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1.
Bioorg Chem ; 77: 101-105, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29353727

RESUMO

Herein, we report that acridine intermediates 5 were obtained from the reduction of nitro acridine derivatives 4, which were synthesized via condensation of dimedone, p-nitrobenzaldehyde with 4-amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide, respectively. Then acridine sulfonamide/carboxamide (7a-i) compounds were synthesized by reaction of amino acridine 5 with sulfonyl chlorides and carbamoyl chlorides. The new compounds were characterized by melting points, FT-IR, 1H NMR, 13C NMR and HRMS analyzes. The evaluation of in vitro test of the synthesized compounds against hCA I, II, IV and VII showed that some of them are potent inhibitors. Among them, compound 7e showed the most potent activity against hCA II with a KI of 7.9 nM.


Assuntos
Acridinas/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/farmacologia , Tiadiazóis/farmacologia , Acridinas/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IV/antagonistas & inibidores , Anidrase Carbônica IV/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Anidrases Carbônicas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tiadiazóis/síntese química , Tiadiazóis/química
2.
Bioorg Chem ; 70: 245-255, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28153340

RESUMO

A novel series of tacrine derivatives containing sulfonamide group were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized tacrine-sulfonamides (VIIIa-o) exhibited inhibitory activity on both cholinesterases. VIIIg showed the highest inhibitory activity on AChE IC50=0.009µM. This value is 220-fold greater than that of galantamine (IC50=2.054µM) and 6-fold greater than tacrine (IC50=0.055µM). VIIIf displayed the strongest inhibition of BuChE (IC50=2.250µM), which is close to donepezil (IC50=2.680µM) and 8-fold greater than that of galantamine (IC50=18.130µM) Furthermore, all of the synthesized tacrine derivatives showed higher inhibition of BuChE than that of galantamine. In addition, the cupric reducing antioxidant capacities (CUPRAC) and ABTS cation radical scavenging abilities of the synthesized compounds were investigated for the antioxidant activity. Among them, VIIIb (IC50=94.390±2.310µM) showed significantly better ABTS cation radical scavenging ability than all of the new synthesized compounds.


Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Tacrina/análogos & derivados , Tacrina/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/enzimologia , Animais , Antioxidantes/síntese química , Benzotiazóis/química , Compostos de Bifenilo/química , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Electrophorus , Radicais Livres/química , Cavalos , Humanos , Micro-Ondas , Picratos/química , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Ácidos Sulfônicos/química , Tacrina/síntese química
3.
Bioorg Med Chem ; 24(16): 3548-55, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27298005

RESUMO

4-Amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide was condensed with cyclic-1,3-diketones (dimedone and cyclohexane-1,3-dione) and aromatic aldehydes under microwave irradiation, leading to a series of acridine-acetazolamide conjugates. The new compounds were investigated as inhibitors of carbonic anhydrases (CA, EC 4.2.1.1), and more precisely cytosolic isoforms hCA I, II, VII and membrane-bound one hCA IV. All investigated isoforms were inhibited in low micromolar and nanomolar range by the new compounds. hCA IV and VII were inhibited with KIs in the range of 29.7-708.8nM (hCA IV), and of 1.3-90.7nM (hCA VII). For hCA I and II the KIs were in the range of 6.7-335.2nM (hCA I) and of 0.5-55.4nM (hCA II). The structure-activity relationships (SAR) for the inhibition of these isoforms with the acridine-acetazolamide conjugates reported here were delineated.


Assuntos
Acetazolamida/química , Acetazolamida/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Isoenzimas/efeitos dos fármacos , Micro-Ondas , Inibidores da Anidrase Carbônica/química , Humanos , Análise Espectral/métodos
4.
J Enzyme Inhib Med Chem ; 31(sup2): 63-69, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27237188

RESUMO

Novel sulfaguanidines incorporating acridine moiety were synthesized by the reaction of cyclohexane-1,3-dione, sulfaguanidine, and aromatic aldehydes. Synthesis of these compounds was performed in water at room temperature, and their structures were confirmed by using spectral analysis (IR, 1H-NMR, 13C-NMR, and HRMS). Human carbonic anhydrase isoenzymes (hCA I and II) were purified from erythrocyte cells with affinity chromatography. hCA I was purified 83.40-fold with a specific activity, 1060.9 EU mg protein-1, and hCA II was purified 262.32-fold with a specific activity, 3336.8 EU mg protein-1. The inhibitory effects of newly synthesized sulfaguanidines and acetazolamide, (AAZ) as a control compound, on hydratase and esterase activities of these isoenzymes have been studied in vitro. Synthesized compounds have moderate inhibition potentials on hCA I and hCA II isoenzymes. IC50 values of compounds for esterase activity are in the range of 118.4 ± 7.0 µM-257.5 ± 5.2 µM for hCA I and 86.7 ± 3.0 µM-249.4 ± 10.2 µM for hCA II, respectively.


Assuntos
Acridinas/farmacologia , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Sulfaguanidina/farmacologia , Acridinas/química , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Cromatografia de Afinidade , Relação Dose-Resposta a Droga , Eritrócitos/enzimologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade , Sulfaguanidina/química
5.
Bioorg Med Chem ; 23(20): 6573-80, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26422787

RESUMO

By using a multi component reaction system (MCR), nitro acridine sulfonamides were obtained from cyclic-1,3-diketones, 4-aminobenzene sulfonamide and aromatic aldehydes. Some novel acridine bis-sulfonamides 6a-l were then synthesized by the reaction between sulfonyl chlorides and the novel amino-acridine sulfonamides 5a and 5b, obtained by reduction of nitro-acridine sulfonamide derivatives 4a and 4b. The newly synthesized compounds were investigated as inhibitors of 4 human carbonic anhydrase isoforms (hCA, EC 4.2.1.1). Several of the compounds showed low micromolar inhibition against the medically relevant isoforms hCA I, II, IX, and XII.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
6.
Bioorg Med Chem ; 21(18): 5799-805, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23910989

RESUMO

4-Amino-N-(4-sulfamoylphenyl)benzamide was synthesized by reduction of 4-nitro-N-(4-sulfamoylphenyl)benzamide and used to synthesize novel acridine sulfonamide compounds, by a coupling reaction with cyclic-1,3-diketones and aromatic aldehydes. The new compounds were investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), and more precisely the cytosolic isoforms hCA I, II and VII. hCA I was inhibited in the micromolar range by the new compounds (KIs of 0.16-9.64 µM) whereas hCA II and VII showed higher affinity for these compounds, with KIs in the range of 15-96 nM for hCA II, and of 4-498 nM for hCA VII. The structure-activity relationships for the inhibition of these isoforms with the acridine-sulfonamides reported here were also elucidated.


Assuntos
Acridinas/química , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/química , Sulfonamidas/química , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/metabolismo , Humanos , Cinética , Ligação Proteica , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
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