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1.
J Enzyme Inhib Med Chem ; 34(1): 1498-1505, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31423863

RESUMO

Recent studies identified the benzoxaborole moiety as a new zinc-binding group able to interact with carbonic anhydrase (CA) active site. Here, we report a structural analysis of benzoxaboroles containing urea/thiourea groups, showing that these molecules are very versatile since they can bind the enzyme assuming different binding conformations and coordination geometries of the catalytic zinc ion. In addition, theoretical calculations of binding free energy were performed highlighting the key role of specific residues for protein-inhibitor recognition. Overall, these data are very useful for the development of new inhibitors with higher selectivity and efficacy for various CAs.


Assuntos
Compostos de Boro/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Compostos de Boro/síntese química , Compostos de Boro/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade
2.
J Enzyme Inhib Med Chem ; 34(1): 1526-1533, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31431095

RESUMO

A library of 4-[(3-methyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulphonamides (EMAC8002a-m) was designed and synthesised to evaluate the effect of substituents in the positions 3 and 4 of the dihydrothiazole ring on the inhibitory potency and selectivity toward human carbonic anhydrase isoforms I, II, IX, and XII. Most of the new compounds preferentially inhibit the isoforms II and XII. Both electronic and steric features on the aryl substituent in the position 4 of the dihydrothiazole ring concur to determine the overall biological activity of these new derivatives.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , 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 , Relação Estrutura-Atividade
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): 1457-1464, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31411080

RESUMO

Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses. We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were in vitro evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with KIs in the range of 0.966-9.091 µM, whereas hCA II in the range of 0.083-3.594 µM. The primary 7-chloro-6-flouro substituted sulphfonamide derivative 6e (KI = 0.083 µM) proved to be the most active quinoline in inhibiting hCA II, whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 µM, confirming the crucial role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Inibidores da Anidrase Carbônica/química , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Sulfonamidas/química
5.
J Enzyme Inhib Med Chem ; 34(1): 1186-1192, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282228

RESUMO

A series of sixteen benzenesulfonamide derivatives has been synthesised and tested as inhibitors of Vibrio cholerae carbonic anhydrase (CA) enzymes, belonging to α-CA, ß-CA, and γ-CA classes (VchCAα, VchCAß, and VchCAγ). The determined Ki values were compared to those of selected human CA isoforms (hCA I and hCA II). Structure-affinity relationship analysis highlighted that all tested compounds proved to be active inhibitors of VchCAα at nanomolar concentration. The VchCAß activity was lower to respect inhibitory efficacy toward VchCAα, whereas, these benzenesulfonamide derivatives failed to inhibit VchCAγ. Interestingly, compound 7e combined the best activity toward VchCAα and VchCAß. In order to obtain a model for binding mode of our inhibitors toward bacterial CAs, we carried out docking simulations by using the available crystal structures of VchCAß.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Cólera/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Inibidores da Anidrase Carbônica/química , Cólera/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Vibrio cholerae/enzimologia
6.
Eur J Med Chem ; 179: 547-556, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276899

RESUMO

Herein we report the design and synthesis of three different sets of novel benzenesulfonamides (5a-e, 7a-e and 10a-d) incorporating hydrophilic/hydrophobic tails by hydrazido or hydrazino linkers. The newly synthesized benzenesulfonamides were examined in vitro for their inhibitory activity towards four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII using a stopped-flow CO2 hydrase assay. All these isoforms were inhibited by the sulfonamides (5a-e, 7a-e and 10a-d) with variable degrees in the following KI ranges: 76.8-357.4 nM for hCA I, 8.2-94.6 nM for hCA II, 2.0-46.3 nM for hCA XI, and 8.3-88.3 nM for hCA XII. The sulfonamide 7d exhibited potent anti-proliferative activity against breast MCF-7 cancer cell line under both normoxic and hypoxic conditions with IC50 values equal 3.32 ±â€¯0.06 and 8.53 ±â€¯0.32 µM, respectively, which are comparable to the reference drug doxorubicin (IC50 = 2.36 ±â€¯0.04 and 8.39 ±â€¯0.25 µM, respectively). Furthermore, 7d was screened for cell cycle disturbance and apoptosis induction in MCF-7 cells. It was found to persuade cell cycle arrest at G2-M stage as well as to alter the Sub-G1 phase, also, 7d resulted in a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Molecular docking study was carried out for 7d within the hCA IX and hCA XII active sites to rationalize the obtained inhibition results.


