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Publication Abstract from PubMed

The alpha-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten- 6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture. Ongoing efforts to improve the potency and specificity over the lead compound led us to synthesize 14 manicol derivatives that retain the divalent metal-chelating alpha-hydroxytropolone pharmacophore. These efforts were augmented by a high resolution structure of p66/p51 HIV-1 RT containing the nonnucleoside reverse transcriptase inhibitor (NNRTI), TMC278 and manicol in the DNA polymerase and RNase H active sites, respectively. We demonstrate here that several modified alpha-hydroxytropolones exhibit antiviral activity at noncytotoxic concentrations. Inclusion of RNase H active site mutants indicated that manicol analogues can occupy an additional site in or around the DNA polymerase catalytic center. Collectively, our studies will promote future structure-based design of improved alpha-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.

Synthesis, activity, and structural analysis of novel alpha-hydroxytropolone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H.,Chung S, Himmel DM, Jiang JK, Wojtak K, Bauman JD, Rausch JW, Wilson JA, Beutler JA, Thomas CJ, Arnold E, Le Grice SF J Med Chem. 2011 Jul 14;54(13):4462-73. Epub 2011 Jun 2. PMID:21568335^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.