jm050437n_si_001.pdf (136.55 kB)

Improving the Antiviral Efficacy and Selectivity of HIV-1 Reverse Transcriptase Inhibitor TSAO-T by the Introduction of Functional Groups at the N-3 Position

Download (136.55 kB)
journal contribution
posted on 20.10.2005, 00:00 by María-Cruz Bonache, Cristina Chamorro, Sonsoles Velázquez, Erik De Clercq, Jan Balzarini, Fátima Rodríguez Barrios, Federico Gago, María-José Camarasa, Ana San-Félix
Novel derivatives of the anti-HIV-1 agent, TSAO-T, bearing at the N-3 position a variety of polar, lipophilic, or aromatic groups linked to that position through flexible polymethylene linkers of different length, were prepared and evaluated for their anti-HIV activity. Several compounds (within the series of polar bearing groups) exhibited a 2−6-fold improved antiviral potency with regard to the lead compound, TSAO-T. Moreover, some of the most active N-3 TSAO derivatives retain antiviral activity against the TSAO-T-resistant HIV-1 strain (Glu138 → Lys). Interestingly, the N-methylcarboxamide derivative 17 was 5- to 6-fold more active (IC50:  0.56 μM) against recombinant HIV-1 reverse transcriptase than the lead compound, thus becoming the most active TSAO derivative synthesized so far. On the other hand, the N-3 methylcarboxamide TSAO derivative 12 turned out to have the highest selectivity index yet reported for this class of compounds (around ≥12 000).