Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.156
Filtrar
1.
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
2.
Nat Commun ; 10(1): 3061, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296858

RESUMO

The importance of axial chirality in enantioselective synthesis has been widely recognized for decades. The practical access to certain structures such as biaryl amino phenols known as NOBINs in enantiopure form, however, still remains a challenge. In drug delivery, the incorporation of axially chiral molecules in systematic screening has also received a great deal of interest in recent years, which calls for innovation and practical synthesis of structurally different axially chiral entities. Herein we present an operationally simple catalytic N-alkylation of sulfonamides using commercially available chiral amine catalysts to deliver two important classes of axially chiral compounds: structurally diverse NOBIN analogs as well as axially chiral N-aryl sulfonamides in excellent enantiopurity. Structurally related chiral sulfonamide has shown great potential in drug molecules but enantioselective synthesis of them has never been accomplished before. The practical catalytic procedures of our methods also bode well for their wide application in enantioselective synthesis.


Assuntos
Aminofenóis/síntese química , Sistemas de Liberação de Medicamentos , Sulfonamidas/síntese química , Alquilação , Catálise , Química Farmacêutica/métodos , Estrutura Molecular , Estereoisomerismo
3.
AAPS PharmSciTech ; 20(5): 210, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161269

RESUMO

Dorzolamide HCl (DRZ) ophthalmic drop is one of the most common glaucoma medications which rapidly eliminates after instillation leading to short residence time of the drug on cornea. The purpose of the present study is to develop a pH-triggered in situ gel system for ophthalmic delivery of DRZ for treatment of ocular hypertension. In this study, a 32 full factorial design was used for preparation of in situ gel formulations using different levels of Carbopol® and hydroxyl propyl methyl cellulose (HPMC). Rheological behavior, in vitro drug release, ex vivo corneal permeability, and IOP-lowering activity were investigated. DRZ solution (2% w/v) containing of 0.1% (w/v) Carbopol® and 0.1% (w/v) HPMC was selected as the optimal formulation considering its free flow under non-physiological conditions (initial pH and 25 ± 2°C) and transition to appropriate gel form under physiological circumstance (pH 7.4 and 34°C). This in situ gel presented the mucoadhesive property. Ex vivo corneal permeability of this combined solution was similar to those of DRZ solution. The developed formulation compared to the marketed drop (Biosopt®) and DRZ 2% solution had a better performance in intraocular pressure activity. The efficiency and long duration of IOP reduction could be due to the prolonged residence time of the in situ gel. The presence of Carbopol® as a pH triggered and mucoadhesive polymer causes to attach to the ocular mucosal surface for a long term.


Assuntos
Resinas Acrílicas/farmacocinética , Anti-Hipertensivos/farmacocinética , Portadores de Fármacos/farmacocinética , Derivados da Hipromelose/farmacocinética , Sulfonamidas/farmacocinética , Tiofenos/farmacocinética , Resinas Acrílicas/administração & dosagem , Resinas Acrílicas/síntese química , Administração Oftálmica , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/síntese química , Córnea/efeitos dos fármacos , Córnea/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos , Géis , Glaucoma/tratamento farmacológico , Glaucoma/metabolismo , Concentração de Íons de Hidrogênio , Derivados da Hipromelose/administração & dosagem , Derivados da Hipromelose/síntese química , Pressão Intraocular/efeitos dos fármacos , Pressão Intraocular/fisiologia , Masculino , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/síntese química , Soluções Oftálmicas/farmacocinética , Coelhos , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese química , Suínos , Tiofenos/administração & dosagem , Tiofenos/síntese química
4.
Eur J Med Chem ; 176: 50-60, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31096118

RESUMO

New sulfonamides 5/6 derived from 4-methoxyacetophenone 1 were synthesized by N-sulfonation reaction of ammonia (3) and aminopyrimidinone (4) with its sulfonyl chloride derivative 2. Sulfonamides 5 and 6 were used as precursors of two new series of chalcones 8a-f and 9a-f, which were obtained through Claisen-Schmidt condensation with aromatic aldehydes 7a-f. Compounds 5/6, 8a-d, 8f, 9a-d, and 9f were screened by the US National Cancer Institute (NCI) at 10 µM against sixty different human cancer cell lines (one-dose trial). Chalcones 8b and 9b satisfied the pre-determined threshold inhibition criteria and were selected for screening at five different concentrations (100, 10, 1.0, 0.1, and 0.01 µM). Compound 8b exhibited remarkable GI50 values ranging from 0.57 to 12.4 µM, with cytotoxic effects being observed in almost all cases, especially against the cell lines K-562 of Leukemia and LOX IMVI of Melanoma with GI50 = 0.57 and 1.28 µM, respectively. Moreover, all compounds were screened against Mycobacterium tuberculosis H37Rv, chalcones 8a-c and 9a-c were the most active showing MIC values between 14 and 42 µM, and interestingly they were devoid of antibacterial activity against Mycobacterium smegmatis and Staphylococcus aureus. These antituberculosis hits showed however low selectivity, being equally inhibitory to M. tuberculosis and mammalian T3T cells. The chalcone-sulfonamide hybrids 8a-f and 9a-f resulted to be appealing cytotoxic agents with significant antituberculosis activity.


Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Chalconas/farmacologia , Sulfonamidas/farmacologia , Células 3T3 , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/toxicidade , Linhagem Celular Tumoral , Chalconas/síntese química , Chalconas/química , Chalconas/toxicidade , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/toxicidade
5.
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
6.
Eur J Med Chem ; 177: 198-211, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136894

RESUMO

A series of 3-amino-substituted rutacecarpine derivatives were synthesized to identify novel multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD). Biological evaluation showed that most of the synthesized compounds inhibited butyrylcholinesterase (BuChE) and exerted antioxidant effects. Among the synthesized compounds, 6n was subjected to further biological evaluation. Lineweaver-Burk plotting and molecular modeling illustrated that 6n bound simultaneously to the peripheral anionic site (PAS) and catalytic sites (CAS) of BuChE. Furthermore, 6n modulated Aß aggregation; chelated biometals; presented good absorption, distribution, metabolism, excretion, and toxicity properties; and showed remarkable neuroprotective activity. Previous research has shown that the optimized compound 6n has considerable potential for development as an MTDL for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Substâncias Protetoras/farmacologia , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/química , Quelantes/farmacocinética , Quelantes/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacocinética , Desenho de Drogas , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Substâncias Protetoras/síntese química , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Multimerização Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética
7.
Eur J Med Chem ; 174: 252-264, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31048140

RESUMO

The superfamily of adenylate-forming enzymes all share a common chemistry. They activate a carboxylate group, on a specific substrate, by catalyzing the formation of a high energy mixed phosphoanhydride-linked nucleoside intermediate. Members of this diverse enzymatic family play key roles in a variety of metabolic pathways and therefore many have been regarded as drug targets. A generic approach to inhibit such enzymes is the use of non-hydrolysable sulfur-based bioisosteres of the adenylate intermediate. Here we compare the activity of compounds containing a sulfamoyl and sulfonamide linker respectively. An improved synthetic strategy was developed to generate inhibitors containing the latter that target isoleucyl- (IleRS) and seryl-tRNA synthetase (SerRS), two structurally distinct representatives of Class I and II aminoacyl-tRNA synthetases (aaRSs). These enzymes attach their respective amino acid to its cognate tRNA and are indispensable for protein translation. Evaluation of the ability of the two similar isosteres to inhibit serRS revealed a remarkable difference, with an almost complete loss of activity for seryl-sulfonamide 15 (SerSoHA) compared to its sulfamoyl analogue (SerSA), while inhibition of IleRS was unaffected. To explain these observations, we have determined a 2.1 Šcrystal structure of Klebsiella pneumoniae SerRS in complex with SerSA. Using this structure as a template, modelling of 15 in the active site predicts an unfavourable eclipsed conformation. We extended the same modelling strategy to representative members of the whole adenylate-forming enzyme superfamily, and were able to disclose a new classification system for adenylating enzymes, based on their protein fold. The results suggest that, other than for the structural and functional orthologues of the Class II aaRSs, the O to C substitution within the sulfur-sugar link should generally preserve the inhibitory potency.


Assuntos
Adenosina/análogos & derivados , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Inibidores Enzimáticos/química , Sulfonamidas/química , Adenosina/síntese química , Aminoacil-tRNA Sintetases/química , Aminoacilação , Bacillus subtilis/enzimologia , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Klebsiella pneumoniae/enzimologia , Modelos Moleculares , Mycobacterium tuberculosis/enzimologia , Pectobacterium chrysanthemi/enzimologia , Sulfolobus/enzimologia , Sulfonamidas/síntese química , Thermus thermophilus/enzimologia
8.
Talanta ; 201: 111-118, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122400

RESUMO

Thiophenols as high toxic environmental pollutants are poisonous for animals and aquatic organisms. Therefore, it is indispensable to monitor thiophenols in the environment. Herein, a novel near-infrared fluorescent probe was developed for the detection of thiophenols, which was easily prepared by one-step coupling of 2,4-dinitrobenzenesulfonyl chloride with Nile blue. The probe showed a significant near infrared (∼675 nm) fluorescence "turn-on" response to thiophenols with some good features including chromogenic reaction, high sensitivity and selectivity, fast response, near-infrared emission along with low detection limit (1.8 nM). The probe was employed to rapidly and visually determine thiophenols in several industrial wastewaters with good recoveries (90-110%). Moreover, this probe has been demonstrated good capability for imaging thiophenol in HeLa cells.


