Design and synthesis of novel β-diketo derivatives as HIV-1 integrase inhibitors

College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 11/2011; 20(1):177-82. DOI: 10.1016/j.bmc.2011.11.014
Source: PubMed


A series of novel β-diketo derivatives which combined the virtues of 1,3-diketo, 1,2,3-triazole and polyhydroxylated aromatics moieties, were designed and synthesized as potential HIV-1 integrase (IN) inhibitors and evaluated their inhibition to the strand transfer process of HIV-1 integrase. The result indicates that 3,4,5-trihydroxylated aromatic derivatives exhibit good inhibition to HIV-1 integrase, but dihydroxylated aromatic derivatives and corresponding methoxy aromatic derivatives appear little inhibition to HIV-1 integrase.

11 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: A QSAR study was performed on curcumine derivatives as HIV-1 integrase inhibitors using multiple linear regression. The statistically significant model was developed with squared correlation coefficients (r2) 0.891 and cross validated r2 (r2cv) 0.825. The developed model revealed that electronic, shape, size, geometry, substitution's information and hydrophilicity was important atomic properties for determining the inhibitory activity of these molecules. The model was also tested successfully for external validation (r2pred = 0.849) as well as Tropsha's test for model predictability. Furthermore, the domain analysis was carried out to evaluate the prediction reliability of external set molecules model. The model was statistically robust and had good predictive power which can be successfully utilized for screening of new molecules.
    No preview · Article · Nov 2012 · Current Computer - Aided Drug Design
  • [Show abstract] [Hide abstract]
    ABSTRACT: We describe a fragment-based approach for the discovery of a novel class of inhibitors of the HIV-1 integrase (IN) interaction with the cellular cofactor lens epithelium-derived growth factor (LEDGF/p75). On the basis of an initial molecular modeling study suggesting the favorable binding of the "privileged" fragment 8-hydroxyquinoline with IN at the IN-LEDGF/p75 interface, a set of modified 8-hydroxyquinoline fragments was evaluated for potency with an established AlphaScreen assay. Micromolar IC50 values for inhibition of IN-LEDGF/p75 were observed, but significant cytotoxicity was associated with these initial compounds. Diverse modifications at the C5 and C7 carbons of the 8-hydroxyquinoline core improved potency, but reduction of diversity to only modifications at the C5 position ultimately yielded potent inhibitors with low cytotoxicity. Two of these particular compounds, 5-((p-tolylamino)methyl)quinolin-8-ol and 5-(((3,4-dimethylphenyl)amino)methyl)quinolin-8-ol, inhibited viral replication in MT-4 cells with low micromolar EC50. An approximately 7-fold increase in potency and reduction in cytotoxicity was achieved from the initial 8-hydroxyquinoline fragments to our most potent lead compound. This is the first study providing evidence for 8-hydroxyquinolines as novel inhibitors of the IN-LEDGF/p75 interaction. Our lead compounds are drug-like, have low molecular weights, and are amenable to various substitutions suitable for enhancing their potency and selectivity.
    No preview · Article · Feb 2013 · Journal of Medicinal Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of N-hydroxytriazole-4-carboxamide derivatives were synthesized, and their potential HIV integrase inhibitory activities were evaluated.
    No preview · Article · Jan 2014 · Medicinal Chemistry Research
Show more