Assuntos
Antineoplásicos/farmacologia , Benzeno/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzeno/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Domínio Catalítico/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Hidrazinas/síntese química , Hidrazinas/química , Interações Hidrofóbicas e Hidrofílicas , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/química
7.
J Enzyme Inhib Med Chem ; 34(1): 1199-1209, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237458

RESUMO

The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the "click-tail" approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with Kis in the range of 50.8-966.8 nM, while the glaucoma associated hCA II was inhibited with Kis in the range of 6.5-760.0 nM. Isoform hCA IV was inhibited with Kis in the range of 65.3-957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with Kis in the range of 30.8-815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.


Assuntos
Inibidores da Anidrase Carbônica/síntese química , Isoenzimas/antagonistas & inibidores , Sulfonamidas/farmacologia , Triazóis/química , Triazóis/farmacologia , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/química , Relação Estrutura-Atividade , Sulfonamidas/química
8.
J Enzyme Inhib Med Chem ; 34(1): 1164-1171, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31219348

RESUMO

Chagas disease and leishmaniasis are neglected tropical disorders caused by the protozoans Trypanosoma cruzi and Leishmania spp. Carbonic anhydrases (CAs, EC 4.2.1.1) from these protozoans (α-TcCA and ß-LdcCA) have been validated as promising targets for chemotherapic interventions. Many anti-protozoan agents, such as nitroimidazoles, nifurtimox, and benznidazole possess a nitro aromatic group in their structure which is crucial for their activity. As a continuation of our previous work on N-nitrosulfonamides as anti-protozoan agents, we investigated benzenesulfonamides bearing a nitro aromatic moiety against TcCA and LdcCA, observing selective inhibitions over human off-target CAs. Selected derivatives were assessed in vitro in different developmental stages of T. cruzi and Leishmania spp. A lack of significant growth inhibition has been found, which has been connected to the low permeability of this class of derivatives through cell membranes. Further strategies necessarily need to be designed for targeting Chagas disease and leishmaniasis with nitro-containing CA inhibitors.


Assuntos
Antiprotozoários/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Leishmania donovani/efeitos dos fármacos , Trypanosoma cruzi/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 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Leishmania donovani/enzimologia , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Trypanosoma cruzi/enzimologia
9.
J Enzyme Inhib Med Chem ; 34(1): 1172-1177, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31218888

RESUMO

A series of novel 8-substituted-N-(4-sulfamoylphenyl)quinoline-2-carboxamides was synthesised by the reaction of 8-hydroxy-N-(4-sulfamoylphenyl) quinoline-2-carboxamide with alkyl and benzyl halides. The compounds were assayed for carbonic anhydrase (CA) inhibitory activity against four hCA isoforms, hCA I, hCA II, hCA IV, and hCA IX. Barring hCA IX, all the isoforms were inhibited from low to high nanomolar range. hCA I was inhibited in the range of 61.9-8126 nM, with compound 5h having an inhibition constant of KI = 61.9 nM. hCA II was inhibited in the range of 33.0-8759 nM, with compound 5h having an inhibition constant of 33.0 nM and compounds 5a and 5b having inhibition constants of 88.4 and 85.7 nM, respectively. hCA IV was inhibited in the range of 657.2-6757 nM. Hence, compound 5h, possessing low nanomolar hCA I and II inhibition, can be selected as a lead for the design of novel CA I and II inhibitors.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
10.
J Enzyme Inhib Med Chem ; 34(1): 1078-1082, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31124389

