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Diketoacid-genre HIV-1 integrase inhibitors containing enantiomeric arylamide functionality

  1. Author:
    Zhao, X. Z.
    Maddali, K.
    March, C.
    Pommier, Y.
    Burke, T. R.

  2. Author Address

    Zhao, Xue Zhi, Burke, Terrence R., Jr.] NCI, Lab Med, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Maddali, Kasthuraiah, Marchand, Christophe, Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.
    1. Year: 2009
  2. Journal: Bioorganic & Medicinal Chemistry
    1. 17
    2. 14
    3. Pages: 5318-5324
  4. Type of Article: Article
  1. Abstract:

    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. Published by Elsevier Ltd.

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  2. DOI: 10.1016/j.bmc.2009.05.008
  3. PMID: 19527935

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