Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 695
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
J Enzyme Inhib Med Chem ; 35(1): 489-497, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31914827

RESUMO

A series of amino acid-sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid-sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.


Assuntos
Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sulfonamidas/farmacologia , Aminoácidos/síntese química , Aminoácidos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Sulfonamidas/síntese química , Sulfonamidas/química
2.
J Enzyme Inhib Med Chem ; 35(1): 298-305, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31809607

RESUMO

Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (4a,b, 5a,b, 9a-c, and 10a-d), featuring the zinc anchoring benzenesulfonamide moiety linked to a benzofuran tail via a hydrazine or hydrazide linker. All the target benzofurans were examined for their inhibitory activities toward isoforms hCA I, II, IX, and XII. The target tumour-associated hCA IX and XII isoforms were efficiently inhibited with KIs spanning in ranges 10.0-97.5 and 10.1-71.8 nM, respectively. Interestingly, arylsulfonehydrazones 9 displayed the best selectivity toward hCA IX and XII over hCA I (SIs: 39.4-250.3 and 26.0-149.9, respectively), and over hCA II (SIs: 19.6-57.1 and 13.0-34.2, respectively). Furthermore, the target benzofurans were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Only benzofurans 5b and 10b possessed selective and moderate growth inhibitory activity toward certain cancer cell lines.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sulfonamidas/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
3.
J Enzyme Inhib Med Chem ; 35(1): 325-329, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31813300

RESUMO

A series of compounds incorporating 3-(3-(2/3/4-substituted phenyl)triaz-1-en-1-yl) benzenesulfonamide moieties were synthesised and their chemical structure was confirmed by physico-chemical methods. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were evaluated against human isoforms hCA I and II. KI values of these sulphonamides were in the range of 21 ± 4-72 ± 2 nM towards hCA I and in the range of 16 ± 6-40 ± 2 nM against hCA II. The 4-fluoro substituted derivative might be considered as an interesting lead due to its effective inhibitory action against both hCA I and hCA II (KIs of 21 nM), a profile rarely seen among other sulphonamide CA inhibitors, making it of interest in systems where the activity of the two cytosolic isoforms is dysregulated.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Triazenos/farmacologia , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Triazenos/química
4.
J Enzyme Inhib Med Chem ; 35(1): 21-30, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619095

RESUMO

Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Doença de Chagas/tratamento farmacológico , Ciclamatos/farmacologia , Tripanossomicidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Doença de Chagas/metabolismo , Ciclamatos/síntese química , Ciclamatos/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia
5.
J Enzyme Inhib Med Chem ; 35(1): 59-64, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31663383

RESUMO

A primary strategy to combat antimicrobial resistance is the identification of novel therapeutic targets and anti-infectives with alternative mechanisms of action. The inhibition of the metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) from pathogens (bacteria, fungi, and protozoa) was shown to produce an impairment of the microorganism growth and virulence. As phosphonamidates have been recently validated as human α-CA inhibitors (CAIs) and no phosphorus-based zinc-binding group have been assessed to date against ß-class CAs, herein we report an inhibition study with this class of compounds against ß-CAs from pathogenic bacteria, fungi, and protozoa. Our data suggest that phosphonamidates are among the CAIs with the best selectivity for ß-class over human isozymes, making them interesting leads for the development of new anti-infectives.


Assuntos
Amidas/farmacologia , Anti-Infecciosos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Compostos Organometálicos/farmacologia , Ácidos Fosfóricos/farmacologia , Amidas/química , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Bactérias/enzimologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Fungos/enzimologia , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/enzimologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Ácidos Fosfóricos/química , Fósforo/química , Fósforo/farmacologia , Relação Estrutura-Atividade , Zinco/química , Zinco/farmacologia
6.
J Enzyme Inhib Med Chem ; 35(1): 65-71, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31663386

RESUMO

We investigated a panel of 14 compounds belonging to the monothiocarbamate (MTC) and dithiocarbamate (DTC) series against the ß-carbonic anhydrase 3 (ß-CA3) of Mycobacterium tuberculosis (Mtb). We also evaluated all compounds for toxicity using 1-5-day post fertilisation zebrafish embryos. 11 out of the 14 investigated derivatives showed effective nanomolar or submicromolar in vitro inhibition against the ß-CA3 (KIs 2.4-812.0 nM), and among them four DTCs of the series (8-10 and 12) showed very significant inhibition potencies with KIs between 2.4 and 43 nM. Out of 14 compounds screened for toxicity and safety 9 compounds showed no adverse phenotypic effects on the developing zebrafish larvae at five days of exposure. The results of in vitro inhibition and the toxicological evaluation of our study suggest that 5 compounds are suitable for further in vivo preclinical characterisation in zebrafish model.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade , Peixe-Zebra
7.
J Enzyme Inhib Med Chem ; 35(1): 109-117, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31687859