RESUMO

3-Methylpentyl(4-sulphamoylphenyl)carbamate (MSPC) came as the most potent compound out of a new series of carbamates composed of phenyl-ethanol or branched aliphatic alcohols, and 4-benzenesulphonamide-carbamic acid. In this study, the anticonvulsant activity and pharmacokinetics (PKs) of MSPC-two individual enantiomers were comparatively analysed in rats as well as their carbonic anhydrase (CA) inhibition. The anticonvulsant activity of MSPC enantiomers was evaluated at the rat-maximal electroshock (MES) test, and their CA inhibition evaluated. (R)-MSPC had a 29% higher clearance and consequently, a lower plasma exposure area under the curve (AUC) than (S)-MSPC and racemic-MSPC. Nevertheless, (R)-MSPC had a better brain permeability than its (S)-enantiomer with brain-to-plasma-(AUC)-ratio (BPR) of 2.07 ((R)-enantiomer), 1.85 (racemate), and 0.79 ((S)-enantiomer). As a whole body (in vivo) pharmacodynamic (PD) measure, MSPC-anticonvulsant maximal electroshock seizure (MES) activity was less enantioselective than MSPC-CA inhibition. The lack of significant differences between racemic-MSPC and its individual enantiomers suggest that their anticonvulsant activity might be due to multiple mechanisms of action.


Assuntos
Anticonvulsivantes/farmacologia , Carbamatos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Fármacos do Sistema Nervoso Central/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Carbamatos/síntese química , Carbamatos/química , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Sistema Nervoso Central/metabolismo , Fármacos do Sistema Nervoso Central/síntese química , Fármacos do Sistema Nervoso Central/química , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
11.
Comput Biol Chem ; 80: 307-313, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31078112

RESUMO

In this study, we present four multilinear regression quantitative structure-activity relationship (QSAR) models, the first of which tackles the experimental CA IX isozyme inhibitory activities of a mixed set of 59 compounds (coumarins and sulfocoumarins), while the second and the third ones are local models for coumarins (42 compounds) and sulfocoumarins (17 compounds) for the same endpoint respectively. The fourth model deals with the selective inhibitory activity of 29 compounds on CA II and CA IX isozymes which was defined as differences of inhibition constants between CA II and CA IX (ΔpKi=pKi_CAII- pKi_CAIX) in logarithmic scale. All presented models are statistically significant, robust and internally and externally validated. Most of the descriptors involved in these models are DFT-based physically-interpretable ones. Existence of the eigenvalues of chemical reactivity-related orbitals such as HOMO-1 Energy and LUMO Energy in the models allow us to speculate that the hydrolyzing reactions of the coumarins and sulfocoumarins in the active pocket of CA isozymes play a critical role in (or modulate) the binding free energy of the ligand-isozyme complexes. We believe that presented models may be used to design new virtual analogues of existing compounds with desired activity and selectivity towards CA IX or CA II.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Cumarínicos/química , Relação Quantitativa Estrutura-Atividade , Teoria da Densidade Funcional , Humanos , Modelos Químicos , Estrutura Molecular
12.
Eur J Med Chem ; 177: 188-197, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136893

RESUMO

Carbonic Anhydrases have been recently validated as novel therapeutic targets in neuropathic pain. In this study, we combine the anticonvulsant propriety of spyrohydantoin and the CA inhibitor moiety of benzenesulfonamide to synthesize a novel series of spyrohydantoin bearing sulfonamides with strong activity against hCA II and VII. These isoforms are present in the nervous system and largely expressed both at the central as well as at peripheral level and can be modulated for pain relief. The crystal structures of hCA II in complex with selected compounds 5a-c demonstrate the importance of the tail in the binding modes within the isoform. Finally, in vivo, in an animal model of oxaliplatin induced neuropathy, compounds with organoselenium tails (8b-c) showed potent neuropathic pain attenuating effects. Taken together, these data strongly suggest the translational utility of these inhibitors as novel pain relievers.


