Butylated Hydroxytoluene Analogs: Synthesis and Evaluation of Their <em>Multipotent </em>Antioxidant Activities

Abstract

A computer-aided predictions of antioxidant activities were performed with the Prediction Activity Spectra of Substances (PASS) program. Antioxidant activity of compounds <strong>1</strong>, <strong>3</strong>, <strong>4</strong> and <strong>5</strong> were studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and lipid peroxidation assays to verify the predictions obtained by the PASS program. Compounds <strong>3</strong> and <strong>5</strong> showed more inhibition of DPPH stable free radical at 10⁻⁴ M than the well-known standard antioxidant, butylated hydroxytoluene (BHT). Compound <strong>5</strong> exhibited promising <em>in</em> <em>vitro</em> inhibition of Fe²⁺-induced <em>lipid peroxidation</em> of the essential egg yolk as a lipid-rich medium<em> </em>(83.99%, IC₅₀ 16.07 ± 3.51 µM/mL) compared to a-tocopherol (a-TOH, 84.6%, IC₅₀ 5.6 ± 1.09 µM/mL). The parameters for drug-likeness of these BHT analogues were also evaluated according to the Lipinski’s “rule-of-five” (RO5). All the BHT analogues were found to violate one of the Lipinski’s parameters (Log<em>P</em> > 5), even though they have been found to be soluble in protic solvents. The predictive polar surface area (PSA) and absorption percent (% ABS) data allow us to conclude that they could have a good capacity for penetrating cell membranes. Therefore, one can propose these new multipotent antioxidants (MPAOs) as potential antioxidants for tackling <em>oxidative stress</em> and <em>lipid peroxidation processes.</em><em> </em> <strong> </strong>

Keywords

• butylated hydroxyltolouene
• drug-likeness properties
• DPPH
• lipid peroxidation
• multipotent antioxidant
• rule-of-five
• PASS and activity prediction
• thiosemicarbazide
• 1,2,4-triazole
• 1,3,4-thiadiazole