RESUMO

With the aim to obtain novel compounds possessing both strong affinity against human carbonic anhydrases and low toxicity, we synthesised novel thiourea and sulphonamide derivatives 3, 4 and 10, and studied their in vitro inhibitory properties against human CA I, CA II and CA IX. We also evaluated the toxicity of these compounds using zebrafish larvae. Among the three compounds, derivative 4 showed efficient inhibition against hCA II (KI = 58.6 nM). Compound 10 showed moderate inhibition against hCA II (KI = 199.2 nM) and hCA IX (KI = 147.3 nM), whereas it inhibited hCA I less weakly at micromolar concentrations (KI = 6428.4 nM). All other inhibition constants for these compounds were in the submicromolar range. The toxicity evaluation studies showed no adverse effects on the zebrafish larvae. Our study suggests that these compounds are suitable for further preclinical characterisation as potential inhibitors of hCA I, II and IX.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IV/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Nitroimidazóis/farmacologia , Animais , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IV/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Larva/efeitos dos fármacos , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Relação Estrutura-Atividade , Peixe-Zebra
8.
J Enzyme Inhib Med Chem ; 35(1): 165-171, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752557

RESUMO

Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase (bCA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency. [Formula: see text].


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Nitrilos/farmacologia , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Bovinos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fluorometria , Humanos , Estrutura Molecular , Nitrilos/síntese química , Nitrilos/química , Relação Estrutura-Atividade
9.
J Enzyme Inhib Med Chem ; 35(1): 245-254, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31790605

RESUMO

A new series of homosulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) possessing various substitution patterns and moieties in the 7, 8 or 9 position of the heterocylic ring were prepared by original procedures and investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. The 8-substituted homosulfocoumarins were the most effective hCA IX/XII inhibitors followed by the 7-substituted derivatives, whereas the substitution pattern in position 9 led to less effective binders for the transmembrane, tumour-associated isoforms IX/XII. The cytosolic isoforms hCA I and II were not inhibited by these compounds, similar to the sulfocoumarins/coumarins investigated earlier. As hCA IX and XII are validated anti-tumour targets, with one sulphonamide (SLC-0111) in Phase Ib/II clinical trials, finding derivatives with better selectivity for inhibiting the tumour-associated isoforms over the cytosolic ones, as the homosulfocoumarins reported here, is of crucial importance.


Assuntos
Benzotiepinas/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Benzotiepinas/síntese química , Benzotiepinas/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
10.
J Enzyme Inhib Med Chem ; 35(1): 289-297, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31797703

RESUMO

In this study, newly synthesised compounds 6, 8, 10 and other compounds (1-5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1-10 showed effective inhibition profiles with KI values in the range of 5.13-16.9 nM for hCA I and of 11.77-67.39 nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Desenho de Drogas , Pirazóis/farmacologia , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
11.
J Enzyme Inhib Med Chem ; 35(1): 306-310, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31797704

RESUMO

The differential scanning fluorimetry (DSF) screening of 5.692 fragments in combination with benzenesulfonamide (BSA) against bovine carbonic anhydrase (bCA) delivered >100 hits that either caused, on their own, a significant thermal shift (ΔTm, °C) in the protein melting temperature or significantly influenced the thermal shift observed for BSA alone. Three hits based on 1,2,3-triazole moiety represent the periphery of the recently reported potent inhibitors of hCA II, IX and XII which were efficacious in vivo. Such a re-discovery of suitable BSA periphery essentially validates the new fragment-based approach to the discovery of future CAIs. Structures of other validated fragment hits are reported.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Fluorometria , Sulfonamidas/farmacologia , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Sulfonamidas/síntese química , Sulfonamidas/química
12.
J Enzyme Inhib Med Chem ; 34(1): 1722-1729, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31576761

