Inhibition with the cyclooxynase-1 (COX-1) enzyme [168]. In 350 of sufferers. On the other hand, oral administration of indomethacin has been linked with systemic and nearby upper gastrointestinal unwanted side effects, for instance erosions, ulcerative lesions, and petechial bleeding inside the mucosa of your stomach [191]. Other studies show that the oral administration of indomethacin in rats and humans causes ulcerative lesions in the gastric mucosa stemming in the generation of reactive oxygen species and lipid peroxidation [224]. 5-aminosalicyate (5-ASA) or its prodrugs (e.g., sulfasalazine, mesalazine, olsalazine, and balsalazide) have already been employed as first-line medicines to treat ulcerative colitis for upkeep or remission [25,26]. These drugs can trigger some adverse effects, including diarrhea, nausea, vomiting, headache, abdominal pain, fatigue, weakness, hepatic abnormalities, arthralgia, and myalgia [279]. Therefore, it truly is necessary to learn new alternative drugs capable of inhibiting myeloperoxidase (MPO) and generating an anti-inflammatory effect without generating such extreme adverse effects [30,31]. For this objective, our research group has focused on the development of 5-ASA derivatives. Soon after becoming made and synthesized inside a previous study, they have been assessed in vitro and ex vivo [32,33]. The in vitro assays evidenced antioxidant properties when employing the 2,two -azino-bis(3-ethylbenzo thiazoline)-6-sulfonic acid (ABTS) and two,2 -diphenyl-1-picrylhydrazyl (DPPH) procedures. Specifically, the compound 5-[(2E)3-bromo-3-carboxyprop-2-enoyl]amino-2-hydroxybenzoic acid (C1) (Figure 1), can lessen the production from the free Y-27632 Technical Information radical DPPH about 90 in comparison to 5-ASA which generates a reduced reduction of this radical, being about 85 at the identical concentration (0.408 mM). Interestingly, C1 also exhibited anti-inflammatory activity in a 12-O-tetradecanoylphorbol acetate (TPA)-induced mouse ear edema model. As an inhibitor of MPO, its effect proved to be Anle138b Autophagy comparable to that of indomethacin based on an evaluation with all the o-dianisidine strategy [32,33].Figure 1. Chemical structure of 5-[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino-2-hydroxybenzoic acid (C1).Inside the preclinical testing of a brand new drug candidate, the lack of in vivo activity can be attributed to inappropriate pharmacokinetic properties or toxicity (the formation of reactive metabolites) [34]. The aim on the current contribution was to take another step in the preclinical evaluation of C1 by examining its acute toxicity and pharmacokinetic profile. Acute toxicity was explored using the up-and-down OECD approach, even though the pharmacokinetic profile was established by administering the compound to Wistar rats through the intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. After p.o. administration, the distribution of C1 was determined in organs and tissues. The boundMolecules 2021, 26,3 ofand unbound fraction of C1 in rat plasma was quantified as well as the blood/plasma (BP) partition coefficient was calculated. 2. Benefits 2.1. Acute Toxicity of C1 Median lethal dose (LD50) values in Wistar rats had been 2000 mg/kg and 1098 mg/kg for p.o. and i.p. routes of administration, respectively. Animals didn’t show any signs of toxicity with the p.o. route. During the necropsy, in addition, no macroscopic alterations have been observed inside the liver, compact intestine, colon, heart, spleen, stomach, or kidneys. For that reason, in accordance with the Globally Harmonized Program (GHS) of Classification and Labeling of Chemical Pro.