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1.
Yakugaku Zasshi ; 140(9): 1087-1094, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879240

RESUMO

This review, based on my research work, introduces and summarizes the synthesis and characterization of novel cyclic compounds containing aminobenzenesulfonamide. The review discusses the (1) development of sequential Nicholas and Pauson-Khand reactions for the synthesis of unique polyheterocyclic compounds, (2) production of 2-aminobenzenesulfonamide-containing cyclononyne (ABSACN) as a multifunctional click cycloalkyne agent, and (3) improvement of the intramolecular Pauson-Khand reaction of the nitroarene-enyne substrate for the synthesis of cyclopenta[c]piperidine alkaloids. This research work will facilitate the discovery of sulfonamide or sultam-based functional molecules and pharmaceuticals. Thus, I believe that aminobenzenesulfonamide derivatives are versatile and valuable chemical moieties not only in organic syntheses but also in the pharmaceutical industry. If you are interested in the details of this topic, please refer to the original papers.


Assuntos
Sulfonamidas/síntese química , Ciclização , Cicloparafinas/síntese química , Fenômenos de Química Orgânica , Piperidinas/síntese química , Sulfonamidas/química
2.
PLoS One ; 15(7): e0235483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697773

RESUMO

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.


Assuntos
Inibidores Enzimáticos/química , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Piperidinas/farmacologia , Cristalografia por Raios X , Darunavir/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Infecções por HIV/virologia , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , HIV-1/química , HIV-1/patogenicidade , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
3.
Int J Nanomedicine ; 15: 3161-3180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440116

RESUMO

Aim: With the rapid emergence of antibiotic resistance, efforts are being made to obtain new selective antimicrobial agents. Hybridization between quinazolinone and benzenesulfonamide can provide new antimicrobial candidates. Also, the use of nanoparticles can help boost drug efficacy and lower side effects. Materials and Methods: Novel quinazolinone-benzenesulfonamide derivatives 5-18 were synthesized and screened for their antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, MRSA and yeast. The most potent compound 16 was conjugated with copper oxide nanoparticles 16-CuONPs by gamma irradiation (4.5 KGy). Characterization was performed using UV-Visible, TEM examination, XRD patterns and DLS. Moreover, compound 16 was used to synthesize two nanoformulations: 16-CNPs by loading 16 in chitosan nanoparticles and the nanocomposites 16-CuONPs-CNPs. Characterization of these nanoformulations was performed using TEM and zeta potential. Besides, the inhibitory profile against Staphylococcus aureus DNA gyrase was assayed. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs on normal VERO cell line was carried out to determine its relative safety. Molecular docking of 16 was performed inside the active site of S. aureus DNA gyrase. Results: Compound 16 was the most active in this series against all the tested strains and showed inhibition zones and MICs in the ranges of 25-36 mm and 0.31-5.0 µg/mL, respectively. The antimicrobial screening of the synthesized nanoformulations revealed that 16-CuONPs-CNPs displayed the most potent activity. The MBCs of 16 and the nanoformulations were measured and proved their bactericidal mode of action. The inhibitory profile against S. aureus DNA gyrase showed IC50 ranging from 10.57 to 27.32 µM. Cytotoxic evaluation of 16, 16-CNPs and 16-CuONPs-CNPs against normal VERO cell lines proved its relative safety (IC50= 927, 543 and 637 µg/mL, respectively). Molecular docking of 16 inside the active site of S. aureus DNA gyrase showed that it binds in the same manner as that of the co-crystallized ligand, ciprofloxacin. Conclusion: Compound 16 could be considered as a new antimicrobial lead candidate with enhanced activity upon nanoformulation.


Assuntos
Antibacterianos/farmacologia , Quinazolinonas/farmacologia , Sulfonamidas/farmacologia , Tioacetamida/farmacologia , Antibacterianos/química , Bactérias/efeitos dos fármacos , Cobre/farmacologia , DNA Girase/metabolismo , Raios gama , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Quinazolinonas/síntese química , Quinazolinonas/química , Sulfonamidas/síntese química , Sulfonamidas/química , Tioacetamida/síntese química , Tioacetamida/química , Inibidores da Topoisomerase II/farmacologia
4.
J Med Chem ; 63(8): 4315-4333, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32223236

RESUMO

The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ∼50% of human cancers and is considered a highly validated anticancer target. Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5-MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for in vivo studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5-MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.