RESUMO

In this study, new chalcone compounds having the chemical structure of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones (1-8) were synthesised and were characterised by 1H-NMR, 13 C-NMR, and HRMS spectra. Cytotoxic and carbonic anhydrase (CA) inhibitory effects of the compounds were investigated. Cytotoxicity results pointed out that compound 4, 6-[3-(4-trifluoromethylphenyl)-2-propenoyl]-3H-benzoxazol-2-one, showed the highest cytotoxicity (CC50) and potency-selectivity expression (PSE) value, and thus can be considered as a lead compound of this study. According to the CA inhibitory results, IC50 values of the compounds 1-8 towards hCA I were in the range of 29.74-69.57 µM, while they were in the range of 18.14 - 48.46 µM towards hCA II isoenzyme. Ki values of the compounds 1-8 towards hCA I were in the range of 28.37 ± 6.63-70.58 ± 6.67 µM towards hCA I isoenzyme and they were in the range of 10.85 ± 2.14 - 37.96 ± 2.36 µM towards hCA II isoenzyme.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzoxazóis/química , Benzoxazóis/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/toxicidade , Anidrases Carbônicas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Chalcona/química , Criança , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
13.
Eur J Med Chem ; 183: 111704, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557608

RESUMO

Curcumin is a small organic molecule with pleiotropic biological activities. However, its multiple structural-pharmacokinetic challenges prevent its development into a clinical drug. Various structural modifications have been made to improve its drug profile. In this review, we focus on the methods adopted in the synthesis of asymmetric curcumin derivatives and their biological activities and forecast the future of this exciting class of compounds in the field of medicine.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Curcumina/farmacologia , Neoplasias/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Curcumina/síntese química , Curcumina/química , Humanos , Estrutura Molecular
14.
Eur J Med Chem ; 183: 111702, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31542715

RESUMO

Carbonic anhydrases isoforms CA IX, and XII are known to be highly expressed in various human tissues and malignancies. CA IX is a prominent target for especially colorectal cancers, because it is overexpressed in colorectal cancer and this overexpression leads poor prognosis. Inhibition of CA IX activity by small molecule CA inhibitors like sulfonamides, sulfonamide derivative or coumarins leads to inhibition of tumorigenesis. Novel twenty-seven compounds in three series (sulfonamide-based imines (6a-6i), coumarin-based aldehydes (7a-7i), and coumarin-sulfonamide-based target molecules (8a-8i)) were synthesized and characterized by means of IR, NMR, and mass spectra. All compounds were tested for their ability to inhibit CA I, CA II, CA IX, and CA XII isoforms. 4-((((2-((1-(3-((2-oxo-2H-chromen-7-yl)oxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalen-1-yl)-methylene)amino)methyl)benzenesulfonamide (8i) exhibited the highest hCA IX inhibition with the Ki of 45.5 nM. In addition, 8i was found to be potent in inhibiting cancer cell proliferation as selective (IC50 = 17.01 ±â€¯1.35 µM for HT-29, IC50 = 118.73 ±â€¯1.19 µM for HEK293T). This novel compound inhibited the CA IX and CA XII protein expression in HT-29 cells. These findings indicate that 8i can inhibit cellular proliferation in human colon cancer cells by specifically targeting the CA IX and CA XII expression.


Assuntos
Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Cumarínicos/farmacologia , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Relação Dose-Resposta a Droga , Células HEK293 , Células HT29 , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
15.
J Enzyme Inhib Med Chem ; 34(1): 1697-1710, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31537132

RESUMO

Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors.


Assuntos
Benzimidazóis/química , Inibidores da Anidrase Carbônica/síntese química , Sulfonamidas/síntese química , Aminas/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/química , Humanos , Isoenzimas/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bases de Schiff/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
16.
J Enzyme Inhib Med Chem ; 34(1): 1652-1659, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530034

RESUMO

Eight genetically distinct carbonic anhydrase (EC 4.2.1.1) enzyme families (α-, ß-, γ- δ-, ζ-, η-, θ- and ι-CAs) were described to date. On the other hand, 16 mammalian α-CA isoforms are known to be involved in many diseases such as glaucoma, edema, epilepsy, obesity, hypoxic tumors, neuropathic pain, arthritis, neurodegeneration, etc. Although CA inhibitors were investigated for the management of a variety of such disorders, the activators just started to be investigated in detail for their in vivo effects. This review summarizes the activation profiles of α-, ß, γ-, δ-, ζ- and η- CAs from various organisms (animals, fungi, protozoan, bacteria and archaea) with the most investigated classes of activators, the amines and the amino acids.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Aminas/síntese química , Aminas/química , Aminoácidos/síntese química , Aminoácidos/química , Bactérias/enzimologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Entamoeba histolytica/enzimologia , Fungos/enzimologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular
17.
Eur J Med Chem ; 183: 111698, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31539777

