title: Antioxidant function of phenethyl-5-bromo-pyridyl thiourea compounds with potent anti-HIV activity.
abstract: In a systematic search for novel dual function antioxidants with potent anti-HIV activity, we evaluated 9 rationally designed non-nucleoside inhibitors (NNI) of HIV-1 RT for antioxidant and anti-HIV activities. Our lead phenethyl-5-bromopyridyl thiourea (PEPT) compounds, N-[2-(2-methoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thioure a (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 microM, respectively. Both compounds effectively inhibited the oxidation-induced green fluorescence emission from the free radical-sensitive indicator dye 2',7'-dichlorodihydrofluorescein diacetate in CEM human T-cells 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 activity. Furthermore, the activity center was defined as the sulfhydryl group since alkylated PEPT derivatives were inactive. The presence of a free thiourea group was also essential for the anti-HIV activity of the PEPT compounds.
authors.affiliation: Drug Discovery Program, Department of Chemistry, Hughes Institute, St Paul, MN 55113, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Dong
authors.forename: T K
authors.initials: TK
authors.lastname: Venkatachalam
authors.forename: R K
authors.initials: RK
authors.lastname: Narla
authors.forename: V N
authors.initials: VN
authors.lastname: Trieu
authors.forename: E A
authors.initials: EA
authors.lastname: Sudbeck
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry* / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D005434:Flow Cytometry; D005453:Fluorescence; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000975:Antioxidants; D016166:Free Radical Scavengers; D011725:Pyridines; D006861:Hydrogen Peroxide; D054303:HIV Reverse Transcriptase; D013890:Thiourea