Assuntos
Analgésicos/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Hidantoínas/uso terapêutico , Neuralgia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/química , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Cristalografia por Raios X , Desenho de Drogas , Humanos , Hidantoínas/síntese química , Hidantoínas/química , Masculino , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
13.
Eur J Med Chem ; 175: 40-48, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31071549

RESUMO

Sixteen 5-aryl-substituted isothiazol-3(2H)-one-1,(1)-(di)oxide analogs have been prepared from the corresponding 5-chloroisothiazol-3(2H)-one-1-oxide or -1,1-dioxide by a Suzuki-Miyaura cross-coupling reaction and screened for their inhibition potency against four human carbonic anhydrase isoenzymes: the transmembrane tumor-associated hCA IX and XII and the cytosolic off-target hCA I and II. Most of the synthesized derivatives inhibited hCA IX and XII isoforms in nanomolar range, whereas remained inactive or modestly active against both hCA I and II isoenzymes. In the N-tert-butylisothiazolone series, the 5-phenyl-substituted analog (1a) excelled in the inhibition of tumor-associated hCA IX and XII (Ki = 4.5 and Ki = 4.3 nM, respectively) with excellent selectivity against off target hCA I and II isoenzymes (S > 2222 and S > 2325, respectively). Since the highest inhibition activities were observed with N-tert-butyl derivatives, lacking a zinc-binding group, we suppose to have a new binding mode situated out of the active site. Additionally, three free-NH containing analogs (3a, 4a, 3i) have also been prepared in order to study the impact of free-NH containing N-acyl-sulfinamide- (-SO-NH-CO-) or N-acyl-sulfonamide-type (-SO2-NH-CO-) derivatives on the inhibitory potency and selectivity. Screening experiments evidenced 5-phenylisothiazol-3(2H)-one-1,1-dioxide (4a), the closest saccharin analog, to be the most active derivative with inhibition constants of Ki = 40.3 nM and Ki = 9.6 nM against hCA IX and hCA XII, respectively. The promising biological results support the high potential of 5-arylisothiazolinone-1,(1)-(di)oxides to be exploited for the design of potent and cancer-selective carbonic anhydrase inhibitors.


Assuntos
Anidrase Carbônica IX/efeitos dos fármacos , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Neoplasias/enzimologia , Tiazóis/síntese química , Tiazóis/farmacologia , Humanos , Análise Espectral/métodos , Relação Estrutura-Atividade , Tiazóis/química
14.
J Enzyme Inhib Med Chem ; 34(1): 1051-1061, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074307

RESUMO

A large library of fibrate-based N-acylsulphonamides was designed, synthesised, and fully characterised in order to propose them as zinc binders for the inhibition of human carbonic anhydrase (hCA) enzymatic activity. Synthesised compounds were tested against four hCAs (I, II, IX, and XII) revealing a promising submicromolar inhibitory activity characterised by an isozyme selectivity pattern. Structural modifications explored within this scaffold are: presence of an aryl ring on the sulphonamide, p-substitution of this aryl ring, benzothiazole or benzophenone as core nuclei, and an n-propyl chain or a geminal dimethyl at Cα carbon. Biological results fitted well with molecular modelling analyses, revealing a putative direct interaction with the zinc ion in the active site of hCA I, II and IX. These findings supported the exploration of less investigated secondary sulphonamides as potential hCA inhibitors.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Simulação de Acoplamento Molecular , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Domínio Catalítico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Comput Biol Chem ; 80: 234-243, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31009872

