RESUMO
11-Beta hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regulates cortisol levels mainly in adipose, hepatic and brain tissues. There is a relationship between the high activity of this enzyme and the development of obesity and metabolic disorders. The inhibition of 11ß-HSD1 has been shown to attenuate the development of type 2 diabetes mellitus, insulin resistance, metabolic syndrome and other diseases mediated by excessive cortisol production. In this work, fifteen benzothiazole derivatives substituted with electron-withdrawing and electron-donating groups were designed to explore their affinity for 11ß-HSD1 using in silico methods. The results show that (E)-5-((benzo[d]thiazol-2-ylimino)(methylthio)methylamino)-2-hydroxybenzoic acid (C1) has good physicochemical properties and favorable interactions with 11ß-HSD1 through hydrogen bonding and hydrophobic interactions in the catalytic site formed by Y183, S170 and Y177. Furthermore, C1 was synthesized and evaluated in vitro and ex vivo using clobenzorex (CLX) as a reference drug in obese Zucker rats. The in vitro results showed that C1 was a better inhibitor of human 11ß-HSD1 than CLX. The ex vivo assay results demonstrated that C1 was capable of reducing 11ß-HSD1 overexpression in mesenteric adipose tissue. Therefore, C1 was able to decrease the activity and expression of 11ß-HSD1 better than CLX.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Benzotiazóis/química , Benzotiazóis/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Anfetaminas/farmacologia , Animais , Benzotiazóis/farmacologia , Domínio Catalítico/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Ligação de Hidrogênio/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos , Ratos ZuckerRESUMO
Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2â¢- ). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2-C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π-π interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity.
Assuntos
Acetofenonas/farmacologia , Compostos de Bifenilo/farmacologia , NADPH Oxidases/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Acetofenonas/síntese química , Acetofenonas/química , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Simulação por Computador , Humanos , Ratos , Relação Estrutura-Atividade , Superóxidos/metabolismoRESUMO
The title compound, C12H13NO4, is one of the few examples that exhibits a syn conformation between the amide and ester carbonyl groups of the oxalyl group. This conformation allows the engagement of the amide H atom in an intramolecular three-centred hydrogen-bonding S(6)S(5) motif. The compound is self-assembled by C=O...C=O and amide-π interactions into stacked columns along the b-axis direction. The concurrence of both interactions seems to be responsible for stabilizing the observed syn conformation between the carbonyl groups. The second dimension, along the a-axis direction, is developed by soft C-H...O hydrogen bonding. Density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level of theory were performed to support the experimental findings.