New Bicyclam-AZT conjugates: Design, synthesis, Anti-HIV evaluation, and their interaction with CXCR-4 coreceptor

We report the synthesis of mono- and bis-tetraazamacrocycle-AZT conjugates. All new compounds were screened for their ability to inhibit HIV-1 replica tion in MT4 cell line and were compared to AZT alone. It appears that N-pro tected covalent prodrugs are equipotent to AZT as inhibitor of HIV replicat ion, while N-deprotected analogues exhibit both higher activity and selecti vity against HIV-infected cells. The most active antiviral compounds 27, 28 , 34, and 35 were then tested for their binding capability to CXCR-4 recept or. N-Boc analogues 27 and 34 were only weakly effective; in contrast, N-de protected conjugates 28 and 35 were antagonists to 12G5 mAb binding until 0 .05 and 5 mu g/mL, respectively. The stability of compound 28 in human plas ma was evaluated, and half-life was found to be approximately 8 h in the de scribed conditions. All these results seem to demonstrate the confidence of our prodrug approach, with analogue 28 emerging as the best candidate as l ead compound in HIV-1 polytherapy perspective.