Preparation of a small library of derivatives of the potent HIV-1 Reverse Transcriptase inhibitor TSAO-T bearing mono or di-carbonyl substituents (designed after docking analysis) at position N-3 is reported. A one-pot synthetic methodology has been developed that involves: (i) mono-reaction of TSAO-T with glutaryl dichloride under phase transfer conditions and (ii) in situ acyclic substitution of the remaining chloro atom by oxygen or nitrogen nucleophiles. The method is compatible with the polyfunctionality of the TSAO-T molecule, proceeds with high conversion yields and allows introducing molecular diversity. The anti-HIV-1 and -HCV activity was studied in cell culture. The new N-3 acylated TSAO-T derivatives are active against HIV-1 (nanomolar range). Anti-HCV activity was observed in the micromolar range, that is at compound concentrations that were found cytostatic against human T-lymphocytes. © 2011 Elsevier Masson SAS. All rights reserved.
Moura, M., Josse, S., Van Nhien, A. N., Fournier, C., Duverlie, G., Castelain, S., … Postel, D. (2011). Synthesis and in vitro activity of novel N-3 acylated TSAO-T compounds against HIV-1 and HCV. European Journal of Medicinal Chemistry, 46(10), 5046–5056. https://doi.org/10.1016/j.ejmech.2011.08.017