RESUMEN
Quantum chemical calculations at the B3LYP/6-31G* level of theory were employed for the structure-activity relationship and prediction of the antioxidant activity of edaravone and structurally related derivatives using energy (E), ionization potential (IP), bond dissociation energy (BDE), and stabilization energies (ΔE(iso)). Spin density calculations were also performed for the proposed antioxidant activity mechanism. The electron abstraction is related to electron-donating groups (EDG) at position 3, decreasing the IP when compared to substitution at position 4. The hydrogen abstraction is related to electron-withdrawing groups (EDG) at position 4, decreasing the BDE(CH) when compared to other substitutions, resulting in a better antioxidant activity. The unpaired electron formed by the hydrogen abstraction from the C-H group of the pyrazole ring is localized at 2, 4, and 6 positions. The highest scavenging activity prediction is related to the lowest contribution at the carbon atom. The likely mechanism is related to hydrogen transfer. It was found that antioxidant activity depends on the presence of EDG at the C(2) and C(4) positions and there is a correlation between IP and BDE. Our results identified three different classes of new derivatives more potent than edaravone.
Asunto(s)
Antioxidantes/química , Antipirina/análogos & derivados , Modelos Químicos , Antipirina/química , EdaravonaRESUMEN
This paper describes the synthesis of new cyclic imides obtained by reaction with N-antipyrine-3,4-dichloromaleimides and different aromatic amines. The analgesic activity of the synthesized compounds was initially investigated against the writhing test in mice, followed by analysis of the most promising compounds in this model and in the formalin-induced model. The results indicate that the compounds containing the electron-withdrawing substituents in the para position of the substitute ring exerted more potent analgesic activity in mice, being much more potent than the prototype N-antipyrine-3,4-dichloromaleimide and some reference drugs. Some compounds exhibited activity against human opportunistic and pathogenic fungi, with MIC values of between 40 and 100 µg/mL (91.74 and 236.96 µM), and it was verified that only a few compounds presented potential for cytotoxic activity.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Antipirina/química , Maleimidas/síntesis química , Maleimidas/farmacología , Analgésicos/química , Animales , Ensayos de Selección de Medicamentos Antitumorales , Maleimidas/química , Ratones , Relación Estructura-ActividadRESUMEN
To examine whether hepatic drug metabolism is altered in patients with cystic fibrosis (CF), we evaluated the pharmacokinetics of three model pharmacologic substrates (antipyrine, a marker of hepatic oxidative metabolism; lorazepam, a marker of hepatic glucuronosyltransferase activity; and indocyanine green (ICG), a marker of hepatic blood flow and biliary secretion) in 14 patients with CF (14.6 to 29.2 years of age) and in 12 children and adolescents with cancer (7.2 to 19.4 years of age), which was treated with only surgery and radiation. Each study subject received a single intravenous dose of the combined model substrates (0.03 mg/kg lorazepam, 10 mg/kg antipyrine, and 0.5 mg/kg ICG) for 5 minutes, followed by repeated blood sampling (n = 10) during a 24-hour postinfusion period. Patients with CF had a significantly greater plasma clearance of lorazepam (56.5 +/- 5.2 vs 25.9 +/- 1.9 ml/min/m2) and ICG (892.5 +/- 176.4 vs 256.5 +/- 41.7 ml/min/m2) but not of antipyrine (27.2 +/- 3.8 vs 20.7 +/- 2.0 ml/min/m2) in comparison with control subjects. The apparent steady-state volume of distribution for lorazepam, ICG, and antipyrine was significantly higher in the patients with CF (2.0-, 3.1-, and 1.4-fold, respectively) than in control subjects. Clearance of the model substrates did not correlate with standard biochemical markers of hepatic function. Similarly, no significant relationships were observed between the clearance or steady-state volume of distribution of the compounds and the National Institutes of Health prognostic scores for the patients with CF. These data demonstrate that the plasma clearance of lorazepam and ICG is increased in patients with CF and suggest that hepatic glucuronosyltransferase activity and biliary secretory capacity are enhanced in this disease.