Discovery of HIV-1 protease inhibitors with picomolar affinities incorporating N-aryl-oxazolidinone-5-carboxamides as novel P2 ligands.
Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors incorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold as P2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2' phenylsulfonamide moieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2 show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl, and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in each series, with K(i) values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2' phenyl ring, as compounds with other substitutions show lower binding affinities. Attempts to replace the isobutyl group at P1' with small cyclic moieties caused significant loss of affinities in the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with the HIV-1 protease provided valuable information on the interactions between the inhibitor and the protease enzyme. In both inhibitor - enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogenbond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each series incorporating various phenyloxazolidinone based P2 ligands were selected and their activities against a panel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent protease inhibitor starts out with extremely tight affinity for the wild-type enzyme (K(i) = 0.8 pM), and even against the MDR variants it retains picomolar to low nanomolar K(i), which is highly comparable with the best FDA-approved protease inhibitors.
Ali
Akbar
A
Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Reddy
G S Kiran Kumar
GS
Cao
Hong
H
Anjum
Saima Ghafoor
SG
Nalam
Madhavi N L
MN
Schiffer
Celia A
CA
Rana
Tariq M
TM
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D024921:Drug Resistance, Multiple, Viral; D031541:Fluorescence Resonance Energy Transfer; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D015394:Molecular Structure; D009154:Mutation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry
C517230:3-(3-acetylphenyl)-N-(1-benzyl-2-hydroxy-3-(isobutyl((4-methoxyphenyl)sulfonyl)amino)propyl)-2-oxooxazolidine-5-carboxamide; D000577:Amides; D017320:HIV Protease Inhibitors; D008024:Ligands; D010080:Oxazoles; D013449:Sulfonamides; D016333:HIV Protease