamate) are able to express an outstanding enantioselectivity towards the structure of 2-(benzylsulfinyl)benzamide. We now introduce two homologue series of chiral sulfoxides based on the same 2-(sulfinyl)benzoyl core as the prototype of new selectands for HPLC, whose enantioselectivity could be modulable through the replacement of the benzyl group with an unbranched alkyl chain varying in length from 1 to 5 carbon atoms. HPLC parameters such as mobile phase composition and column temperature have been carefully evaluated in order to get pertinent structure-enantioselectivity relationships. The enantiomer elution order was unambiguously determined by a combined strategy involving theoretical and experimental procedures. Two cases of temperature-dependent inversion of the elution order of enantiomers in the operative temperature range of chiral chromatographic support were observed.

3.
J Enzyme Inhib Med Chem ; 34(1): 1400-1413, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401897

RESUMO

A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.


Assuntos
Ácido Benzoico/química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Desenho de Drogas , Isoenzimas/efeitos dos fármacos , Inibidores da Anidrase Carbônica/síntese química , Domínio Catalítico , Cromatografia Líquida de Alta Pressão , Humanos , Simulação de Acoplamento Molecular , Estereoisomerismo , Relação Estrutura-Atividade
4.
J Enzyme Inhib Med Chem ; 34(1): 1511-1525, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31422706

RESUMO

A series of benzo[b]thiophen-3-ols were synthesised and investigated as potential human monoamine oxidase (hMAO) inhibitors in vitro as well as ex vivo in rat cortex synaptosomes by means of evaluation of 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratio and lactate dehydrogenase (LDH) activity. Most of these compounds possessed high selectivity for the MAO-B isoform and a discrete antioxidant and chelating potential. Molecular docking studies of all the compounds underscored potential binding site interactions suitable for MAO inhibition activity, and suggested structural requirements to further improve the activity of this scaffold by chemical modification of the aryl substituents. Starting from this heterocyclic nucleus, novel lead compounds for the treatment of neurodegenerative disease could be developed.


Assuntos
Desenho de Drogas , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
5.
Expert Opin Ther Pat ; 29(10): 769-780, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385719

RESUMO

Introduction: Glaucoma is one of the main leading causes of irreversible blindness in the world. The treatment of this disease relies on the use of drugs able to reduce/control the intraocular pressure (IOP), one of the main risk factors for glaucoma. Current therapies are based on the use of compounds belonging to well-established categories (prostaglandin analogs, ß-adrenergic blockers, α-adrenergic agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and cholinergic agonists). However, even if they are effective in reducing IOP, important side effects impair patient compliance, accounting for the necessity of novel therapy approaches. Therefore, new targets are emerging as alternative and more complete routes to fight glaucoma disease. Areas covered: This review provides a comprehensive update on the development state of innovative strategies against glaucoma describing results, administration routes, pharmaceutical compositions, structures, and SARs as well as the related shortcomings within the 2013-2019 range. Expert opinion: New innovative pharmacological targets have been explored in the last six years, allowing a broader therapeutic arsenal against glaucoma and IOP-related pathologies. The endocannabinoid system and FAAH inhibitors were the most investigated from a medicinal chemistry point of view.


Assuntos
Desenvolvimento de Medicamentos , Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Animais , Glaucoma/fisiopatologia , Humanos , Adesão à Medicação , Patentes como Assunto , Fatores de Risco , Relação Estrutura-Atividade
6.
Expert Opin Drug Discov ; 14(10): 995-1035, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31268358

RESUMO

Introduction: Selective monoamine oxidase-B (MAO-B) inhibitors are currently used as coadjuvants for the treatment of early motor symptoms in Parkinson's disease. They can, based on their chemical structure and mechanism of inhibition, be categorized into reversible and irreversible agents. Areas covered: This review provides a comprehensive update on the development state of selective MAO-B inhibitors describing the results, structures, structure-activity relationships (SARs) and Medicinal chemistry strategies as well as the related shortcomings over the past five years. Expert opinion: Researchers have explored and implemented new and old chemical scaffolds achieving high inhibitory potencies and isoform selectivity. Most of them were characterized and proposed as multitarget agents able to act at different levels (including AChE inhibition, H3R or A2AR antagonism, antioxidant and chelating properties, Aß1-42 aggregation reduction) in the network of aetiologies of neurodegenerative disorders. These results can also be used to avoid 'cheese-reaction' effects and the occurrence of serotonergic syndrome in patients.

