4-Nerolidylcatechol and its synthetic analogues: antioxidant activity and toxicity evaluation

• Published in: European journal of medicinal chemistry 2013-04, Vol.62, p.371-378
• Main Authors: Mendanha da Cunha, Carla Rosane, Mendanha Neto, Sebastião Antônio, Carlos da Silva, Claudio, Cortez, Alane Pereira, Gomes, Marcelo do Nascimento, Martins, Fabiula Ines, Alonso, Antônio, Rezende, Kênnia Rocha, Menegatti, Ricardo, de Magalhães, Mariana Torquato Quezado, Valadares, Marize Campos
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Antioxidants - toxicity; Catechols - chemical synthesis; Catechols - chemistry; Catechols - pharmacology; Catechols - toxicity; Cell Death - drug effects; Dose-Response Relationship, Drug; Erythrocytes - drug effects; Fibroblasts - drug effects; Granulocytes - drug effects; Humans; Macrophages - drug effects; Mice; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.12.028

4-Nerolidylcatechol (1) is a secondary metabolite of plants and is described as a promising anti-inflammatory, antimalarial, antiulcerogenic, analgesic and cytotoxic compound possibly due to its antioxidant profile. In this study, we evaluated the pharmacologic activity and the antioxidant and toxicological profiles of compound (1) and its synthetic analogues (2-6). The synthetic analogues were designed from the lead compound, (1), using a molecular-simplification strategy. Compound 5 showed, by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and β-carotene systems, similar antioxidant activity when compared to compound (1). The oxidative stress in erythrocyte membrane demonstrated the highly protective effect of compounds (4), (5) and (6) and high antioxidant/pro-oxidant activity in relation to the concentrations of compounds (1) and (3). Compounds (2), (4), (5) and (6) were haemobiocompatible. All compounds (1-6) showed cytotoxic effects in 3T3 cells, but compounds (2) and (6) were highly cytotoxic in this lineage when compared to compound (1). Compound (5) had a lower myelosuppressive effect in haematopoietic progenitor cells compared to (1). Both compounds, (1) and (5), showed low genotoxic effects in vitro, on human lymphocyte cells. In addition, these compounds also showed low-toxicity in vivo as defined a LD50 > 2000 mg/kg. In this assay, we did not observe death in the animals exposed to treatment with (1) and (5) compound. In conclusion, the structural design of the analogues as validated once compound (5) was found to have an antioxidant profile that was as potent as the lead compound (1). In addition, considering the safety profile, these compounds are promising as preventive and/or therapeutic agents against oxidative damage.