Assuntos
Corantes Fluorescentes/química , Oxazinas/química , Fenóis/análise , Compostos de Sulfidrila/análise , Sulfonamidas/química , Águas Residuárias/análise , Poluentes Químicos da Água/análise , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Limite de Detecção , Microscopia Confocal/métodos , Modelos Químicos , Oxazinas/síntese química , Oxazinas/efeitos da radiação , Oxazinas/toxicidade , Espectrometria de Fluorescência/métodos , Sulfonamidas/síntese química , Sulfonamidas/efeitos da radiação , Sulfonamidas/toxicidade
9.
J Enzyme Inhib Med Chem ; 34(1): 1030-1040, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31074303

RESUMO

A series of sulphonamide benzoquinazolinones 5-18 was synthesized and evaluated for cytotoxic activity against MDA-MB-231 cell line. The compounds showed IC50 ranging from 0.26 to 161.49 µM. The promising compounds were evaluated for their inhibitory profile against epidermal growth factor (EGFR) and HER2 enzymes. Compound 10 showed more potent activity on both EGFR and HER2 than erlotinib (IC50 3.90 and 5.40 µM versus 6.21 and 9.42 µM). The pro-apoptotic activity of 10 was evaluated against caspase-3, Bax, B-cell lymphoma protein 2 (Bcl-2) expression levels, and cell cycle analysis. Compound 10 increased the level of caspase-3 by 10 folds, Bax level by 9 folds, decreased the level of the Bcl-2 by 0.14 and arrested the cell cycle in the G2/M phase. The radio-sensitizing activity of 10 was measured using a single dose of 8 Gy gamma radiation (IC50 decreased from 0.31 to 0.22 µM). Molecular docking was performed on EGFR and HER2 receptors.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Radiossensibilizantes/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/síntese química , Quinazolinonas/química , Radiossensibilizantes/síntese química , Radiossensibilizantes/química , Receptor ErbB-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
10.
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
11.
Eur J Med Chem ; 172: 48-61, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30939353

RESUMO

As the mutant estrogen receptor (ER) continues to be characterized, breast cancer is becoming increasingly difficult to cure when treated with hormone therapy. In this regard, a strategy to selectively and effectively degrade the ER might be an effective alternative to endocrine therapy for breast cancer. In a previous study, we identified a novel series of 7-oxabicyclo[2.2.1]heptene sulfonamide (OBHSA) compounds as full ER antagonists while lacking the prototypical ligand side chain that has been widely used to induce antagonism of ERα. Further crystal structure studies and phenotypic assays revealed that these compounds are selective estrogen receptor degraders (SERDs) with a new mechanism of action. However, from a drug discovery point of view, there still is room to improve the potency of these OBHSA compounds. In this study, we have developed new classes of SERDs that contain the OBHSA core structure and different side chains, e.g., basic side chains, long alkyl acid side chains, and glycerol ether side chains, to simply mimic the degrons of proteolysis targeting chimera (PROTAC) and then investigated the structure-activity relationships of these PROTAC-like hybrid compounds. These novel SERDs could effectively inhibit MCF-7 cell proliferation and demonstrated good ERα degradation efficacy. Among the SERDs, compounds 17d, 17e and 17g containing a basic side chain with a N-trifluoroethyl substituent and a para methoxyl group at the phenyl group of the sulfonamide turned out to be the best candidates for ER degraders. A further docking study of these compounds with ERα elucidates their structure-activity relationships, which provides guidance to design new PROTAC degrons targeting ER for breast cancer therapy. Lastly, easy modification of these PROTAC-like SERDs enables further fine-tuning of their pharmacokinetic properties, including oral availability.


