Synthesis Activity and Structural Analysis of Novel alpha-Hydroxytropolone Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase-Associated Ribonuclease H

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm2000757· OSTI ID:1041706

Chung, S; Himmel, D; Jiang, J; Wojtak, K; Bauman, J; Rausch, J; Wilson, J; Beutler, J; Thomas, C

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.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041706
• Report Number(s): BNL--97384-2012-JA
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 13 Vol. 54; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
AIDS VIRUS
DESIGN
DNA POLYMERASES
IN VITRO
LEAD COMPOUNDS
MUTANTS
RESOLUTION
RNA-ASE
SPECIFICITY
SYNTHESIS