Drug Discov Ther. 2010;4(4):246-256.

Di(hetero)arylamines in the benzo[b]thiophene series as novel potent antioxidants.

Silva JP, Machado VA, Calhelha RC, Queiroz MRP, Coutinho OP


The damaging consequences of oxidative stress are known to be involved in several pathologies. So, the development of new drugs that can aid cells to cope with excessive levels of free radicals still assumes great relevance. Here, we investigated the antioxidant properties of four novel di(hetero)arylamines (named MJQ1, MJQ3, MJQ4 and MJQ5), sharing a common benzo[b]thiophene nucleus (an indole analogue), against oxidative damage induced to H9c2 myoblasts. Cell proliferation, evaluated by the sulforhodamine B assay, was not compromised by the presence of any of these compounds for concentrations below 50 μM (at 24 h) and 1 μM (72 h). Moreover, all of them showed a dose-dependent protective effect against tert-butylhydroperoxide (t-BHP)-induced cell death for concentrations in the nanomolar range. Their ability to scavenge free radicals seems to account for their protective effects, as they were able to prevent almost completely, at 25 nM, t-BHP-induced intracellular ROS formation, assessed by DCF fluorescence. Furthermore, their relatively high partition coefficient values are indicative of their ability to easily permeate lipid membranes and act intracellularly. Additionally, these novel diarylamines led to a reduction, between 60-70%, of the amount of DNA strand breaks induced by t-BHP, evaluated by the Comet assay, and lipid peroxidation (TBARS assay) induced by the oxidant pair ascorbate/iron. In all these parameters, which show their ability to prevent the oxidation of the main biomolecules, their protective role was superior to the traditional antioxidant Trolox. Although the mechanisms underlying the action of these diarylamines are currently under investigation, the data obtained so far reveals their high pharmacological potential as antioxidant molecules.

KEYWORDS: Di(hetero)arylamines, benzo[b]thiophene derivatives, antioxidants, cardiac oxidative stress, H9c2 myoblasts

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