RESUMO
Glutathione reductase (GR) is a crucial antioxidant enzyme which is responsible for the maintenance of antioxidant GSH molecule. Antimalarial effects of some chemical molecules are attributed to their inhibition of GR, thus inhibitors of this enzyme are expected to be promising candidates for the treatment of malaria. In this work, GR inhibitory properties of N-Methylpyrrole derivatives are reported. It was found that all compounds have better inhibitory activity than the strong GR inhibitor N,N-bis(2-chloroethyl)-N-nitrosourea, especially three molecules, 8 m, 8 n, and 8 q, were determined to be the most powerful among them. Findings of our study indicates that these Schiff base derivatives are strong GR inhibitors which can be used as leads for designation of novel antimalarial candidates.
Assuntos
Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutationa Redutase/antagonistas & inibidores , Malária/tratamento farmacológico , Pirróis/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glutationa Redutase/metabolismo , Malária/metabolismo , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
This study represents an expansion of the application of catalysis in air through conventional coupling and free radical processes. A reactive free aryl radical intermediate was generated via the oxidation of an activated Ar-NH-NH2 bond by air as a simple and readily available oxidant. For this purpose, the usability of phenylhydrazine and phenylhydrazine hydrochloride salt reagents for the direct arylation of pyrrole with aryl radicals was investigated. The facile coupling of N-methylpyrrole with aryl radicals was easily applied for the convenient direct synthesis of C-2 arylated pyrroles without a transition-metal catalyst.
RESUMO
The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with some 3,4-dihydroxypyrrolidine-2,5-dione and 3,5-dihydroxybenzoic acid derivatives, were investigated by using the esterase assay, with 4-nitrophenyl acetate (4-NPA) as substrate. Compounds 10-13 showed KI values in the range of 112.7-441.5 µM for hCA I and of 3.5-10.76 µM against hCA II, respectively. These hydroxyl group containing compounds generally were competitive inhibitors. Some hydroxyl group containing compounds investigated here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide acetazolamide, and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents.
Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Hidroxibenzoatos/química , Hidroxibenzoatos/farmacologia , Resorcinóis/química , Resorcinóis/farmacologia , Succinimidas/farmacologia , Anidrase Carbônica I/isolamento & purificação , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/isolamento & purificação , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Hidroxibenzoatos/síntese química , Estrutura Molecular , Resorcinóis/síntese química , Relação Estrutura-Atividade , Succinimidas/síntese química , Succinimidas/químicaRESUMO
Several 1,4-bis(indolin-1-ylmethyl)benzene-based compounds containing substituents such as five, six and seven cyclic derivatives on indeno part (9a-c) were prepared and tested against two members of the pH regulatory enzyme family, carbonic anhydrase (CA). The inhibitory potencies of the compounds at the human isoforms hCA I and hCA II targets were analyzed and KI values were calculated. KI values of compounds for hCA I and hCA II human isozymes were measured in the range of 39.3-42.6µM and 0.17-0.29µM, respectively. The structurally related compound indole was also tested in order to understand the structure-activity relationship. Most of the compounds showed good CA inhibitory efficacy. In silico docking studies of these derivatives within hCA I and II were also carried out and results are supported the kinetic assays.
Assuntos
Derivados de Benzeno/química , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica I/antagonistas & inibidores , Inibidores da Anidrase Carbônica/síntese química , Indóis/química , Derivados de Benzeno/metabolismo , Sítios de Ligação , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/metabolismo , Domínio Catalítico , Humanos , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Here we synthesized four novel indole conduritol derivatives 1-4 for the first time in the literature and probed their biological activities with the α and ß-glucosidases. The compounds showed quite effective glucosidase inhibitory action. IC(50) values of the compounds were compared with the known glucosidase inhibitor acarbose and it was determined that newly synthesized indole conduritols had more powerful effect against ß-glucosidase in addition to exhibiting moderate influence against α-glucosidase. Our molecules thus constitute an important starting point for the design and exploitation of novel glucosidase inhibitors since glucosidase inhibitors have widespread applications in the treatment of diabetes, viral infections, lysosomal storage diseases and cancers.
Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Indóis/farmacologia , Inositol/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/metabolismo , Indóis/síntese química , Indóis/química , Inositol/análogos & derivados , Inositol/síntese química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Several 5,10-dihydroindeno[1,2-b]indole derivatives incorporating methoxy, hydroxyl, and halogen (F, Cl, and Br) moieties on the indene fragment of the molecule were prepared and tested against five carbonic anhydrase (CA, EC 4.2.1.1) isoforms. The inhibitory potencies of these compounds against the human (h) isoforms hCA I, II, IV, VI and bovine (b) isoform bCA III were assessed. Most of them exhibited low micromolar inhibition of these enzymes. K(I) values of these compounds against hCA I and hCA II were in the range of 2.14-16.32 µM, and 0.34-2.52 µM, respectively. Isozyme hCA IV was inhibited with K(I)-s in the range of 0.435-5.726 µM, while hCA VI with K(I)-s of 1.92-12.84 µM bCA III was inhibited with K(I)-s in the range of 2.13-17.83 µM. The structurally related compounds, 1,2-dimethoxybenzene, catechol and indole were also tested in order to understand the structure activity relationship. In silico docking studies of some derivatives within the active site of hCA I and II were also carried out in order to rationalize the inhibitory properties of these compounds and understand their inhibition mechanism.
