A new class of HIV-1 integrase inhibitors: the 3,3,3', 3'-tetramethyl-1,1'-spirobi(indan)-5,5',6,6'-tetrol family.
Integration is a required step in HIV replication, but as yet no inhibitors of the integration step have been developed for clinical use. Many inhibitors have been identified that are active against purified viral-encoded integrase protein; of these, many contain a catechol moiety. Though this substructure contributes potency in inhibitors, it is associated with toxicity and so the utility of catechol-containing inhibitors has been questioned. We have synthesized and tested a systematic series of derivatives of a catechol-containing inhibitor (1) with the goal of identifying catechol isosteres that support inhibition. We find that different patterns of substitution on the aromatic ring suffice for inhibition when Mn(2+) is used as a cofactor. Importantly, the efficiency is different when Mg(2+), the more likely in vivo cofactor, is used. These data emphasize the importance of assays with Mg(2+) and offer new catechol isosteres for use in integrase inhibitors.
Molteni
V
V
Department of Chemistry, University of California, San Diego, La Jolla, California 92093-0358, USA.
Rhodes
D
D
Rubins
K
K
Hansen
M
M
Bushman
F D
FD
Siegel
J S
JS
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002413:Cations, Divalent; D002470:Cell Survival / Q000187:drug effects; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D008274:Magnesium / Q000494:pharmacology; D008345:Manganese / Q000494:pharmacology; D015394:Molecular Structure; D008977:Molluscum contagiosum virus / Q000201:enzymology; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
C409871:3,3,3',3'-tetramethyl-1,1'-spirobi(indan)-5,5',6,6'-tetrol; D000998:Antiviral Agents; D002396:Catechols; D002413:Cations, Divalent; D019428:HIV Integrase Inhibitors; D013141:Spiro Compounds; D059004:Topoisomerase I Inhibitors; D008345:Manganese; D008274:Magnesium