Assuntos
Desenho de Fármacos , Descoberta de Drogas/métodos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-myc/metabolismo , Relação Estrutura-Atividade
5.
J Med Chem ; 63(6): 3317-3326, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32031797

RESUMO

The design of three dual-tailed sulfonamide series 11a-11g, 14a-14h, and 16a-16e as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds 11a-11g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (Ki in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds 11b-11d and 11g were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/química , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Masculino , Estrutura Molecular , Ligação Proteica , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
6.
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
7.
Eur J Med Chem ; 188: 112021, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901743

RESUMO

A series of novel sulfonamide derivatives bearing pyrrole and pyrrolopyrimidine scaffolds were synthesized and screened as carbonic anhydrase inhibitors. The inhibition activity of the synthesized compounds was evaluated against the cytosolic human carbonic anhydrase isoforms I and II and the transmembranal isoforms IX and XII. Several candidates showed potent inhibitory activity against IX and XII isoforms. Furthermore, ex vivo screening of cytotoxic selectivity and activity of the most potent derivatives were carried out against normal cells (WI38) and cervical cancer cell line (HeLa) under normal and hypoxic conditions using acetazolamide as reference drug. Compound 11b potency was nearly three folds higher in hypoxic than normoxic condition whereas that of compound 11f was nearly four folds higher in hypoxic vs. normoxic HeLa cells. All the screened derivatives exhibited less potency on normal cells (WI38). Molecular docking was carried out to discover the possible binding mode of compounds within the active site of isoform CA IX.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Sulfonamidas/farmacologia , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Anidrase Carbônica IX/química , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/toxicidade , Domínio Catalítico , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Pirimidinas/toxicidade , Pirróis/síntese química , Pirróis/toxicidade , Sulfonamidas/síntese química , Sulfonamidas/toxicidade
8.
J Med Chem ; 63(3): 1281-1297, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935086

RESUMO

Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (DDO-5936), which was previously reported by our group, we conducted a preliminary investigation of the structure-activity relationships and pharmacodynamic evaluations to improve the potency and drug-like properties. Here, our efforts resulted in the currently best inhibitor 18h with improved binding affinity (Kd = 0.5 µM) and cellular inhibitory activity (IC50 = 1.73 µM). Both in vitro and in vivo assays revealed that 18h could efficiently block the Hsp90-Cdc37 interaction to specifically inhibit kinase clients of Hsp90. Furthermore, 18h showed ideal physiochemical properties with favorable stability, leading to an oral efficacy in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Chaperoninas/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Ligação Proteica/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Sítios de Ligação , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chaperoninas/química , Chaperoninas/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
9.
J Med Chem ; 63(3): 1313-1327, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31972088

RESUMO

Emerging and resurging mosquito-borne flaviviruses are an important public health challenge. The increased prevalence of dengue virus (DENV) infection has had a significant socioeconomic impact on epidemic countries. The recent outbreak of Zika virus (ZIKV) has created an international public health emergency because ZIKV infection has been linked to congenital defects and Guillain-Barré syndrome. To develop potentially prophylactic antiviral drugs for combating these acute infectious diseases, we have targeted the host calcium/calmodulin-dependent kinase II (CaMKII) for inhibition. By using CaMKII structure-guided inhibitor design, we generated four families of benzenesulfonamide (BSA) derivatives for SAR analysis. Among these substances, N-(4-cycloheptyl-4-oxobutyl)-4-methoxy-N-phenylbenzenesulfonamide (9) showed superior properties as a lead CaMKII inhibitor and antiviral agent. BSA 9 inhibited CaMKII activity with an IC50 value of 0.79 µM and displayed EC50 values of 1.52 µM and 1.91 µM against DENV and ZIKV infections of human neuronal BE(2)C cells, respectively. Notably, 9 significantly reduced the viremia level and increased animal survival time in mouse-challenge models.


