Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.238
Filtrar
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): 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
3.
J Enzyme Inhib Med Chem ; 35(1): 255-260, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31790601

RESUMO

Among the diagnostic techniques for the identification of tumour biomarkers, the liquid biopsy is considered one that offers future research on precision diagnosis and treatment of tumours in a non-invasive manner. The approach consists of isolating tumor-derived components, such as circulating tumour cells (CTC), tumour cell-free DNA (ctDNA), and extracellular vesicles (EVs), from the patient peripheral blood fluids. These elements constitute a source of genomic and proteomic information for cancer treatment. Within the tumour-derived components of the body fluids, the enzyme indicated with the acronym CA IX and belonging to the superfamily of carbonic anhydrases (CA, EC 4.2.1.1) is a promising aspirant for checking tumours. CA IX is a transmembrane-CA isoform that is strongly overexpressed in many cancers being not much diffused in healthy tissues except the gastrointestinal tract. Here, it is summarised the role of CA IX as tumour-associated protein and its putative relationship in liquid biopsyfor diagnosing and monitoring cancer progression.


Assuntos
Biomarcadores Tumorais/antagonistas & inibidores , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Neoplasias/diagnóstico , Animais , Biomarcadores Tumorais/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/química , Humanos , Biópsia Líquida , Neoplasias/enzimologia
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
J Enzyme Inhib Med Chem ; 35(1): 365-371, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31854205

RESUMO

The selectivity for a specific human Carbonic Anhydrase (hCA) isoform is an important property a hCA inhibitor (CAI) should be endowed with, in order to constitute a valuable therapeutic tool for the treatment of a desired pathology. In this context, we developed a chemoinformatic platform that allows the analysis of the structure and selectivity profile of known CAIs reported in literature, with the aim of identifying structural motifs connected to ligand selectivity, thus providing useful guidelines for the design of novel ligands selective for the desired hCA isoform. The platform is able to perform ultrafast structure and selectivity analyses through ligand fingerprint similarity, with no need of structural information about the target receptor and ligands' binding mode. It is easily accessible to the non-expert user through the implementation of a KNIME Analytic Platform workflow and could be extended to analyze the selectivity profile of known ligands of different target proteins.


Assuntos
Inibidores da Anidrase Carbônica/análise , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Análise por Conglomerados , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade
12.
J Enzyme Inhib Med Chem ; 35(1): 377-382, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31856608

RESUMO

The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum, have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (KIs 0.81-65.4 µM) and PfCA (KIs 0.62-78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA, which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria.


Assuntos
Antiprotozoários/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Diatomáceas/enzimologia , Fenóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Fenóis/síntese química , Fenóis/química , Plasmodium falciparum/enzimologia , Relação Estrutura-Atividade
13.
J Enzyme Inhib Med Chem ; 35(1): 391-397, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31865754

RESUMO

The emergence of tumour recurrence and resistance limits the survival rate for most tumour-bearing patients. Only, combination therapies targeting pathways involved in the induction and in the maintenance of cancer growth and progression might potentially result in an enhanced therapeutic efficacy. Herein, we provided a prospective combination treatment that includes suberoylanilide hydroxamic acid (SAHA), a well-known inhibitor of histone deacetylases (HDACs), and SLC-0111, a novel inhibitor of carbonic anhydrase (CA) IX. We proved that HDAC inhibition with SAHA in combination with SLC-0111 affects cell viability and colony forming capability to greater extent than either treatment alone of breast, colorectal and melanoma cancer cells. At the molecular level, this therapeutic regimen resulted in a synergistically increase of histone H4 and p53 acetylation in all tested cell lines. Overall, our findings showed that SAHA and SLC-0111 can be regarded as very attractive combination providing a potential therapeutic strategy against different cancer models.


Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Compostos de Fenilureia/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Estrutura Molecular , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas
14.
J Enzyme Inhib Med Chem ; 35(1): 383-390, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31865756

RESUMO

A series of new carbohydrate-based sulphonamide derivatives were designed, synthesised by employing the so-call 'sugar-tail' approach. The compounds were evaluated in vitro against a panel of CAs. Compared to their parent compound p-sulfamoylbenzoic acid, these compounds showed nearly 100-fold improvement in their binding affinities against hCA II in vitro. All of compounds showed great water solubility and the pH value of their water solutions of compounds is 7.0. Such properties are advantageous to make them much less irritating to the eye when applied topical glaucomatous drugs, compared to the relatively highly acidic dorzolamide preparations (pH 5.5). Notably, compounds 7d, 7 g, 7 h demonstrated to topically lower intraocular pressure (IOP) in glaucomatous animals better than brinzolamide when applied as a 1% solution directly into the eye. Low cytotoxicity on human cornea epithelial cell was observed in the tested concentrations by the MTT assay.


Assuntos
Anti-Hipertensivos/farmacologia , Carboidratos/farmacologia , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Desenho de Drogas , Sulfonamidas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Carboidratos/química , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células Epiteliais , Humanos , Concentração de Íons de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
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
16.
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
17.
Expert Opin Ther Pat ; 29(10): 781-792, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31596641

RESUMO

Introduction: Glaucoma affects more than 70 million people worldwide. One of the major therapeutic options for its management is based on the inhibition of the metalloenzyme carbonic anhydrases (CAs, EC 4.2.1.1). CA inhibitors (CAIs) diminish ocular hypertension in glaucomatous patients by reducing the rate of bicarbonate formation and thus, the secretion of the aqueous humor. Areas covered: This review is intended to cover the major contributions in terms of patent literature reports for the treatment of ophthalmic diseases by means of CAIs in a time frame spanning from 2013 to date. Expert opinion: The patent literature is dominated by innovative pharmaceutical formulations including a CAI alone or in combination with other therapeutic agents. Very few novelties within drug discovery are currently present and they mainly account for new CAI moieties and classical CAIs merged into scaffolds bearing additional chemical functionalities beneficial for the pharmacological treatment of the disease. It is reasonable to expect that in the near future the so-called 'old drugs' will achieve pharmacological performances in the management of ocular hypertension beyond any expectations and thus open a new era of drug repurposing merely based on material science advancements.


Assuntos
Inibidores da Anidrase Carbônica/administração & dosagem , Glaucoma/tratamento farmacológico , Hipertensão Ocular/tratamento farmacológico , Animais , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Desenho de Drogas , Reposicionamento de Medicamentos , Glaucoma/enzimologia , Humanos , Hipertensão Ocular/enzimologia , Patentes como Assunto
18.
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
19.
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
20.
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
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA