Diketoacid-genre HIV-1 integrase inhibitors containing enantiomeric arylamide functionality.
Using our recently disclosed 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione integrase inhibitors, we report differential effects on inhibitory potency induced by introduction of an alpha-chiral center into a key aryl substituent. We show that introduction of the chiral center is uniformly deleterious to binding, with the (R)-enantiomer being more deleterious than the (S)-enantiomer. A greater enantiomeric difference in potency is shown by inhibitors that have restricted rotation of the aryl ring, with the larger difference being due to poorer potency of the (R)-enantiomer rather than higher potency of the (S)-enantiomer. The potency difference for enantiomers based on the isoindoline-1,3-dione ring system is less than for those derived from the isoindol-1-one ring system. Our findings provide useful information that should aid in understanding molecular binding interactions of DKA-derived IN inhibitors.
Zhao
Xue Zhi
XZ
Laboratory of Medicinal, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, United States.
Maddali
Kasthuraiah
K
Marchand
Christophe
C
Pommier
Yves
Y
Burke
Terrence R
TR
D000577:Amides / Q000737:chemistry*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D019428:HIV Integrase Inhibitors; D006841:Hydrocarbons, Aromatic; D019427:HIV Integrase