Assuntos
Antivirais/uso terapêutico , Dengue/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas/antagonistas & inibidores , Infecção por Zika virus/tratamento farmacológico , Animais , Antivirais/síntese química , Antivirais/metabolismo , Domínio Catalítico , Vírus da Dengue/efeitos dos fármacos , Desenho de Fármacos , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas/química , Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêutico , Zika virus/efeitos dos fármacos
10.
Med Chem ; 16(1): 24-38, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31218962

RESUMO

More than 10 million people around the world are afflicted by Neglected Tropical Diseases, such as Chagas Disease, Human African Trypanosomiasis, and Leishmania. These diseases mostly occur in undeveloped countries that suffer from a lack of economic incentive, research, and policy for new compound development. Sulfonamide moieties are effective scaffolds present in several compounds that are determinants to treat various diseases, principally neglected tropical diseases. This review article examines the contribution of these scaffolds in medicinal chemistry in the last five years, focusing on three trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei, and Leishmania ssp. We also present perspectives for their use in drug designs in an effort to contribute to new drug development. In addition, we consider the physicochemical parameters, whose molecules all presented according to Lipinski's rule. The correlation between the selective index and LogP was evaluated, showing that sulfonamide derivatives can act differently against each trypanosomatid parasite. Moreover, the approaches of novel drugs and technologies are very important for the eventual drug discovery against trypanosomatid diseases.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Sulfonamidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
11.
Eur J Med Chem ; 186: 111905, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31785819

RESUMO

Farnesyl pyrophosphate synthase (FPPS) is known to participate in a variety of disease-related cell signaling pathway and bisphosphonates (BPs) are served as FPPS inhibitors. However, the high polarity of BPs often induces a series of side effects, limiting their applications. In the present study, novel non-BP FPPS inhibitors were discovered by in silico screening and experimental validation. From the structure-based virtual screening (SBVS) strategy combining molecular docking, pharmacophore and binding affinity prediction, 10 hits with novel scaffolds were filtered. The inhibition activity of hits against FPPS was identified and 7 hits showed comparable or higher inhibition activity than Zoledronate. The hit VS-4 with higher lipophilicity (XlogP = 1.81) and binding affinity (KD = 14.3 ± 2.63 µM) to FPPS was selected for further study on cancer cells with different FPPS expression level. Experimental results revealed that VS-4 could better target the FPPS high-expressing colon LoVo and HCT116 cancer cell lines with IC50 of 51.772 ± 0.473 and 43.553 ± 1.027 µM, respectively, whereas the IC50 value against FPPS low expressing MDA-MB-231 cells was >100 µM. The mechanism of VS-4 against colon cancer cells was investigated by flow cytometry and the results indicated that VS-4 induced cell apoptosis by increasing the intracellular reactive oxygen species (ROS) level. Taken together, the SBVS strategy could be used to discover promising non-BP FPPS inhibitors and the lead compound VS-4 might shed a light on designing more potent inhibitors as novel anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Geraniltranstransferase/antagonistas & inibidores , Piperazinas/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Geraniltranstransferase/metabolismo , Células HCT116 , Humanos , Células MCF-7 , Estrutura Molecular , Piperazinas/líquido cefalorraquidiano , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade , Sulfonamidas/líquido cefalorraquidiano , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas
12.
Med Chem ; 16(1): 104-118, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30398118

RESUMO

OBJECTIVE: Due to the incidence of resistance, a series of sulfonamide-derived 1,2,4- triazoles were synthesized and evaluated. METHOD: The novel sulfonamide-derived 1,2,4-triazoles were prepared starting from commercial acetaniline and chlorosulfonic acid by sulfonylation, aminolysis, N-alkylation and so on. The antimicrobial activity of the synthesized compounds were evaluated in vitro by two-fold serial dilution technique. RESULTS: In vitro antimicrobial evaluation found that 2-chlorobenzyl sulfonamide 1,2,4-triazole 7c exhibited excellent antibacterial activities against MRSA, B. subtilis, B. typhi and E. coli with MIC values of 0.02-0.16 µmol/mL, which were comparable or even better than Chloromycin. The preliminary mechanism suggested that compound 7c could effectively bind with DNA, and also it could bind with human microsomal heme through hydrogen bonds in molecular docking. Computational chemical studies were performed on compound 7c to understand the structural features that are essential for activity. Additionally, compound 7c could generate a small amount of reactive oxygen species (ROS). CONCLUSION: Compound 7c could serve as a potential clinical antimicrobial candidate.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Sulfonamidas/farmacologia , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bacillus/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Saccharomyces cerevisiae/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Triazóis/síntese química , Triazóis/química
13.
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
14.
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
15.
Eur J Med Chem ; 187: 111984, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881455

RESUMO

Targeting the nuclear receptor RORγt is thought to be effective in autoimmune disorders. Tertiary sulfonamide 1 was found to be a potent RORγt inverse agonist previously. However, the high hepatic clearance value limits its druggability. In this study, we designed and synthesized a series of N-sulfonamide-tetrahydroquinolines by molecular modeling and scaffold hopping strategy, aiming at improving the metabolic stabilities. Detailed SAR exploration led to identification of potent RORγt inverse agonists such as 13 with moderate binding affinity and inhibitory activity of Th17 cell differentiation. Binding mode of 13 with RORγt-LBD was revealed by molecular docking. Moreover, 13 showed lower intrinsic clearance in mouse liver microsomes compared with 1 and potent in vivo efficacy and safety in psoriasis models, which can be used as a good starting point for the further optimization.


