Antioxidant function of phenethyl-5-bromo-pyridyl thiourea compounds with potent anti-HIV activity

In a systematic search for novel dual function antioxidants with potent ant i-HIV activity, we evaluated 9 rationally designed non-nucleoside inhibitor s (NNI) of HIV-1 RT for antioxidant and anti-HIV activities. Our lead phene thyl-5-bromopyridyl thiourea (PEPT) compounds, N-[2-(2-methoxyphenylethyl)] -N'-[2-(5-bromopyridyl)]-thiourea (2) and N-[2-(2-chlorophenylethyl)]-N'-[2 -(5-bromopyridyl)]-thiourea (9), inhibited the oxidation of ABTS to ABTS(.) by metmyoglobin in the presence of hydrogen peroxide with EC50 values of 79 and 75 mu M, respectively. Both compounds effectively inhibited the oxid ation-induced green fluorescence emission from the free radical-sensitive i ndicator dye 2',7'-dichlorodihydrofluorescein diacetate in CEM human T-cell s and Nalm-6 human B-cells exposed to hydrogen peroxide. To our knowledge, compounds 2 and 9 are the first NNI of HIV-1 RT with potent anti-oxidant ac tivity. Furthermore, the activity center was defined as the sulfhydryl grou p since alkylated PEPT derivatives were inactive. The presence of a free th iourea group was also essential for the anti-HIV activity of the PEPT compo unds. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.