Assuntos
Antineoplásicos/farmacologia , Receptores Estrogênicos/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Estrutura Molecular , Receptores Estrogênicos/metabolismo , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
12.
Eur J Med Chem ; 171: 372-382, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30928709

RESUMO

Two new series of 1,2-benzisothiazol-3(2H)-one-1,1-dioxide derivatives containing either five membered heterocyclic rings or aryl hydrazones were synthesized and evaluated for their in vitro COX-1/COX-2 inhibitory activity. In vivo anti-inflammatory evaluation revealed that benzenesulfonamides bearing pyrazole moiety 19, 20 and its cyclized form 23 exhibited the highest anti-inflammatory activity with comparable potency to celecoxib. Furthermore, the ulcerogenic activity evaluation showed that compounds 19, 20 and 23 exerted the minimal ulcer index in comparison to indomethacin as a reference drug. Docking studies of the most selective COX-2 derivatives were also carried out against COX-2 active site. Benzenesulfonamide derivatives 19 and 20 displayed higher predicted binding affinities inside the COX-2 active site. Molecular modelling simulation and drug likeness studies showed good agreement with the obtained biological evaluation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Sulfonamidas/farmacologia , Triazóis/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/química , Relação Dose-Resposta a Droga , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Triazóis/síntese química , Triazóis/química
13.
Org Lett ; 21(7): 2402-2407, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30900906

RESUMO

An efficient protocol to construct ß-d-gluco-/galactosaminosyl linkages was established using nonparticipating and strong electron-withdrawing C-2-2,4-dinitrobenzenesulfonamide (DNsNH)-directed SN2-like glycosylation of glycosyl ortho-hexynylbenzoates. The reaction is applicable to a wide range of O-, N-, and C-nucleophiles and features convenient conversion of DNsNH into AcNH in high yield under mild conditions. Oligomerization-ready trisaccharide, composed of ß-d-(1→3)-glucosamino residues, has been achieved, setting a solid foundation for the synthesis of oligosaccharides associated with Neisseria meningitidis capsular polysaccharide.


Assuntos
Amino Açúcares/síntese química , Derivados de Benzeno/síntese química , Oligossacarídeos/síntese química , Sulfonamidas/síntese química , Trissacarídeos/síntese química , Amino Açúcares/química , Derivados de Benzeno/química , Glicosilação , Estrutura Molecular , Oligossacarídeos/química , Sulfonamidas/química , Trissacarídeos/química
14.
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
15.
Med Chem ; 15(6): 676-684, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799793

RESUMO

BACKGROUND: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor. OBJECTIVE: The goal of this research effort was to identify and optimize synthetic ligands for RORα starting from the known LXR agonist T0901317. METHODS: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays. Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.) and per oral (p.o.)dosing. RESULTS: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by varying substitution patterns throughout the molecule proved challenging. CONCLUSION: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of RORα in vitro and in vivo.


Assuntos
Agonismo Inverso de Drogas , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/farmacologia , Animais , Humanos , Hidrocarbonetos Fluorados/química , Ligantes , Receptores X do Fígado/agonistas , Camundongos , Estrutura Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Ratos , Relação Estrutura-Atividade , Sulfonamidas/agonistas , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Células Th17
16.
Pak J Pharm Sci ; 32(1): 61-68, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30772791

RESUMO

In the current research work, a series of new N-(alkyl/aralkyl)-N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamides has been synthesized by reacting 1,4-benzozzdioxan-6-amine (1) with 4-chlorobenzenesulfonyl chloride (2) to yield N-(2,3-dihydro-1,4-benzodioxan-6-yl)-4-chlorobenzenesulfonamide (3) which was further reacted with different alkyl/aralkyl halides (4a-n) to afford the target compounds (5a-n). Structures of the synthesized compounds were confirmed by IR, 1H-NMR, EI-MS spectral techniques and CHN analysis data. The results of enzyme inhibition showed that the molecules, N-2-phenethyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5j) and N-(1-butyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5d), exhibited moderate inhibitory potential against acetylcholinesterase with IC50 values 26.25±0.11 µM and 58.13±0.15 µM respectively, whereas, compounds N-benzyl-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5i) and N-(pentane-2-yl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-chlorobenzenesulfonamide (5f) showed moderate inhibition against α-glucosidase enzyme as evident from IC50 values 74.52±0.07 and 83.52±0.08 µM respectively, relative to standards Eserine having IC50 value of 0.04±0.0001 µM for cholinesterases and Acarbose having IC50 value 38.25±0.12 µM for α-glucosidase, respectively.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/enzimologia , Butirilcolinesterase/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Espectrometria de Massas , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo
17.
Chemistry ; 25(28): 6928-6940, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-30807667

RESUMO

Two novel solid reagents-1-sulfonimidoyl- and 1-sulfamimidoyl-3-methylimidazolium derivatives-for the synthesis of sulfonimidamides and imidosulfuric diamides, respectively, were developed. It is shown that these reagents are very effective in substitution reactions with various N- and O-nucleophiles; therefore, they significantly extend the accessibility to the chemical space covered by organosulfur(VI) compounds with S=N bonds. In addition, previously unknown imidosulfuric diamides with free imino nitrogen groups were prepared, and their physical and chemical properties were characterized (including molecular geometry, pKa , Log P, microsomal stability, and reactivity towards typical electrophiles). Similar to other organosulfur(VI) derivatives with S=N bonds, these compounds can be considered as promising bioisosteres of amides, ureas, or sulfonamides.