7.
Molecules ; 24(10)2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31130597

RESUMO

Gliomas are malignant brain tumors characterized by rapid spread and growth into neighboring tissues and graded I-IV by the World Health Organization. Glioblastoma is the fastest growing and most devastating IV glioma. The aim of this paper is to evaluate the biological effects of two potent and selective Monoamine Oxidase B (MAO-B) inhibitors, Cmp3 and Cmp5, in C6 glioma cells and in CTX/TNA2 astrocytes in terms of cell proliferation, apoptosis occurrence, inflammatory events and cell migration. These compounds decrease C6 glioma cells viability sparing normal astrocytes. Cell cycle analysis, the Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) production were detected, revealing that Cmp3 and Cmp5 induce a G1 or G2/M cell cycle arrest, as well as a MMP depolarization and an overproduction of ROS; moreover, they inhibit the expression level of inducible nitric oxide synthase 2, thus contributing to fatal drug-induced oxidative stress. Cmp5 notably reduces glioma cell migration via down-regulating Matrix Metalloproteinases 2 and 9. This study demonstrated that our novel MAO-B inhibitors increase the oxidative stress level resulting in a cell cycle arrest and markedly reduces glioma cells migration thus reinforcing the hypothesis of a critical role-played by MAO-B in mediating oncogenesis in high-grade gliomas.

8.
J Enzyme Inhib Med Chem ; 34(1): 597-612, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30727777

RESUMO

A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure-activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties.


Assuntos
Antioxidantes/farmacologia , Hidrazonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Tiazóis/farmacologia , Acetilcolinesterase/metabolismo , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Modelos Moleculares , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Tiazóis/síntese química , Tiazóis/química
9.
Molecules ; 24(3)2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30700029

RESUMO

New N-acetyl/N-thiocarbamoylpyrazoline derivatives were designed and synthesized in high yields to assess their inhibitory activity and selectivity against human monoamine oxidase A and B. The most important chiral compounds were separated into their single enantiomers and tested. The impact of the substituents at N1, C3 and C5 positions as well the influence of the configuration of the C5 on the biological activity were analyzed. Bulky aromatic groups at C5 were not tolerated. p-Prenyloxyaryl moiety at C3 oriented the selectivity toward the B isoform. The results were also corroborated by molecular modelling studies providing new suggestions for the synthesis of privileged structures to serve as lead compounds for the treatment of mood disorders and neurodegenerative diseases.


Assuntos
Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/metabolismo , Ativação Enzimática/efeitos dos fármacos , Modelos Moleculares , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Pirazóis/síntese química , Pirazóis/química , Pirazóis/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
10.
Eur J Med Chem ; 156: 641-651, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-30031975

RESUMO

The thiadiazole scaffold is an important core moiety in a variety of clinical drug candidates targeting a range of diseases. For example, the 2,4,5-substituted 1,3,4-thiadiazole scaffold is present in a lead compound and at least two clinical candidates targeting the human motor protein Eg5, against neoplastic diseases. An inhibitor named K858 has in vivo activity in various mouse xenografts whereas the clinical candidates (S)-ARRY-520 and (R)-Litronesib have entered clinical trials with the former one in phase III clinical trials either alone or in combination with a proteasome inhibitor against relapsed/refractory multiple myeloma. Astonishingly, structural data are lacking for all thiadiazole-containing Eg5 inhibitors. Here we report the structure determination of two crystal forms of the ternary Eg5-ADP-K858 complex, locking the motor in the so-called final inhibitor bound state, thus blocking ADP release, a crucial stage for Eg5 activity. K858 acts at the established allosteric inhibitor-binding pocket formed of helix α2, loop L5 and helix α3. The structure of the complex has far reaching consequences for thiadiazole containing Eg5 inhibitors. For example, we could rationalise the structure-activity relationship in the crucial 5-position of the thiadiazole scaffold and the complex will serve in the future as a basis for strucutre-based drug design.


Assuntos
Desenho de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cinesina/antagonistas & inibidores , Tiadiazóis/química , Tiadiazóis/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Humanos , Cinesina/química , Cinesina/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 143: 1543-1552, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29126727

RESUMO

New 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives are proposed as dual-target-directed monoamine oxidase B (MAO-B) and acetylcholinesterase (AChE) inhibitors, as well as antioxidant agents, for the treatment of neurodegenerative disorders such as Parkinson's disease. Rational molecular design, target recognition and predicted pharmacokinetic properties have been evaluated by means of molecular modelling. Based on these properties, compounds were synthesized and evaluated in vitro as MAO-B and AChE inhibitors, and compared to the activities at their corresponding isozymes, monoamine oxidase A (MAO-A) and butyrylcholinesterase (BuChE), respectively. Anti-oxidant properties, potentially useful in the treatment of neurodegenerative disorders, have been also investigated in vitro. Among the evaluated compounds, three inhibitors may be considered as promising dual inhibitors of MAO-B and AChE, in vitro. MAO-B inhibition was also shown to be competitive and reversible for compound 19.


Assuntos
Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Drogas , Hidrazonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/tratamento farmacológico , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/síntese química , Antioxidantes/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Modelos Moleculares , Estrutura Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
12.
J Enzyme Inhib Med Chem ; 32(1): 1-11, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28776447

RESUMO

This paper reports the MEPS-HPLC-DAD method for the simultaneous determination of 12 azole drugs (bifonazole, butoconazole, clotrimazole, econazole, itraconazole, ketoconazole, miconazole, posaconazole, ravuconazole, terconazole, tioconazole and voriconazole) administered to treat different systemic and topical fungal infections, in biological samples. Azole drugs separation was performed in 36 min. The analytical method was validated in the ranges as follows: 0.02-5 µg mL-1 for ravuconazole; 0.2-5 µg mL-1 for terconazole; 0.05-5 µg mL-1 for the other compounds. Human plasma and urine were used as biological samples during the analysis, while benzyl-4-hydroxybenzoate was used as an internal standard. The precision (RSD%) and trueness (Bias%) values fulfill with International Guidelines requirements. To the best of our knowledge, this is the first HPLC-DAD procedure coupled to MEPS, which provides the simultaneous analysis of 12 azole drugs, available in the market, in human plasma and urine. Moreover, the method was successfully applied for the quantitative determination of two model drugs (itraconazole and miconazole) after oral administration in real samples.


Assuntos
Imidazóis/análise , Microextração em Fase Sólida , Triazóis/análise , Adsorção , Cromatografia Líquida de Alta Pressão , Estrutura Molecular
13.
Phytother Res ; 31(8): 1257-1264, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28635142

