Synthesis and in vitro anti-HIV activity in human monocyte-derived macrophages of 2-oxothiazolidine-4(R)-carboxylic acid derivatives

Oxidative stress and glutathione (GSH) deficit may play an important role i n HIV infection pathogenesis, and oral administration of GSH-replenishing d rugs such as N-acetylcysteine (NAC) and 2-oxothiazolidine-4(R)-carboxylic a cid (OTC) may be associated with an increased survival rate of HIV-infected patients. Nevertheless, beneficial effects of these molecules are restrict ed in vivo by the high concentrations that are necessary to obtain biologic al effects, rapid extracellular metabolization, and low availability and pl asma concentrations. We synthesized OTC derivatives that are more lipophili c than OTC and theoretically able to overcome these limitations and to gene rate, in addition to cysteine, other substrates of the gamma-glutamyl cycle . Their antiviral effects were investigated in human HIV-1/Ba-L-infected mo nocyte-derived macrophages. In our experimental conditions, OTC exhibited a nti-HTV-1 effects and little cytotoxicity at high doses. None of the nine t ested derivatives showed higher cytotoxicity than OTC, nor anti-HIV-1/Ba-L activity.