RESUMO

Nowadays, different approaches have been pursued with the intent to develop sulfonamide-like carbonic anhydrase inhibitors that possess better selectivity profiles toward the different human isoforms of the enzyme. Here, we used conventional 3D-QSAR methods, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA, to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models for benzenesulfonamide derivatives as human carbonic anhydrase (hCA) II/IX inhibitors. The theoretical models had good reliability (R2>0.75) and predictability (Q2>0.55), and the contour maps could graphically present the contributions of the force fields for activity and identify the structural divergence between human carbonic anhydrase II inhibitors and human carbonic anhydrase IX inhibitors. Consequently, we explored the selectivity of inhibitor for human carbonic anhydrase II and IX through molecular docking, and the difference of activity coincides with the potential binding mode well. According to the results of the predicted values and the molecule docking, we found that the inhibitors published in the literature had stronger inhibition on the hCA IX; based on the theoretical models, we designed seven new compounds with good potential activity and reasonably good ADMET profile, which could selectively inhibit hCA IX. Molecular Dynamics Simulation showed that newly-designed compound D7 had good selectivity on hCA IX. The findings from 3D-QSAR and docking studies maybe helpful in the rational drug design of isoform-selective inhibitors.


Assuntos
Antígenos de Neoplasias/química , Anidrase Carbônica II/química , Anidrase Carbônica IX/química , Inibidores da Anidrase Carbônica/química , Sulfonamidas/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Inibidores da Anidrase Carbônica/farmacocinética , Conjuntos de Dados como Assunto , Desenho de Drogas , Humanos , Análise dos Mínimos Quadrados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética
16.
J Enzyme Inhib Med Chem ; 34(1): 773-782, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30843736

RESUMO

In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general formula [ReCl(CO)3(L)] (L = 3a or 3b) were prepared and fully characterised by spectroscopic methods (IR, NMR, MS, UV-Vis), elemental analysis, X-ray diffraction, and theoretical studies using DFT and TD-DFT methods. In particular, we showed that, in the solid state, the pyridine and the triazole rings of 3b adopted an uncommon cis configuration which stems from intermolecular hydrogen bonds. Preliminary assays demonstrated a promising nanomolar inhibitory activity against carbonic anhydrase isoform IX for both ligands and complexes with a strong affinity Ki of 2.8 nM for ligand 3a. More interestingly, complex 4b exhibited a pronounced selectivity against hCA IX over the off-targets hCA I and hCA II which makes this compound a promising potential anticancer drug candidate.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Teoria da Densidade Funcional , Antígenos de Neoplasias/metabolismo , Monóxido de Carbono/química , Monóxido de Carbono/farmacologia , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Rênio/química , Rênio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Triazóis/química , Triazóis/farmacologia
17.
Eur J Med Chem ; 168: 301-314, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30826507

RESUMO

An expanded set of pyridazine-containing benzene sulfonamides was investigated for inhibition of four human carbonic anhydrase isoforms, which revealed a pronounced inhibition trend toward hCA IX, a cancer-related, membrane-bound isoform of the enzyme. Comparison of antiproliferative effects of these compounds against cancer (PANC-1) and normal (ARPE-19) cells at 50 µM concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentration-dependent mode against normal (ARPE-19) and two cancer cell lines (PANC-1 and SK-MEL-2) identified two lead compounds one of which displayed a notable cytotoxicity toward pancreatic cancer cells while the other targeted the melanoma cells. These findings significantly expand the knowledge base concerning the hCA IX inhibitors whose inhibitory potency against a recombinant enzyme translates into selective anticancer activity under hypoxic conditions which are aimed to model the environment of a growing tumor.