RESUMO

Harpagophytum procumbens is a plant species that displays anti-inflammatory properties in multiple tissues. The iridoid glycosides arpagoside, harpagide, and procumbide appear to be the most therapeutically important constituents. In addition, harpagoside treatment exerted neuroprotective effects both in vitro and in vivo. Considering these findings, the aim of the present work is to explore the possible protective role of the previously described microwave-assisted aqueous extract of H. procumbens on rat hypothalamic (Hypo-E22) cells, and in rat cortex challenged with amyloid ß-peptide (1-40). In this context, we assayed the protective effects induced by H. procumbens by measuring the levels of malondialdehyde, 3-hydroxykynurenine (3-HK), brain-derived neurotrophic factor, and tumor necrosis factor-α, 3-HK. Finally, we evaluated the effects of H. procumbens treatment on cortex levels of dopamine, norepinephrine, and serotonin. H. procumbens extract was well tolerated by Hypo-E22 cells and upregulated brain-derived neurotrophic factor gene expression but down-regulated tumor necrosis factor-α gene expression. In addition, the extract reduced amyloid ß-peptide stimulation of malondialdehyde and 3-HK and blunted the decrease of dopamine, norepinephrine, and serotonin, in the cortex. In this context, our work supports further studies for the evaluation and confirmation of Harpagophytum in the management of the clinical symptoms related to Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Harpagophytum/química , Micro-Ondas , Extratos Vegetais/farmacologia , Sinaptossomos/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Dopamina/metabolismo , Glicosídeos/farmacologia , Cinurenina/análogos & derivados , Cinurenina/metabolismo , Masculino , Malondialdeído/metabolismo , Norepinefrina/metabolismo , Raízes de Plantas/química , Piranos/farmacologia , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
J Enzyme Inhib Med Chem ; 32(1): 746-758, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28537532

RESUMO

We designed and synthesised novel N-substituted 1,3-thiazolidin-4-one derivatives for the evaluation of their anti-Toxoplasma gondii efficacy. This scaffold was functionalised both at the N1-hydrazine portion with three structurally different moieties and at the lactam nitrogen with substituted benzyl groups selected on the basis of our previous structure-activity relationships studies. Using three different assay methods, the compounds were assessed in vitro to determine both the levels of efficacy against the tachyzoites of T. gondii (IC50 = 5-148 µM), as well as any evidence of cytotoxicity towards human host cells (TD50 = 68 to ≥320 µM). Results revealed that ferrocene-based thiazolidinones can possess potent anti-tachyzoite activity (TI =2-64).


Assuntos
Antiprotozoários/farmacologia , Tiazolidinas/farmacologia , Toxoplasma/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiazolidinas/síntese química , Tiazolidinas/química , Toxoplasma/crescimento & desenvolvimento
15.
J Pharm Biomed Anal ; 140: 38-44, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28340473

RESUMO

Direct HPLC separation of the enantiomers of triclabendazole sulfoxide (TCBZ-SO), which is the main metabolite of the anthelmintic drug triclabendazole, was carried out using the polysaccharide-based Chiralpak AS-H and Chiralpak IF-3 chiral stationary phases (CSPs). The chromatographic behaviour of both CSPs was evaluated and compared using normal-phase and reversed-phase eluents at different column temperatures. The eluent mixture of n-hexane-2-propanol-trifluoroacetic acid 70:30:0.1 (v/v/v) and a column temperature of 40°C were identified as the best operational conditions to carry out semipreparative enantioseparations on a 1-cm I.D. AS-H column. Under these conditions, 12.5mg of racemic sample were resolved in a single chromatographic run within 15min. Comparison of calculated and experimental chiroptical properties provided the absolute configuration assignment at the sulfur atom. The salification of the isolated enantiomers of TCBZ-SO by reaction with sodium hydroxide solution produced water-soluble Na salts which are potentially useful in the development of new anthelmintic enantiomerically pure formulations.


Assuntos
Benzimidazóis/análise , Sulfóxidos/análise , Cromatografia Líquida de Alta Pressão , Hexanos , Sódio , Estereoisomerismo , Triclabendazol
16.
J Pharm Biomed Anal ; 139: 1-7, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28258982

RESUMO

Albendazole (ABZ) is a sulfanyl-benzimidazole anthelmintic drug used worldwide in the treatment and prevention of parasitic diseases in animals and humans. Following oral administration, ABZ is rapidly oxidized into the pharmacologically active chiral sulfoxide metabolite known as ricobendazole (RBZ). As its achiral precursor, RBZ shows very low intestinal absorption due to its poor solubility in water (0.06mgmL-1). To the best of our knowledge, there is no known example in human medicine of a water-soluble salt form of racemic or enantiomerically pure RBZ. In the present study, we describe in detail the preparation of the sodium (Na) salt of the enantiomers of RBZ through a two-step process: i) the multi-milligram resolution of RBZ by HPLC on the amylose-based Chiralpak IG chiral stationary phase under polar organic mode; ii) the salification of the isolated enantiomers of RBZ by reaction with sodium hydroxide solution. The spectroscopic and chiroptical properties of the RBZ-Na enantiomers were determined. Due to their unique solubility in 0.01M phosphate buffer at physiological pH (14.49mgmL-1) and the high sample throughput obtained on semipreparative separation of the non-salified form, it is potentially possible to develop new anthelmintic enantiopure formulations with improved pharmacokinetic properties and lower toxicity.