Assuntos
Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Indóis/química , Indóis/farmacologia , Animais , Bovinos , Humanos , Modelos Moleculares , Isoformas de Proteínas/metabolismo , Relação Estrutura-AtividadeRESUMO
Carbonic anhydrases (CA) catalyze activated ester hydrolysis in addition to the hydration of CO(2) to bicarbonate. They also show phosphatase activity with 4-nitrophenyl phosphate as substrate but not sulfatase with the corresponding sulfate. Here we prove that the enzyme is catalyzing the synthesis of cyclic diols from sulfate esters. 5-, 6- and 8-membered ring cyclic sulfates incorporating a neighboring secondary alcohol moiety were treated with CA II and yielded the corresponding cyclic diols. Inhibitory properties of obtained cyclic and original sulfate esters were then investigated on human carbonic anhydrase I (hCA I), hCA II, hCA IV and hCA VI (h = human isoform). K(I)-s of these compounds ranged between 32.7-423 µM against hCA I, 2.13-32.4 µM against hCA II, 13.7-234 µM against hCA IV and 76-278 µM against CA VI, respectively. The sulfatase activity of CA with such esters is amazing considering the fact that 4-nitrophenyl-sulfate is not a substrate of these enzymes.
Assuntos
Álcoois/metabolismo , Anidrases Carbônicas/metabolismo , Ésteres/metabolismo , Álcoois/química , Biocatálise , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Ésteres/química , Ésteres/farmacologia , Humanos , Hidrólise , Relação Estrutura-AtividadeRESUMO
Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) are a class of pharmaceuticals used as antiglaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, gastric and duodenal ulcers, neurological disorders, or osteoporosis. We report here the inhibitory capacities of some organic nitrates against two human (hCA) isozymes, hCA I and hCA II. The IC(50) values of compounds 1-12 against hCA I ranged between 7.13mM and 124mM, and against hCA II between 65.1microM and 0.79mM. Nitrate esters are thus interesting hCA I and II inhibitors, and might be used as leads for generating enzyme inhibitors eventually targeting other isoforms which have not been assayed yet for their interactions with such agents.
Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Ésteres/química , Óxido Nítrico/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Humanos , Isoenzimas/antagonistas & inibidores , Masculino , Modelos Biológicos , Óxido Nítrico/metabolismo , Relação Estrutura-AtividadeRESUMO
An efficient synthesis of 5,10-dihydroindeno[1,2-b]indoles (3a-t) containing substituents such as methoxy, hydroxyl, and halogen (F, Cl, and Br) on indeno part was described. Antioxidant and radical scavenging activities of synthesized compounds (3a-t) were determined by various in vitro assays such as 1,1-diphenyl-2-picryl-hydrazyl free radicals (DPPH(*)), 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid radicals (ABTS(*+)), N,N-dimethyl-p-phenylenediamine dihydrochloride radicals (DMPD(*+)), and superoxide anion radicals (O(2)(*-)) scavenging, reducing ability determination by the Fe(3+)-Fe(2+) and Cu(2+)-Cu(+) (CUPRAC method) transformation methods, H(2)O(2) scavenging, and ferrous ion (Fe(2+)) chelating activities. Moreover, these activities were compared to synthetic and standard antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), alpha-tocopherol, and trolox. The results showed that the synthesized compounds (3a-t) had effective antioxidant power.
Assuntos
Antioxidantes/química , Antioxidantes/farmacologia , Indóis/química , Indóis/farmacologia , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Radicais Livres/metabolismo , Peróxido de Hidrogênio/metabolismo , Quelantes de Ferro/química , Quelantes de Ferro/farmacologia , Estrutura MolecularRESUMO
Glutathione reductase (GR), is responsible for the existence of GSH molecule, a crucial antioxidant against oxidative stress reagents. The antimalarial activities of some redox active compounds are attributed to their inhibition of antioxidant flavoenzyme glutathione reductase, and inhibitors are therefore expected to be useful for the treatment of malaria. Twelve organic nitrate derivatives were synthesized and treated with human erythrocyte GR. The molecules were identified as strong GR inhibitors and novel antimalaria candidates.
Assuntos
Antimaláricos/química , Inibidores Enzimáticos/química , Eritrócitos/enzimologia , Glutationa Redutase/antagonistas & inibidores , Nitratos/química , Antimaláricos/síntese química , Antimaláricos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glutationa Redutase/metabolismo , Humanos , Nitratos/síntese química , Nitratos/farmacologiaRESUMO
[reaction: see text] endo- and exo-2,3,4,7-tetrahydro-1H-1,4-methanobenzocycloheptene-7-carboxylic acid ethyl esters have been synthesized, and their Diels-Alder cycloaddition reactions with maleic anhydride, dimethyl acetylenedicarboxylate and singlet oxygen have been investigated. The X-ray analysis of four adducts indicated the pyramidalization of the central double bond. Density functional theory calculations on the isolated products and model compounds showed excellent agreement between the experimental and theoretical determined butterfly angles. Furthermore, it has been shown that a cyclopropyl group fused to [2.2.2] system decreases significantly the degree of the pyramidalization which is attributed to the steric interactions between the cyclopropyl group and ethano bridge of the norbornene systems. Due to the instability of the bicyclic endoperoxides, their X-ray analysis could not be carried out. DFT calculations on model compounds showed increased bending in the case of the product obtained by the addition of singlet oxygen to endo-2,3,4,7-tetrahydro-1H-1,4-methanobenzocycloheptene-7-carboxylic acid ethyl ester.