Search

The reaction of 5-aminosalicylic acid (5-ASA) with nitrous acid has been studied at low pH under conditions that simulate a gastric environment. The course of the reaction was followed by UV-visible and fluorescence spectroscopy and the products were analyzed by high performance liquid chromatography (HPLC) with UV-visible and mass spectroscopic detectors. In addition, the formation of nitric oxide (NO) was estimated electrochemically. 5-ASA was readily consumed in a process catalyzed by chloride and thiocyanate, whose rate is first order in 5-ASA and second order in nitrous acid. 2-Hydroxy-5-diazonium benzoic acid (diazonium derivative) and NO were detected as products of the reaction. From the NO formation profiles, it is concluded that NO is produced as a minor product in a process parallel to the path that leads to generation of the diazonium derivative. While the formation of NO could be beneficial for the protection of the stomach, the generation of the diazonium derivative could be considered a potentially toxic process. Key words: 5-aminosalicylic acid, mesalazine, nitrous acid, nitrite, diazonium derivative, nitric oxide. On a etudie la reaction de l'acide 5-aminosalicylique (5-AAS) avec l'acide nitreux, a un pH faible, dans des conditions qui simulent un environnement gastrique. On a suivi l'evolution de la reaction par spectroscopies UV-visible et de fluorescence et on a analyse les produits par chromatographie liquide a haute performance (CLHP) avec des detecteurs par spectroscopie UV-visible et de masse. De plus, on a fait appel a une methode electrochimique pour evaluer la formation d'oxyde nitrique (NO). L'acide 5-aminosalicylique est rapidement consomme dans un processus catalyse par les ions chlorure et thiocyanate et pour lequel la vitesse est du premier ordre en 5-AAS et du second ordre en acide nitreux. On a detecte de l'acide 2-hydroxy-5-diazoniumbenzoique (derive diazonium) et du NO comme produis de la reaction. D'apres les profils de formation du NO, on en conclut que le NO se forme comme produit mineur dans un processus parallele a la voie qui conduit a la formation du derive diazonium. Alors que la formation du NO pourrait etre benefique pour la protection de l'estomac, la formation du derive diazonium peut etre consideree comme un processus potentiellement toxique. Mots-cles : acide 5-aminosalicylique, mesalazine, acide nitreux, nitrite, derive diazonium, oxyde nitrique., Introduction Chronic inflammatory bowel pathologies such as ulcerative colitis and Crohn's disease cause inflammatory changes and ulcers of different types in the gastrointestinal mucosa. (1) 5-Aminosalicylic acid (5-ASA), the active [...]

In this work we have collected a set of 30 trypanosomicidal naphthoquinones and developed pharmacophoric and 3D-QSAR models as tools for the design of new potential anti-Chagasic compounds. Firstly, qualitative information was obtained from SAR and pharmacophoric models identifying some fragments around the 2-aryloxynaphthoquinone scaffold important for the antiparasitic activity. Then, 3D-QSAR CoMFA and CoMSIA models were developed. The models showed adequate statistical parameters where the steric, electrostatic, and hydrophobic features explain the trypanosomicidal effect. Therefore, to validate our models, we carried out the design, synthesis, and biological evaluation on T. cruzi epimastigotes of five new compounds (33a-e). According to CoMFA model, three out of five compounds showed pIC50 values within one logarithmic unit of deviation. The two compounds that did not fit the predictions were those with high lipophilicity, which agreed with the SAR and pharmacophore models. Docking and molecular dynamic studies were performed on T. cruzi trypanothione reductase, in a proposed binding site for this type of naphthoquinone. Interestingly, 33a-e showed the same interaction pattern as a naphthoquinone inhibitor (2). Finally, predicted drug-likeness properties indicated that 33a-e have optimal oral bioavailability. Thus, this study provides new in silico models for obtaining novel trypanosomicidal compounds. [ABSTRACT FROM AUTHOR]

A major problem today is bacterial resistance to antibiotics and the small number of new therapeutic agents approved in recent years. The development of new antibiotics capable of acting on new targets is urgently required. The filamenting temperature-sensitive Z (FtsZ) bacterial protein is a key biomolecule for bacterial division and survival. This makes FtsZ an attractive new pharmacological target for the development of antibacterial agents. There have been several attempts to develop ligands able to inhibit FtsZ. Despite the large number of synthesized compounds that inhibit the FtsZ protein, there are no quantitative structure–activity relationships (QSAR) that allow for the rational design and synthesis of promising new molecules. We present the first 3D-QSAR study of a large and diverse set of molecules that are able to inhibit the FtsZ bacterial protein. We summarize a set of chemical changes that can be made in the steric, electrostatic, hydrophobic and donor/acceptor hydrogen-bonding properties of the pharmacophore, to generate new bioactive molecules against FtsZ. These results provide a rational guide for the design and synthesis of promising new antibacterial agents, supported by the strong statistical parameters obtained from CoMFA (r2pred= 0.974) and CoMSIA (r2pred= 0.980) analyses. [ABSTRACT FROM AUTHOR]