RESUMO
Thirteen novel hydrazone-Schiff bases (3-15) of fexofenadine were succesfully synthesized, structurally deduced and finally assessed their capability to inhibit urease enzyme (inâ vitro). In the series, six compounds 12 (IC50=10.19±0.16â µM), 11 (IC50=15.05±1.11â µM), 10 (IC50=17.01±1.23â µM), 9 (IC50=17.22±0.81â µM), 13 (IC50=19.31±0.18â µM), and 14 (IC50=19.62±0.21â µM) displayed strong inhibitory action better than the standard thiourea (IC50=21.14±0.24â µM), while the remaining compounds displayed significant to less inhibition. LUMO and HOMO showed the transferring of charges from molecules to biological transfer and MEP map showed the chemically reactive zone appropriate for drug action are calculated using DFT. AIM charges, non-bonding orbitals, and ELF are also computed. The urease protein binding analysis benefited from the docking studies.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Hidrazonas , Simulação de Acoplamento Molecular , Bases de Schiff , Terfenadina , Urease , Urease/antagonistas & inibidores , Urease/metabolismo , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Bases de Schiff/síntese química , Terfenadina/análogos & derivados , Terfenadina/química , Terfenadina/metabolismo , Terfenadina/farmacologia , Terfenadina/síntese química , Teoria da Densidade Funcional , Estrutura Molecular , Relação Estrutura-Atividade , Canavalia/enzimologiaRESUMO
Urinary tract infection caused by Klebsiella, Proteus and Streptococcus is a urease dependent process, hence treatment of these infections by antibacterial compounds lies in inhibition of their virulence factors. The crude methanolic extracts derived from sumac fruit, pomegranate peel and Indian almond leaves were separated into anthocyanin and non-anthocyanin fractions using solid phase cartridges. The inhibitory effect of these fractions was determined on the growth of urease producing species and jack bean urease activity. Known compounds in the fractions were also docked with ureases of different biological origins viz. K. pneumoniae (PDB ID: 8HCN), K. aerogenes (PDB ID: 2KAU), Helicobacter pylori (PDB ID:8HC1)and Canavalia ensiformis (jack bean) (PDB ID: 3LA4) to determine their binding affinities and interaction with the enzyme. All the fractions showed significant inhibition growth for P. mirabilis, S. epidermidis and K.pneumoniae. Among the samples, sumac showed greatest inhibition against all (MIC 6-25 mg.mL-1) while among the fractions, anthocyanin was found to be most active (MIC 6-12 mg/mL). Likewise, all fractions inhibited urease with lowest ICs50 shown by sumac fractions (21-116 µg.mL-1). Out of 39 compounds docked, 27 showed interaction with movable flaps and/or active site of ureases which explains their mode of inhibition.
Assuntos
Polifenóis , Punica granatum , Prunus dulcis , Urease , Urease/antagonistas & inibidores , Urease/metabolismo , Polifenóis/farmacologia , Polifenóis/química , Punica granatum/química , Prunus dulcis/química , Canavalia/enzimologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Antibacterianos/farmacologia , Antibacterianos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Bactérias/efeitos dos fármacos , Bactérias/enzimologiaRESUMO
Ureases are enzymes from plants, fungi and bacteria that catalyze the hydrolysis of urea to form ammonia and carbon dioxide. While fungal and plant ureases are homo-oligomers of 90-kDa subunits, bacterial ureases are multimers of two or three subunit complexes. We showed that some isoforms of jack bean urease, canatoxin and the classical urease, bind to glycoconjugates and induce platelet aggregation. Canatoxin also promotes release of histamine from mast cells, insulin from pancreatic cells and neurotransmitters from brain synaptosomes. In vivo it induces rat paw edema and neutrophil chemotaxis. These effects are independent of ureolytic activity and require activation of eicosanoid metabolism and calcium channels. Helicobacter pylori, a Gram-negative bacterium that colonizes the human stomach mucosa, causes gastric ulcers and cancer by a mechanism that is not understood. H. pylori produces factors that damage gastric epithelial cells, such as the vacuolating cytotoxin VacA, the cytotoxin-associated protein CagA, and a urease (up to 10 percent of bacterial protein) that neutralizes the acidic medium permitting its survival in the stomach. H. pylori whole cells or extracts of its water-soluble proteins promote inflammation, activate neutrophils and induce the release of cytokines. In this paper we review data from the literature suggesting that H. pylori urease displays many of the biological activities observed for jack bean ureases and show that bacterial ureases have a secretagogue effect modulated by eicosanoid metabolites through lipoxygenase pathways. These findings could be relevant to the elucidation of the role of urease in the pathogenesis of the gastrointestinal disease caused by H. pylori.
Assuntos
Humanos , Animais , Canavalia/enzimologia , Eicosanoides/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/enzimologia , Proteínas de Plantas/biossíntese , Urease/biossíntese , Relação Dose-Resposta a Droga , Duodenopatias/metabolismo , Duodenopatias/microbiologia , Infecções por Helicobacter/metabolismo , Gastropatias/metabolismo , Gastropatias/microbiologiaRESUMO
The effect of the extrusion (155 degrees C, 20 per cent moisture, screw speed 75 rpm, feed speed 205 g min-1) on antinutritional factors of Canavalia ensiformis was studied. In vitro protein and starch digestibilities were assessed. The extrusion not affect protein content (23 per cent) in the flours, but significantly (P < 0.01) decrease moisture content. The protein digestibility values were improved from 57.5 to 89.5 per cent, these values were lower than casein (98.19 per cent). The digestibility of starch values were improved from 37.7 to 53 per cent. The protease inhibitors activities (trypsin and chymotrypsin) and alpha-amylase inhibitor activity were reduced by 95 per cent. The haemagglutinating activity was eliminated as result of the high temperature employed during the extrusion process. The canavanine content in the flours were not affect by the treatment of extrusion.