Assuntos
Descoberta de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Psoríase/tratamento farmacológico , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Transferência Ressonante de Energia de Fluorescência , Imiquimode , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Psoríase/induzido quimicamente , Psoríase/metabolismo , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Th17
16.
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
17.
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 Fármacos , 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
18.
Eur J Med Chem ; 185: 111843, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718943

RESUMO

In the presented work, we report the design and synthesis of different new sets of triazolopyrimidine-based (9a-d) and triazole-based (11a-h, 13a-c, 15a,b, 17a,b and 21a-g) benzenesulfonamides. The newly synthesized sulfonamides were assessed for their inhibitory activities toward four human (h) metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms; hCA I, II, IX and XII. The four examined isoforms were inhibited by the prepared sulfonamides (9a-d, 11a-h, 13a-c, 15a,b, 17a,b and 21a-g) in variable degrees with KIs ranges: 94.4-4953.5 nM for hCA I, 6.9-837.6 nM for hCA II, 3.3-85.0 nM for hCA XI, and 4.4-105.0 nM for hCA XII. In particular, sulfonamides 11e, 21a and 21e emerged as single-digit nanomolar hCA IX and hCA XII inhibitors. Interestingly, triazolopyrimidine-based sulfonamide 9d and triazole-based sulfonamide 21e were found to be the most selective hCA IX inhibitors over hCA I (SI = 100.85 and 210.58, respectively) and hCA II (SI = 18.54 and 38.36, respectively). Thereafter, sulfonamides 9d and 21e were docked into the active site of CAs II, IX and XII, then poses showing the best scoring values and favorable binding interactions were subjected to a MM-GBSA based refinement and, limited to CA IX and XII, to a cycle of 100 ns molecular dynamics.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Simulação de Dinâmica Molecular , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Triazóis/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Pirimidinas/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Triazóis/química
19.
Eur J Med Chem ; 185: 111815, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732252

RESUMO

In order to identify new aromatase enzyme inhibitors, thirty aryl sulfonamide derivatives containing an indole nucleus have been synthesized. The enzyme inhibition assay showed that four compounds inhibit aromatase in the sub-micromolar range. Loading concentrations of these four compounds were afterwards tested for cell viability and cytotoxicity on MCF7 human breast cancer cells, revealing a time- and dose-dependent decrease of active metabolizing cells over the time of the culture (0-72 h), starting from a concentration of 100 µM. Likewise LDH released raised up to 40% at early time of exposures (24 h). Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.


Assuntos
Inibidores da Aromatase/farmacologia , Aromatase/metabolismo , Indóis/farmacologia , Sulfonamidas/farmacologia , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
20.
Eur J Med Chem ; 185: 111825, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31740053

RESUMO

By applying an approach of a "ring with two tails", a series of novel inhibitors possessing high-affinity and significant selectivity towards selected carbonic anhydrase (CA) isoforms has been designed. The "ring" consists of 2-chloro/bromo-benzenesulfonamide, where the sulfonamide group is as an anchor coordinating the Zn(II) in the active site of CAs, and halogen atom orients the ring affecting the affinity and selectivity. First "tail" is a substituent containing carbonyl, carboxyl, hydroxyl, ether groups or hydrophilic amide linkage. The second "tail" contains aryl- or alkyl-substituents attached through a sulfanyl or sulfonyl group. Both "tails" are connected to the benzene ring and play a crucial role in selectivity. Varying the substituents, we designed compounds selective for CA VII, CA IX, CA XII, or CA XIV. Since due to binding-linked protonation reactions the binding-ready fractions of the compound and protein are much lower than one, the "intrinsic" affinities were calculated that should be used to study correlations between crystal structures and the thermodynamics of binding for rational drug design. The "intrinsic" affinities together with the intrinsic enthalpies and entropies of binding together with co-crystal structures were used demonstrate structural factors determining major contributions for compound affinity and selectivity.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Halogenação , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
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