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

• Published in: Journal of medicinal chemistry 2011-07, Vol.54 (13), p.4462-4473
• Main Authors: Chung, Suhman, Himmel, Daniel M, Jiang, Jian-Kang, Wojtak, Krzysztof, Bauman, Joseph D, Rausch, Jason W, Wilson, Jennifer A, Beutler, John A, Thomas, Craig J, Arnold, Eddy, Le Grice, Stuart F.J
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; AIDS VIRUS; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - pharmacology; BASIC BIOLOGICAL SCIENCES; Benzocycloheptenes - chemistry; Catalytic Domain; Cations, Divalent; Cell Line; Coordination Complexes - chemistry; Crystallography, X-Ray; DESIGN; DNA POLYMERASES; DNA-Directed DNA Polymerase - chemistry; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV-1 - drug effects; HIV-1 - physiology; Humans; IN VITRO; LEAD COMPOUNDS; Manganese - chemistry; Models, Molecular; Molecular Structure; MUTANTS; Mutation; Nitriles - chemistry; Protein Conformation; Pyrimidines - chemistry; RESOLUTION; Ribonuclease H, Human Immunodeficiency Virus - antagonists & inhibitors; Ribonuclease H, Human Immunodeficiency Virus - chemistry; Ribonuclease H, Human Immunodeficiency Virus - genetics; Rilpivirine; RNA-ASE; SPECIFICITY; Structure-Activity Relationship; SYNTHESIS; Tropolone - analogs & derivatives; Tropolone - chemical synthesis; Tropolone - pharmacology; Virus Replication
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm2000757

The α-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 α-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 α-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 α-hydroxytropolones to complement the NRTI and NNRTI currently in clinical use.