Assuntos
Antineoplásicos/farmacologia , Anidrase Carbônica IX/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Piridazinas/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 , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Piridazinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
18.
Acta Crystallogr F Struct Biol Commun ; 75(Pt 3): 166-170, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30839290

RESUMO

Carbonic anhydrases (CAs) are molecular targets in various diseases. While many sulfonamide-based drugs are in clinical use, CA inhibitor design is moving towards the incorporation of alternative zinc-binding groups, such as carboxylic acids, to promote CA isoform-specific inhibition. Here, X-ray crystal structures of CA II in complex with nicotinic acid and ferulic acid determined to 1.70 and 1.50 Šresolution, respectively, are reported. Furthermore, the structures of these two compounds are superimposed with previously determined structures to compare the mechanisms of inhibition and the properties of carboxylic acid-based CA inhibitors. This study examines an important class of alternative, non-sulfonamide-based CA inhibitors and provides insight to facilitate the structure-guided design of CA isoform-specific inhibitors.


Assuntos
Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Ácidos Carboxílicos/química , Isoformas de Proteínas/metabolismo , Anidrase Carbônica II/química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Desenho de Drogas , Isoformas de Proteínas/química , Relação Estrutura-Atividade , Sulfonamidas/química
19.
Mini Rev Med Chem ; 19(12): 1015-1027, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806314

RESUMO

BACKGROUND: The function of Carbonic anhydrase is to facilitate the physiological process i.e. interconversion of CO2 to HCO3 - by hydration. Carbonic anhydrase enzyme plays a vital role in different physiological processes to regulate pH as well as regulate the inner environment of CO2 and secretion of electrolytes. METHODS: Six representatives of amidophosphate derivatives (L1-L6) were synthesized and evaluated for their biological activities against carbonic anhydrase enzyme. RESULTS: Out of six derivatives, L1 (IC50 = 12.5 ± 1.35 µM), and L2 (IC50 = 3.12 ± 0.45 µM) showed potent activity against BCA-II. While (L3, L4 and L5) showed weak inhibitory activity with IC50 values of 24.5 ± 2.25, 55.5± 1.60, and 75.5 ± 1.25 µM, respectively and were found to be weak inhibitors of carbonic anhydrase as compared to acetazolamide (IC50 =0.12± 0.03µM), used as standard inhibitor. A computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been expanded for the determination of physicochemical parameters governing the bioactivity amidophosphate derivatives (L1-L6) containing (O1 --- O2) pharmacophore site. The six compounds (L1-L6) analyzed here were previously experimentally and now virtually screened for their anti-carbonic anhydrase activity. CONCLUSION: The highest anti-carbonic anhydrase activity was obtained for compound L2, which exhibited excellent bioactivity (% of inhibition = 95%), comparable to acetazolamide (% of inhibition = 89%). The compound L3 represents increased activity as compared to its analogues (L4-L6). The increase of bioactivity from L3 to L4-L6 could be attributed to the presence of a minimum of steric effect of substituents of P=O moiety which plays a decisive template part in the organization of anti-carbonic anhydrase (O1---O2) phramacophore site. Moreover, it is inexpensive, has little side effects and possible inclusions in selective anti-carbonic anhydrase agents design.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Compostos Organofosforados/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Química Física , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Relação Estrutura-Atividade
20.
J Enzyme Inhib Med Chem ; 34(1): 528-531, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30724625

RESUMO

Inhibition of the ß-carbonic anhydrase (CA, EC 4.2.1.1) from pathogenic Candida glabrata (CgNce103) by 1H-indole-2,3-dione 3-[N-(4-sulfamoylphenyl)thiosemicarbazones] 4a-m was investigated. All the compounds were found to be potent inhibitors of CgNce103, with inhibition constants in the range of 6.4-63.9 nM. The 5,7-dichloro substituted derivative 4l showed the most effective inhibition (KI of 6.4 nM) as well as the highest selectivity for inhibiting CgNce103 over the cytosolic human (h) isoforms hCA I and II. A possible binding interaction of compound 4l within the active site of CgNce103 has been proposed based on docking studies.


Assuntos
Candida albicans/enzimologia , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Oxindois/farmacologia , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxindois/síntese química , Oxindois/química , Relação Estrutura-Atividade , Sulfonamidas/química
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