Assuntos
Diamida/síntese química , Imidas/síntese química , Sulfonamidas/síntese química , Compostos de Enxofre/síntese química , Animais , Técnicas de Química Sintética/métodos , Diamida/química , Diamida/metabolismo , Imidas/química , Imidas/metabolismo , Indicadores e Reagentes , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Sulfonamidas/química , Sulfonamidas/metabolismo , Compostos de Enxofre/química , Compostos de Enxofre/metabolismo , Difração de Raios X
18.
J Enzyme Inhib Med Chem ; 34(1): 451-458, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734605

RESUMO

A series of organometallic acylhydrazones was prepared, incorporating Re(CO)3, Mn(CO)3 and ferrocenyl moieties, which were subsequently reacted with amino-sulfonamides in order to obtain carbonic anhydrase (CA, EC 4.2.1.1) inhibitors possessing organometallic moieties in their molecules. The new derivatives were investigated as inhibitors of four human (h) CA isoforms with pharmaceutical applications, such as the cytosolic hCA I, II and VII and the mitochondrial hCA VA. An interesting inhibitory profile against these isoforms was obtained, with some of these metal complexes acting as subnanomolar or low nanomolar inhibitors. They were also thoroughly characterised from the chemical point of view, making them of interest for further developments in the field of metal complexes of sulfonamides with CA inhibitory action.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Hidrazonas/farmacologia , Compostos Organometálicos/farmacologia , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Hidrazonas/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Compostos Organometálicos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
19.
Chem Biodivers ; 16(4): e1800646, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706997

RESUMO

A new series of (sulfonamido)propanamides (6a1-6a13, 6b1-6b15, 7c1-7c5, 6d1-6d5, 6e1-6e6) was designed and synthesized. All the synthesized compounds were characterized by NMR and mass spectrometry. The target compounds were evaluated for their in vitro cytotoxic activity against hepatocellular carcinoma (HepG2), fibrosarcoma (HT-1080), mouth epidermal carcinoma (KB), and breast adenocarcinoma (MCF-7) cell lines with the sulforhodamine B (SRB) assay, with gemcitabine and mitomycin C as positive controls. Most of these compounds exhibit a more potent cytotoxic effect than the positive control group on various cancer cell lines and the most potent compound, 6a7, shows the IC50 values of 29.78±0.516 µm, 30.70±0.61 µm, and 64.89±3.09 µm in HepG2, HT-1080, KB, and MCF-7 cell lines, respectively. Thus, these compounds with potent cytotoxic activity have potential for development as new chemotherapy agents.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Propionatos/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Propionatos/síntese química , Propionatos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
20.
J Enzyme Inhib Med Chem ; 34(1): 510-518, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30688123

RESUMO

Carbonic anhydrases (CAs) are ubiquitous metalloenzymes, which started to be investigated in detail in pathogenic, as well as non-pathogenic species since their pivotal role is to accelerate the physiological CO2 hydration/dehydration reaction significantly. Here, we propose the marine unicellular diatom Phaeodactylum tricornutum as a model organism for testing the membrane penetrability of CA inhibitors (CAIs). Seven inhibitors belonging to the sulphonamide type and possessing a diverse scaffold have been explored for their in vitro inhibition of the whole diatom CAs and the in vivo inhibitory effect on the growth of P. tricornutum. Interesting, inhibition of growth was observed, in vivo, demonstrating that this diatom is a good model for testing the cell wall penetrability of this class of pharmacological agents. Considering that many pathogens are difficult and dangerous to grow in the laboratory, the growth inhibition of P. tricornutum with different such CAIs may be subsequently used to design inhibition studies of CAs from pathogenic organisms.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Diatomáceas/efeitos dos fármacos , Sulfonamidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/isolamento & purificação , Permeabilidade da Membrana Celular/efeitos dos fármacos , Diatomáceas/enzimologia , Diatomáceas/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA