Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki=13.2nM, IC50=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki=62pM and 14pM, respectively) and antiviral activity (IC50=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

Ghosh, A.K., Sean Fyvie, W., Brindisi, M., Steffey, M., Agniswamy, J., Wang, Y., et al. (2017). Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 27(21), 4925-4931 [10.1016/j.bmcl.2017.09.003].

Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

Brindisi, Margherita;
2017-01-01

Abstract

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki=13.2nM, IC50=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki=62pM and 14pM, respectively) and antiviral activity (IC50=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.
Ghosh, A.K., Sean Fyvie, W., Brindisi, M., Steffey, M., Agniswamy, J., Wang, Y., et al. (2017). Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 27(21), 4925-4931 [10.1016/j.bmcl.2017.09.003].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1030059