Assuntos
Albendazol/análogos & derivados , Química Farmacêutica/métodos , Sódio/química , Albendazol/química , Albendazol/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Sódio/metabolismo , Solubilidade , Estereoisomerismo
17.
J Enzyme Inhib Med Chem ; 32(1): 51-59, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27784170

RESUMO

A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Neoplasias/enzimologia , Isoformas de Proteínas/efeitos dos fármacos , Sacarina/química , Sulfonamidas/química , Humanos , Estrutura Molecular , Análise Espectral/métodos
18.
J Agric Food Chem ; 64(47): 9004-9011, 2016 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-27933876

RESUMO

Naturally occurring flavonoids display a plethora of different biological activities, but emerging evidence suggests that this class of compounds may also act as antidepressant agents endowed with multiple mechanisms of action in the central nervous system, increasing central neurotransmission, limiting the reabsorption of bioamines by synaptosomes, and modulating the neuroendocrine and GABAA systems. Due to their presence in foods, food-derived products, and nutraceuticals, we established their role and structure-activity relationships as reversible and competitive human monoamine oxidase (MAO) inhibitors. In addition, molecular modeling studies, which evaluated their modes of MAO inhibition, are presented. These findings could provide pivotal implications in the quest of novel drug-like compounds and for the establishment of harmful drug-dietary supplement interactions commonly reported in the therapy with antidepressant agents.


Assuntos
Flavonoides/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Antidepressivos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Relação Estrutura-Atividade
19.
Bioorg Med Chem ; 24(5): 1095-105, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26810710

RESUMO

Small libraries of N-substituted saccharin and N-/O-substituted acesulfame derivatives were synthesized and tested as atypical and selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). Most of them inhibited hCA XII in the low nanomolar range, hCA IX with KIs ranging between 19 and 2482nM, whereas they were poorly active against hCA II (KIs >10µM) and hCA I (KIs ranging between 318nM and 50µM). Since hCA I and II are ubiquitous off-target isoforms, whereas the cancer-related isoforms hCA IX and XII were recently validated as drug targets, these results represent an encouraging achievement in the development of new anticancer candidates. Moreover, the lack of a classical zinc binding group in the structure of these inhibitors opens innovative, yet unexplored scenarios for different mechanisms of inhibition that could explain the high inhibitory selectivity. A computational approach has been carried out to further rationalize the biological data and to characterize the binding mode of some of these inhibitors.


Assuntos
Antígenos de Neoplasias/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sacarina/farmacologia , Tiazinas/farmacologia , Antígenos de Neoplasias/química , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/química , Humanos , Simulação de Acoplamento Molecular , Sacarina/química , Relação Estrutura-Atividade , Tiazinas/química
20.
Cent Nerv Syst Agents Med Chem ; 16(2): 98-104, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26320583

RESUMO

Despite the considerable interest in the search of new and potent human MAO inhibitors, an increasing number of research works deal with new therapeutic and analytical approaches regarding these molecules. Our interest was focused on the detailed analysis of (i) new pharmacological options for selective hMAO inhibitors; (ii) innovative analytical procedures to discover/screen hMAO inhibitors, and (iii) the recent possibility of using labeled hMAO inhibitors to unravel neurodegenerative diseases and drug distribution. All these three aspects could open new scenarios stimulating the interest of researchers in this field.


Assuntos
Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase , Sítios de Ligação , Humanos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/metabolismo , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/enzimologia , Neuroimagem/métodos , Relação Estrutura-Atividade
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