A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2′ ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies. © 2007 American Chemical Society.
CITATION STYLE
Reddy, G. S. K. K., Ali, A., Nalam, M. N. L., Anjum, S. G., Cao, H., Nathans, R. S., … Rana, T. M. (2007). Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2′ ligands in pseudosymmetric dipeptide isosteres. Journal of Medicinal Chemistry, 50(18), 4316–4328. https://doi.org/10.1021/jm070284z
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