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Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2-ligand: Structure-activity studies and biological evaluation.

Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2-ligand: Structure-activity studies and biological evaluation.
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Bai X, Yang Z, Zhu M, Dong B, Zhou L, Zhang G, Wang J, Wang Y,


Bai X, Yang Z, Zhu M, Dong B, Zhou L, Zhang G, Wang J, Wang Y, (click to view)

Bai X, Yang Z, Zhu M, Dong B, Zhou L, Zhang G, Wang J, Wang Y,

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European journal of medicinal chemistry 2017 05 08137() 30-44 pii 10.1016/j.ejmech.2017.05.024

Abstract

The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2′-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2′-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).

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