RESUMO

A library of twenty two novel 1,2,3-triazole benzenesulfonamides incorporating thiosemicarbazide, 5(4H)-thione-1,2,4-triazole and variously substituted phenacyl appended 1,2,4-triazole as tail were designed, synthesized and assessed for their efficacy as inhibitors against carbonic anhydrase human (h) isoforms hCA I, II, IV and IX. The physiologically important and off-target cytosolic isoform hCA I was weakly inhibited by most of the newly synthesized sulfonamides while the glaucoma associated isoform hCA II was moderately inhibited with KIs spanning in low nanomolar range (KI = 8.0 nM-0.903 µM). The membrane bound isoform hCA IV, which is known to be involved in glaucoma and retinitis pigmentosa among others, was strongly inhibited by all newly synthesized sulfonamides out of which nine compounds inhibited isoform hCA IV even more effectively as compared to standard drug acetazolamide (AAZ). The membrane bound isoform hCA IX, associated with growth of tumor cells, was moderately inhibited with KIs ranging between 51 nM-3.198 µM. The effect of appending variously substituted tails on heterocyclic moieties over inhibition potential of synthesized sulfonamides is also disclosed which can be of further interest in pharmacological studies for exploring synthesis of isoform selective inhibitors.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Triazóis/farmacologia , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IV/antagonistas & inibidores , 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 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Triazóis/química
18.
Eur J Med Chem ; 182: 111642, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476557

RESUMO

By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.


Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IV/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Descoberta de Drogas , Glioma/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IV/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Epiteliais/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/metabolismo , Relação Estrutura-Atividade
19.
Eur J Med Chem ; 182: 111638, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472471

RESUMO

Four new series of aromatic sulfamates were synthesized and investigated for the inhibition of four human (h) isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I, II, IX, and XII. The reported derivatives, obtained by a sulfamoylation reaction of the corresponding phenolic precursors, bear 3,5-diarylpyrazoline moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor. Pyrazolines are biologically privileged scaffolds, endowed with versatile biological activity, such as an anti-proliferative action. The derivatives were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally, hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (KIs in the range of 0.42-90.1 nM), IX (KIs in the range of 0.72-63.6 nM), and XII (KIs in the range of 0.88-85.2 nM). The best substitution fragments at the pyrazoline ring included for CA II a 4-sulfamic group on the 3-aryl and halogens on the 5-aryl or a methoxy group on the 3-aryl and a 4-sulfamate group on the 5-aryl; for CA IX and CA XII they included the sulfamic group on the 3- or 4-position of the 5-aryl and an electronwithdrawing group on the 4-postion of the 3-aryl ring.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Pirazóis/farmacologia , Ácidos Sulfônicos/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Ácidos Sulfônicos/síntese química , Ácidos Sulfônicos/química
20.
Eur J Med Chem ; 181: 111586, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401537

RESUMO

We have synthetized a novel series of ß-hydroxy tellurides bearing the benzenesulfonamide group as potent inhibitors of carbonic anhydrase enzymes. In a one pot procedure, we discovered both the ring opening reaction of the three-membered ring and the cleavage of the sulfonamide protecting moiety at the same time. Moreover, the first X-ray co-crystallographic structure of a ß-hydroxy telluride derivative with hCA II is reported. The potent effects of these compounds against the tumor-associated hCA IX with low nanomolar constant inhibition values give the possibility to evaluate their activity in vitro using a breast cancer cell line (MDA-MB-231). Compounds 7e and 7g induced significant toxic effects against tumor cells after 48 h incubation in normoxic conditions killing over 50% of tumor cells at 3 µM, but their efficacy decreased in hypoxic conditions reaching the 50% of the tumor cell viability only at 30 µM. These unusual features make them interesting lead compounds to act as antitumor agents, not only as Carbonic Anhydrase IX inhibitors, but reasonably in different pathways, where hCA IX is not overexpressed.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Telúrio/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/química , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Linhagem Celular Tumoral , Cristalografia por Raios X , Feminino , Humanos , Simulação de Acoplamento Molecular , Sulfonamidas/síntese química , Sulfonamidas/química , Telúrio/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA